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| author | ShelbySolomonDarnell | 2024-10-17 12:24:26 +0300 |
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| committer | ShelbySolomonDarnell | 2024-10-17 12:24:26 +0300 |
| commit | 00cba4b9a1e88891f1f96a1199320092c1962343 (patch) | |
| tree | 270fd06daa18b2fc5687ee72d912cad771354bb0 /gnqa/paper2_eval/data/responses/gpt4o/de_aging_responses.json | |
| parent | e0b2b0e55049b89805f73f291df1e28fa05487fe (diff) | |
| download | gn-ai-00cba4b9a1e88891f1f96a1199320092c1962343.tar.gz | |
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diff --git a/gnqa/paper2_eval/data/responses/gpt4o/de_aging_responses.json b/gnqa/paper2_eval/data/responses/gpt4o/de_aging_responses.json new file mode 100644 index 0000000..de2fc92 --- /dev/null +++ b/gnqa/paper2_eval/data/responses/gpt4o/de_aging_responses.json @@ -0,0 +1,3222 @@ +{ + "1": { + "results": { + "completion": { + "id": "chatcmpl-AIHWB476q1MhqSkzMBJiel5B4S1fK", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Recent single-cell transcriptomics studies have significantly enhanced our understanding of cellular heterogeneity in aging tissues by providing detailed insights into the molecular and cellular changes that occur with age. These studies allow for the examination of small populations of cells, enabling the detection of low-represented mutations and transcriptional events that may alter cellular identity, supporting hypotheses about the cellular and genetic origins of age-related dysfunctions [1]. \n\nSingle-cell transcriptomics has also been used to gain a more nuanced view of cell type-specific molecular changes during aging, which is not possible with bulk tissue analysis that neglects variations in cell compositions and cell-to-cell aging heterogeneity [2]. This approach has revealed that different cell identities express unique genes with aging, indicating cell-identity-specific aging phenotypes [5]. Furthermore, similar cell types across different tissues have shown broadly similar aging trajectories, suggesting inherent characteristics of cell types play a significant role in shaping aging patterns [5], [8].\n\nAdditionally, single-cell RNA-seq has been applied to study transcriptional heterogeneity within specific cell types, such as hematopoietic stem cells (HSCs), and how this heterogeneity changes with age [4]. This level of detail helps to understand the diversity of cell types and states in young and old tissues, providing insights into the intrinsic complexity of aging at the cellular level [9]. Overall, these studies are revolutionizing our understanding of cellular heterogeneity in aging tissues, opening new avenues for early disease detection and personalized treatments [6].", + "role": "assistant" + } + } + ], + "created": 1728920607, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 299, + "prompt_tokens": 1126, + "total_tokens": 1425 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "91b0d8d4-949d-528f-b56d-8e5d99655fbc", + "score": 0.7524119314656392, + "metadata": { + "text": "Single-cell sequencing has helped to support several hypotheses about the cel-\nlular and genetic origin of age-related dysfunctions. Since single-cell sequencing \nallows us to study small populations of cells, it has been possible to find low repre-\nsented mutations as well as transcriptional events that alter cellular identity. This \nnewly generated data suggests that aging could be the result of mutational accumu-\nlation, epigenetic errors, and transcriptional noise that occurs in cells altering the", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 705, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "7fcf2db7-a5cc-5ffe-aee1-98f447d9b8e5", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "27854d68-63aa-5b56-9580-46c83cd121db", + "score": 0.7382032303325581, + "metadata": { + "text": "structed using data from bulk tissues, which neglect the variationsin cell compositions and cell-to-cell aging heterogeneity. To gain amore detailed and nuanced view of cell type specific molecular\nchanges during aging, several studies have applied machine-learn-\ning models to single-cell transcriptomics and DNA methylation", + "title": "2023 - A transcriptome-based single-cell biological age model.pdf", + "version": "v0", + "chunk_order": 17, + "document_id": "9be234b7-f37d-5cd5-8895-bfe676441b2f", + "extraction_id": "f277b0c9-43b7-542a-828f-1bebcf0cddf9", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "f74570ce-e096-50b2-8061-b9a538299b3a", + "score": 0.7330317378583436, + "metadata": { + "text": "within whole tissues or individual cell types in aging (Rodwellet al. 2004; Jonker et al. 2013; Cosgrove et al. 2014; O Brown\net al. 2015; Su et al. 2015; White et al. 2015; Keyes et al. 2016;\nBenayoun et al. 2019). However, it remains unclear to what degree\nage-related transcriptional changes are shared or unique across cellidentities. To address this outstanding question, we performed dif-ferential expression analysis within each cell identity betweenyoung and old mice.", + "title": "2019 - Murine single-cell RNA-seq reveals cell-identity.pdf", + "version": "v0", + "chunk_order": 48, + "document_id": "0d36d6a5-5c98-5c67-af47-4e00d32ce9c8", + "extraction_id": "6411b0be-b683-56dd-a3a5-e76618ede4e4", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "04c9d851-f9d9-53e6-b1ba-1bf3398395f5", + "score": 0.7270391475488293, + "metadata": { + "text": "populations. Furthermore, single cell analysis should allow us to relate prospective profiles of HSCs that \nhave just been isolated with known heterogeneity in their retrospective functional capacity in transplantation assays. \n \nHere, we leveraged single cell RNA-seq to directly assess transcriptional heterogeneity within the HSCs \nand how it may change with age in the steady-state unperturbed hematopoiesis. Given that HSCs are", + "title": "2015 - Single cell RNA-seq reveals changes in cell cycle and differentiation programs.pdf", + "version": "v0", + "chunk_order": 13, + "document_id": "42f2b0ac-0991-58fb-bb24-128b368cc1d7", + "extraction_id": "e6e9d12b-1784-5f0e-924e-442be1636afb", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "f037fb19-8998-5f24-ab7c-b1ecc0e1b7ef", + "score": 0.7255837052364752, + "metadata": { + "text": "cells. Here, we used single-cell RNA-seq to investigate aging across\na diverse set of murine cell identities in three tissues.\nWe found that cell identities differentially express unique\ngenes with aging, consistent with previous reports of cell-identi-\nty-specific aging phenotypes (Angelidis et al. 2019). Similar celltypes (e.g., kidney capillary endothelial cells and lung endothelial\ncells) showed broadly similar aging trajectories across tissues, and", + "title": "2019 - Murine single-cell RNA-seq reveals cell-identity.pdf", + "version": "v0", + "chunk_order": 116, + "document_id": "0d36d6a5-5c98-5c67-af47-4e00d32ce9c8", + "extraction_id": "a0a95eb8-8214-5918-9b54-7f69eec9df53", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "cdc7970a-4c9a-55c8-accb-8f99d88b0f6c", + "score": 0.7213000225246055, + "metadata": { + "text": "Cellular heterogeneity is revolutionizing the way to study, monitor and dissect complex diseases. This has been possible with the technological and computational advances associated to single-cell genomics and epigenomics. Deeper understanding of cell-to-cell variation and its impact on tissue function will open new avenues for early disease detection, accurate diagnosis and personalized treatments, all together leading to the next generation of health care. This review focuses on the recent dis-coveries", + "title": "2020 - Advances of single?cell genomics and epigenomics in human disease.pdf", + "version": "v0", + "chunk_order": 1, + "document_id": "afe53f5a-3962-520f-be55-9df5bfdaad70", + "extraction_id": "60355441-16f5-53a2-9b24-9616624f8d00", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "9c580ff4-e422-56e4-b774-44cbc2e5d87c", + "score": 0.7190852118356417, + "metadata": { + "text": "Genomics 114 (2022) 110379\n2have been observed in multiple species and tissues [7,8]. Transcriptome \nanalysis using aged oocyte samples have confirmed the impact of aging \non transcriptome landscapes [9,10]. Advances in single-cell sequencing \ntechnology promote our understanding of intrinsic complexity to \nanother level [11]. Recently, we have successfully applied single-cell \ntranscriptome technique to reveal cellular and molecular transitions in", + "title": "2022 - Parallel bimodal single-cell sequencing of transcriptome and methylome.pdf", + "version": "v0", + "chunk_order": 10, + "document_id": "e112f7dc-0ca4-51df-82ed-2f9748f9a3b5", + "extraction_id": "1e4f0bd9-2e45-536b-ae84-33c3ed01ba34", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "225b6504-a754-5aa3-ae95-b4019dbcaa8b", + "score": 0.7190478779020506, + "metadata": { + "text": "present in multiple tissues, such as endothelial cells andepithelial cells, also tended to belong to the same category acrosstissues ( Supplemental Fig. S23). These findings indicate that\ninherent characteristics of cell types play an important role in\nshaping cell aging patterns, even when situated in different tissue\nenvironments.\nDiscussion\nHere we show that tissue-specific aging programs can be learnedfrom scRNA-seq data and applied to describe aging heterogeneity", + "title": "2023 - A transcriptome-based single-cell biological age model.pdf", + "version": "v0", + "chunk_order": 112, + "document_id": "9be234b7-f37d-5cd5-8895-bfe676441b2f", + "extraction_id": "548ece22-253e-512f-8dcd-7ffc6c95d482", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "4a1ef9aa-4fbc-5093-9c53-73937397c715", + "score": 0.7175643780750829, + "metadata": { + "text": "creased in old lung stromal cells. Using matrix factorization andoptimal transport methods, we computed trajectories of agingfor each cell identity and assessed the influence of identity and en-vironment on these trajectories.\nResults\nSingle-cell RNA-sequencing identifies a diversity of cell types and\nstates in young and old mouse tissue\nWe collected transcriptional profiles of young and old cells of\nmany identities by isolating single cells from the kidney, lung,", + "title": "2019 - Murine single-cell RNA-seq reveals cell-identity.pdf", + "version": "v0", + "chunk_order": 21, + "document_id": "0d36d6a5-5c98-5c67-af47-4e00d32ce9c8", + "extraction_id": "4104881f-c452-54ba-b7ab-5c13f9dc8bad", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + }, + { + "id": "1a51a565-e5bf-5659-84a2-39e06def18fd", + "score": 0.7174133995278649, + "metadata": { + "text": "during the last decades. However, different types of cells in the cardiovascular system may be highly heterogeneous dur -\ning aging and disease progression. Single-cell genomics, such \nas massively parallel single-cell RNA-seq, facilitate detailed \ntranscriptome analysis to identify variants of key epigen-etic enzymes/pathways in specific diseased cohorts or cell types.\n54,57,58,146 Altogether, new sequencing technologies have", + "title": "2018 - Epigenetic Modifications in Cardiovascular Aging and Diseases.pdf", + "version": "v0", + "chunk_order": 121, + "document_id": "6559d6a2-bd88-5538-a611-da6288439bed", + "extraction_id": "7109021e-4b15-502a-a9d1-ef6055acdf9d", + "associatedQuery": "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?" + } + } + ], + "kg_search_results": null + } + } + }, + "2": { + "results": { + "completion": { + "id": "chatcmpl-AIHWHar7CqMtwymwPwmCVtJ5SKWUm", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "The latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction highlight several key aspects:\n\n1. SASP factors, which include cytokines, chemokines, proteases, and other inflammatory molecules, are secreted by senescent cells and disrupt tissue homeostasis through paracrine mechanisms [1]. These factors contribute to a deleterious microenvironment that promotes aging and age-related diseases [2].\n\n2. SASP is associated with chronic inflammation and exacerbates age-associated degeneration and hyperplasia in many tissues [4]. This chronic inflammation is a significant contributor to tissue dysfunction as organisms age.\n\n3. The accumulation of senescent cells and their SASP factors is closely linked to aging-related diseases. These factors can induce chronic inflammation and cell proliferation, leading to cell dysfunction and potentially cancer [8].\n\n4. SASP factors exert their effects in both autocrine and paracrine manners, influencing not only the senescent cells themselves but also the surrounding tissue environment [8].\n\nOverall, SASP factors play a critical role in driving the chronic inflammation and tissue dysfunction associated with aging, highlighting their importance in the study of age-related diseases and potential therapeutic targets.", + "role": "assistant" + } + } + ], + "created": 1728920613, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 245, + "prompt_tokens": 1321, + "total_tokens": 1566 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "4d256f76-7065-5eeb-a961-db7e7cbe75ff", + "score": 0.7416803394746592, + "metadata": { + "text": "SASP (senescence-associated secretoryphenotype):cytokines, chemokines,proteases, and otherfactors secreted bysenescent cells, whichare inammatory anddisrupt tissuehomeostasis viaparacrine mechanisms\nATM\n(ataxia-telangiectasiamutated):serine/threoninekinase and centralregulator of the DDR;activated by DNAdamage and transducesthat signal througheffectorphosphorylationphenotype (SASP) (84). SASP proteins include interleukin-6 (IL-6), transforming growth factor-", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 126, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "4b00515d-e599-5ce1-84e3-012d7efe1a30", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "92618cf9-f512-5011-9d76-17f313ad850e", + "score": 0.7378990430265979, + "metadata": { + "text": "SASP is one of the most representative features of senescent cells and may explain \nthe organismal expression of aging and age-related diseases. Senescent cells pro-\nduce a deleterious microenvironment through the production and secretion of pro-\nliferative and proinflammatory molecules such as IL-1 and -1, IL-6, IL-8, the \nchemotactic cytokine GRO, IGBP-7, growth factors, VEGF, TGF-, serine prote-\nases, and matrix remodeling enzymes [146]. It has been determined that the activa-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 149, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "eebc478a-d4b4-5547-a7e0-9c305d8bbd0f", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "77589e08-f16b-5bb2-9f89-833f1833d5be", + "score": 0.7260628505907757, + "metadata": { + "text": "context. For example, SASP likely contributes to early tumorigenesis (84), chemoresistance (94),and potentially neurodegenerative diseases (95). However, SASP is also important for mammalian\ndevelopment (96), tissue repair (97), and wound healing (98). SASP plays an important role in\nstimulating clearance of damaged, senescent cells by the innate immune system (99). However,inefcient immune clearance of senescent cells in aged organisms is thought to contribute to\nchronic inammation of aging.", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 132, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "fe836e95-1d70-51e5-b3fe-2f3005517606", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "e1dde75e-c4f2-51f6-b601-abe56c2109c3", + "score": 0.7254395052528689, + "metadata": { + "text": "many tissues, where theSASP promotes chronic inflammation and exacerbates age-associated\ndegeneration and hyperplasia. Recent evidence suggests that neurological aging and neurode-\ngeneration areaccompanied byanaccumulation ofsecretory cells inbrain, suggesting that cel-\nlular senescence may contribute tobrain aging [2]through ashared mechanism. Overlapping\nmechanisms canbedetected using functional genomics studies ofboth thebiology ofcellular\nsenescence and cognitive aging.", + "title": "2019 - Integration of heterogeneous functional.pdf", + "version": "v0", + "chunk_order": 11, + "document_id": "cf134202-50af-5700-9b1b-962501d9470d", + "extraction_id": "c21052ac-b3d9-59bc-8164-3d2df613929f", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "8c9d1720-5a2d-5559-831d-419208813d61", + "score": 0.7103631073020049, + "metadata": { + "text": "senescence-associated with the secretory phenotype (SASP) are other markers of \ncellular senescence.\n Inflammation andIntercellular Communication\nWhile senescent cells no longer replicate, they are still metabolically active and \nsecrete proteins in a recognizable pattern known as SASP.This is a widely heteroge-\nneous group of proteins with autocrine and paracrine effects [47], including soluble \nsignaling factors, such as interleukins, chemokines, and growth factors, as well as", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1748, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "b1eabac8-e6d1-50ba-9c42-60c107b56a65", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "955cffc5-cb1d-5638-bb3e-bbf5b0fe5dd4", + "score": 0.6998117923960934, + "metadata": { + "text": "matory mediators. This particular phenotype is termed the senescence- associated \nsecretory phenotype (SASP). Replicative cellular aging includes biochemical, mor -\nphological, and functional modifications that lead to the irreversible impairment of \ncell proliferation associated with DNA damage, shortening of the telomeres, and \nchanges in chromatin architecture, as previously described [135, 136].\nThe molecular mechanisms that drive cellular senescence in proliferative and", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 142, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "97753738-7225-59cc-b573-72cdf4ba569d", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "28976d8b-7996-51e7-b35b-213476f6ed7b", + "score": 0.6997167647053752, + "metadata": { + "text": "secretion of a range of proinammatory cyto- and chemokines, a state that has been dened asthe senescence-associated secretory phenotype (SASP) (103). Major SASP factors include IL1,\nIL6, IL8, and various matrix metalloproteases (MMPs), all of which individually are thought to\ndrive aging and age-related diseases. Thus, DNA damage is a major determinant in controllingcell death, stem cell exhaustion, and cellular senescence, which are considered important events", + "title": "2016 - Genome Integrity in Aging.pdf", + "version": "v0", + "chunk_order": 87, + "document_id": "85d5fcbb-5385-5a01-8139-d11fc8b1fe3a", + "extraction_id": "3625a61e-f376-5bea-b2c9-582b6ef16957", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "6d4a1a0b-2af3-5cc4-b7c0-a7223ce3edfa", + "score": 0.6976129800792669, + "metadata": { + "text": "senescent cells [150]. SASP factors exert their functions in either an autocrine or a \nparacrine manner and are responsible for the induction of the chronic inflammation \nand cell proliferation that contributes to cell dysfunction and cancer. Thus, the accu-\nmulation of senescent cells in tissue is closely associated with aging-related dis-\neases. Recently, it was determined that senescent fibroblasts significantly increase \nthe expression of HLA-E, which inhibits the receptor NKG2A in killer cells, and", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 152, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "6a2a94de-cfc0-50eb-b50e-bf3a0f813c78", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "a7675e04-876d-5026-88b5-842cd4ca237a", + "score": 0.6952213826643608, + "metadata": { + "text": "Role of L1 and Alu in cellular senescence and age-related inflammation\nA key feature of cellular senescence is the senescence-associatedsecretory phenotype (SASP), whereby senescent cells secretenumerous proinflammatory cytokines, chemokines, growth\nfactors, and proteases (Campisi, 2013). This altered secretome", + "title": "2020 - Transposable elements, circular RNAs and mitochondrial.pdf", + "version": "v0", + "chunk_order": 60, + "document_id": "7bebb41c-ac73-5917-91d3-4f59fbb3266a", + "extraction_id": "ea17d9f1-0991-5a69-930d-3212a3fabe1f", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + }, + { + "id": "da4ca7c3-653d-584f-8956-7f3f710fd45e", + "score": 0.6779017832396289, + "metadata": { + "text": "8. Coppe JP, Patil CK, Rodier F, et al. Senescence-associated\nsecretory phenotypes reveal cell-nonautonomous func-\ntions of oncogenic RAS and the p53 tumor suppressor. PLoS\nBiol2008; 6:285368.\n9. Wiley CD, Liu S, Limbad C, et al. SILAC analysis reveals\nincreased secretion of hemostasis-related factors by senes-\ncent cells. Cell Rep 2019; 28:33293337 e3325.\n10. Basisty N, Kale A, Jeon OH, et al. A proteomic atlas of\nsenescence-associated secretomes for aging biomarker", + "title": "2022 - Functional genomics of inflamm-aging.pdf", + "version": "v0", + "chunk_order": 93, + "document_id": "435dc081-e3d1-52c5-93a1-caa11206422f", + "extraction_id": "72b29fff-be72-5ede-85c9-7dc81894c956", + "associatedQuery": "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?" + } + } + ], + "kg_search_results": null + } + } + }, + "3": { + "results": { + "completion": { + "id": "chatcmpl-AIHWNXCXElapoM0J1wCt0Uh4pwpDs", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Age-related changes in chromatin architecture contribute to the decline in cellular function through several mechanisms:\n\n1. **Loss of Chromatin Homeostasis**: Sustained alterations in the chromatin landscape, such as changes in DNA methylation and histone modifications, can mediate the propagation of age-associated functional decline [1]. These changes are relatively stable and can persist through cell division, affecting cellular function over time.\n\n2. **Changes in Chromatin Distribution**: During aging, there is an extensive change in the global distribution of euchromatin and heterochromatin. Specifically, there is an overall closing of chromatin in euchromatic gene-rich regions, which contributes to tissue dysfunction and the eventual decline of cellular function [2].\n\n3. **Increased DNA Damage**: Aging-associated defects in chromatin structure lead to increased DNA damage and persistent DNA breaks. This is possibly due to structural changes that increase the genome's susceptibility to damage, further contributing to the decline in cellular function [5].\n\n4. **Histone Loss and Chromatin Remodeling**: There is a general loss of histones and chromatin remodeling, leading to an imbalance of activating and repressive histone modifications. This results in transcriptional changes that are observed in all aging models, contributing to the decline in cellular function [9].\n\n5. **Epigenetic Changes and Gene Expression**: Age-related chromatin dysregulation and epigenetic changes drive the loss of cellular function by altering gene expression patterns. These changes can lead to increased transcriptional activity in certain chromosomal regions, ultimately driving the aging process [10].\n\nThese changes in chromatin architecture collectively contribute to the decline in cellular function observed with aging.", + "role": "assistant" + } + } + ], + "created": 1728920619, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 337, + "prompt_tokens": 1244, + "total_tokens": 1581 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "1290eb6d-c454-5177-b55c-2e0f17265ab8", + "score": 0.8041154146194458, + "metadata": { + "text": "loss of chromatin homeostasis drives aspects of aging. As chroma-tin marks are relatively stable and can even persist through cell divi-sion (Kouskouti and Talianidis 2005), sustained alterations to thechromatin landscape may mediate the propagation of age-associat-\ned functional decline.\nAge-dependent changes in chromatin marks (e.g., DNA meth-\nylation, histone modifications) have been observed in multiple\nspecies and tissues (Benayoun et al. 2015; Booth and Brunet", + "title": "2019 - Remodeling of epigenome and transcriptome.pdf", + "version": "v0", + "chunk_order": 9, + "document_id": "87ffccee-fc33-5373-948d-67736aa0f069", + "extraction_id": "ab26a306-0581-5bdc-a6d1-689622689e90", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "f51d2566-aef3-51af-ac47-cfba546bd293", + "score": 0.7541544437408447, + "metadata": { + "text": "contributes to the onset of tissue dysfunction and the eventual demise of organisms as they age. During replicative senescence of human fibroblasts chromatin \nis subject to extensive changes in the global distribution \nof euchromatin and heterochromatin [25,35]. We found that the fundamental architecture of the genome undergoes profound alterations: an overall closing of \nchromatin in euchromatic gene-rich regions, which is", + "title": "2013 - Transposable elements become active and mobile in the genomes.pdf", + "version": "v0", + "chunk_order": 60, + "document_id": "c6901c06-c8ed-5220-a989-807bacdc9d0d", + "extraction_id": "dab38594-466b-50bc-8213-150f3862ff03", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "212e1fcc-f0f0-5bd0-81af-aea694179b9e", + "score": 0.7349187731742859, + "metadata": { + "text": "impaired function of histone modifying activ-ities, which in turn lead to structural chroma-\ntin changes. The number of known diseasesOrganismal\nagingAging-associated\ngene expression programsCellular\nstress\nDNA\ndamageChromatin\nremodelingEpigenetic\nstatus \nSusceptibilityHistone modifier\nredistribution\nNon-specific\ngene expression events\nFigure 3. Chromatin effects in aging. A complex network of interactions links chromatin structure to aging.", + "title": "2010 - Higher-order Genome Organization.pdf", + "version": "v0", + "chunk_order": 110, + "document_id": "91339298-860e-57d0-b58d-5a4571b4fc2b", + "extraction_id": "c4a47fc1-b528-5e29-9d13-e64be4e04938", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "12a416a1-9833-5e88-b86d-7ce6c54850b7", + "score": 0.7320639491081238, + "metadata": { + "text": "by Pelicci and colleagues in this issue). However, it could \nalso be argued that chromatin structure is directly affected \nby the ageing process through an as-yet-unknown mecha -\nnism that leads to increased DNA damage and a perma -\nnent damage response that alters gene-expression patterns \nin a similar way to the model proposed in this review.\no\nver the coming years, as researchers use mammalian \nmodels to map the global pattern of chromatin modifi -", + "title": "2007 - The role of nuclear architecture.pdf", + "version": "v0", + "chunk_order": 117, + "document_id": "578e2f7d-ddd4-56c8-a5b0-670969f8ff1e", + "extraction_id": "c5185d6d-b244-57d7-886c-2ebb364a3ac7", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "bada4b21-3c6d-55a4-b857-091a3a86f65d", + "score": 0.7274716658907149, + "metadata": { + "text": "and peripheral heterochromatin blocks are lost\nduring aging (Haithcock et al. 2005).\nThe aging-associated defects in chromatin\nstructure have various functional consequences.T o start with, aged genomes are characterized by\nincreased DNA damage and high levels of per-sistent DNA breaks, possibly brought about by\nstructural changes, which increase the suscepti-\nbility of the genome to damage. Furthermore,probably as a consequence of loss of pericentro-\nmeric heterochromatin structure, physiologi-", + "title": "2010 - Higher-order Genome Organization.pdf", + "version": "v0", + "chunk_order": 98, + "document_id": "91339298-860e-57d0-b58d-5a4571b4fc2b", + "extraction_id": "1a3a302a-4009-5ccf-aafa-f5f5a258ffde", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "ebd7a483-80a4-5f16-959d-e021635c88db", + "score": 0.7208220362663269, + "metadata": { + "text": "related changes in gene expression and the ageing \nprocess4,5. Changes in gene expression were already \nknown to contribute to cellular senescence6, a possible \ncause of ageing7, and may provide an explanation for \nthe age-related decline in organ and tissue function in \ncomplex organisms.Although chromatin reorganization was linked to \nageing in budding yeast over 10 years ago8,9, these ideas \nhave remained untested. Recently, a growing appre -\nciation for the importance of chromatin in regulating", + "title": "2007 - The role of nuclear architecture.pdf", + "version": "v0", + "chunk_order": 3, + "document_id": "578e2f7d-ddd4-56c8-a5b0-670969f8ff1e", + "extraction_id": "b36b1865-2949-50be-ad95-bdc9d05b82eb", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "b2d6de59-f3d4-5f74-9bcb-96f00f885ba2", + "score": 0.7171167135238647, + "metadata": { + "text": "tone loss in the ageing process has been attributed to alterations in heterochromatin, \nwhich are characterized by a decrease in its distribution in the genome and the \ncontent of characteristic heterochromatin histone marks (such as H3K9me3 and \nH3K27me3) as evidenced in fibroblasts cells from a HGS patient and healthy aged \nindividuals [59, 60]. Interestingly, it has been suggested that the increase in chroma-\ntin opening in T cells from aged people could be related to histone loss, which in", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1027, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "04e838ad-d90d-5e9d-af94-8e975af339a0", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "fa95b6a0-b4ef-5343-95aa-93d38aa291be", + "score": 0.7140518639699184, + "metadata": { + "text": "long lifespan (Dang et al. 2009). Given theseextensive changes in histone modications,\nnot surprisingly, aged cells show dramatic and\nglobal misregulation of gene expression. Al-though some of these changes are likely part\nof specic aging-related gene expression pro-\ngrams including inammation and cellularstress responses, others likely occur largely sto-\nchastically because of random changes in epi-\ngenetic modications and chromatin structure.\nThe mechanisms that drive chromatin and", + "title": "2010 - Higher-order Genome Organization.pdf", + "version": "v0", + "chunk_order": 102, + "document_id": "91339298-860e-57d0-b58d-5a4571b4fc2b", + "extraction_id": "1a3a302a-4009-5ccf-aafa-f5f5a258ffde", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "a681ba09-0707-5611-9a91-36f9967f91c8", + "score": 0.7083029958100022, + "metadata": { + "text": "general loss of histones coupled with local and global chromatinremodeling, an imbalance of activating and repressive histone\nmodications, and transcriptional change in all aging models.\nAdditionally, particularly in mammalian systems, there is globaland local change in DNA methylation, site-specic loss and\ngain in heterochromatin, and signicant nuclear reorganization\n(Figure 1 ).\nIt is as yet unclear whether changes in the activity of epigenetic", + "title": "2016 - Epigenetic Mechanisms of Longevity and Aging.pdf", + "version": "v0", + "chunk_order": 9, + "document_id": "588185a0-e157-552f-a304-4beefb85d398", + "extraction_id": "718d36c5-299d-596e-90be-416d12f7b5d1", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + }, + { + "id": "14898b2f-4643-5362-be34-31d5ee5a4be6", + "score": 0.7080286741256714, + "metadata": { + "text": "Amarcb1) as well as histone deacetylases (Hdac1, -5, and -6) and a DNA methyltransferace (Dnmt3b) were downregulated in aged cells. They also showed that several chromosomal regions changed with age in a coordinated manner resulting in an overall increase in transcriptional activity. They propos e that chromatin dysregulation and epigenetic changes drive the loss of cellular function and ultimately drive the aging process in HSCs. Consistent with these data, Polycomb proteins (transcriptional", + "title": "2008 - GENETIC REGULATION OF HEMATOPOIETIC STEM CELL AGING (3).pdf", + "version": "v0", + "chunk_order": 66, + "document_id": "7412a162-ee3b-5f09-9886-8e9172dd3ee8", + "extraction_id": "6efb8add-cedc-5089-9374-2466867e388a", + "associatedQuery": "How do age-related changes in chromatin architecture contribute to the decline in cellular function?" + } + } + ], + "kg_search_results": null + } + } + }, + "4": { + "results": { + "completion": { + "id": "chatcmpl-AIHWU7LIWS22cXcNTfkSGgjRTVQIK", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Studying the epigenetic reprogramming of aged cells to a more youthful state has provided several insights:\n\n1. **Reversal of Aging-Associated Epigenetic Features**: Experiments have shown that epigenetic features associated with aging can be reversed. For instance, in successfully reprogrammed induced pluripotent stem cells (iPSCs), the chromatin state of the CDKN2A locus, which is associated with aging, is erased and restored to that of youthful cells [1].\n\n2. **Potential for Longevity**: Proper epigenetic gene silencing is required for longevity, as observed in multiple model organisms. This suggests that the process of epigenetic reprogramming might be evolutionarily conserved and could play a role in extending lifespan [1].\n\n3. **Rewinding the Aging Clock**: There is an apparent ability to rewind the aging clock without losing cellular differentiation. However, this requires clear epigenetic signatures of young and old cells and evidence that aged cells have regained a youthful signature [2].\n\n4. **Risks and Uncertainties**: While reprogramming the epigenome to a youthful state holds promise, it also carries inherent risks and uncertainties, highlighting the need for further research to understand the full implications and safety of such interventions [2].\n\n5. **Mechanisms of Rejuvenation**: The study of epigenetic reprogramming provides a framework for understanding the mechanisms of rejuvenation, suggesting that aging is at least partly a manifestation of epigenetic changes. This offers opportunities to alter the trajectory of age-related diseases [8], [10].\n\n6. **Prolonging Healthy Life Expectancy**: There are at least two ways to reverse or inhibit senescence through epigenetic mechanisms, which could prolong healthy life expectancy. One involves rejuvenation through effective epigenetic reprogramming in cells undergoing senescence or derived from very aged patients [7].\n\nThese insights collectively suggest that epigenetic reprogramming holds significant potential for reversing aging processes and extending healthy lifespan, although further research is needed to fully understand and safely harness these capabilities.", + "role": "assistant" + } + } + ], + "created": 1728920626, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 427, + "prompt_tokens": 1214, + "total_tokens": 1641 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "b4eebcc5-781b-505b-a340-305b29285c66", + "score": 0.7631409905468841, + "metadata": { + "text": "experiments suggest that epigenetic features associated withaging can be reversed. In successfully reprogrammed iPSCs,\nthe chromatin state of CDKN2A locus associated with aging is\nerased and restored to that of youthful cells ( Meissner, 2010 ).\nThe requirement for proper epigenetic gene silencing for\nlongevity has been observed in multiple model organisms, sug-\ngesting an evolutionarily conserved process ( Lin et al., 2000;\nChen et al., 2005; Greer et al., 2010 ). The function of Polycomb", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 89, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "f244a68b-5127-5507-94a2-d2b8ca84f0ee", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "78059a6b-4809-5d36-b961-6fcddbb06f2b", + "score": 0.7370838396995367, + "metadata": { + "text": "apparent rewinding of the aging clock without loss of differenti-ation. Formal demonstration will require clear epigenetic signa-\ntures of young and old cells and evidence that the aged cells\nhave regained a youthful signature. It should be noted thatreprogramming of the epigenome to a youthful state in an\naged cell has inherent risks and uncertainties. For example, the", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 104, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "0e274732-b0df-53b8-999b-30b798af92e2", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "6baf63a6-fa5a-54e2-8290-af586a51243f", + "score": 0.7322699587184228, + "metadata": { + "text": "et al., 2010 ). Clearly, inhibiting single signaling pathways\n(NF-k B and mTOR) is sufcient to restore some features of\nyouthful cells, but the number of transcriptional regulatorsthat need to be modulated to result in full rejuvenation is\nunknown. Third, is the youthful state or the aged state domi-\nnant? It would be interesting to determine which epigeneticand transcriptional prole is more robust in experiments of\nfusion of young and old cells.\nConcluding Remarks", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 113, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "915ca931-d49d-5837-97fd-f06c145764d0", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "ef0f46ad-2e78-5666-b83d-36d2920b64ea", + "score": 0.7291497370854128, + "metadata": { + "text": "Rejuvenation: Is It Epigenetic Reprogramming?By analogy to the attainment of a pluripotent state by epigenetic\nreprogramming of a differentiated cell, is cellular rejuvenation byheterochronic parabiosis, NF- kB inhibition, or inhibition of\nmTOR signaling ( Figure 1 ) a form of epigenetic reprogramming\nfrom an aged state to a youthful state? If so, then these would\nbe examples of an uncoupling of the differentiation program\nfrom the aging clock, with cells in each case manifesting an", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 103, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "0e274732-b0df-53b8-999b-30b798af92e2", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "02361135-a01e-55f2-9efa-b7c465f2498b", + "score": 0.7267110727217503, + "metadata": { + "text": "with a healthy lifestyle may preserve a more intact epigenome and hence experi-ence longevity. Reprogramming of aged cells into iPSCs and regeneration of dif-ferentiated cells may provide a mechanism for epigenetic rejuvenation. In\naddition to epigenetic drift, telomere shortening has been associated with", + "title": "2013 - Age-associated epigenetic drift implications.pdf", + "version": "v0", + "chunk_order": 56, + "document_id": "8513121f-71f3-5bb0-9433-feece9fd9fbc", + "extraction_id": "42343f61-f147-520b-bd14-0c2bf7b63262", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "82815a35-f43e-56fc-a254-92b03a278ab5", + "score": 0.7258869193230026, + "metadata": { + "text": "tion through the lens of epigenetic reprogramming. By dening youthfulness and senescence as\nepigenetic states, a framework for asking new questions about the aging process emerges.\nIntroduction\nThe inexorable tolls of aging are evident in almost all living\nbeings. From the onset of reproductive maturity, organismalaging is generally characterized by a decline in fecundity, an\nincreased susceptibility to disease and tissue dysfunction, and\nincreased risk of mortality ( Kirkwood, 2005; Hayick, 2007; Kirk-", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 2, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "617f523f-b892-5bfc-b99c-2e67a4cc185f", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "b5f6d630-dc24-50d7-af74-b3034cbb1055", + "score": 0.7174960374832204, + "metadata": { + "text": "others (i.e. DNA methylation influences chromatin structures, histones PTMs).\nSeveral important conclusions emerge from the presented findings: there are at \nleast two ways to reverse or inhibit senescence by epigenetic mechanisms, whereby \na healthy life expectancy could be prolonged. The first way involves rejuvenation \nthrough effective epigenetic reprogramming in cells undergoing senescence or cells \nderived from very aged patients or patients with progeroid syndromes, by which the", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1091, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "704a88b4-f49e-57cb-b572-1fa948b6065b", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "8822b363-e906-5f83-a494-caad665c7af2", + "score": 0.7124422363971343, + "metadata": { + "text": "aging is at least in part, if not largely, a manifestation of epigeneticchanges, including those that may be secondary to genomicmutations, offers a theoretical construct for understanding the\nmechanisms of rejuvenation. If so, it should be possible to char-\nacterize young and old cells by specic transcriptional andepigenetic proles and states. Furthermore, the processes that\nunderlie aging and rejuvenation should be identiable in terms", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 84, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "f244a68b-5127-5507-94a2-d2b8ca84f0ee", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "0e8901a7-c123-5e96-97fe-4d5cd85eb0c9", + "score": 0.7098463350626043, + "metadata": { + "text": "determinants of the aged state by genetically manipulatingspecic biochemical pathways. A recent example demonstratesthe power of transcriptional proling and bioinformatic analysis\nto reveal an aging signature that can be genetically engineered\nto reect a more youthful state ( Adler et al., 2007 ). In a compar-\nison of old and young tissues from mice and humans, old tissues\nwere found to express at signicantly higher levels a set of genes\nthat contained sequences in their 5\n0regulatory regions, indica-", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 47, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "7f8f4ca0-9b27-55e3-a889-030af08dc84b", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + }, + { + "id": "0aede05b-f0dd-595a-a11d-acac0970d25d", + "score": 0.6993312835693409, + "metadata": { + "text": "Recently, studying the direct relationship between epigeneticmechanisms and the aging process itself is gaining increasing\nattention. The potential reversibility of these epigenetic\nchanges that occur as a hallmark of aging offers excitingopportunities to alter the trajectory of age-related diseases.\n8\nThis is especially important given the remarkable plasticityof aging.\n9,10In the literature, age-associated epigenetic alter-\nations have been identified by epigenome-wide association", + "title": "2016 - Epigenetic drift in the aging genome a ten-year.pdf", + "version": "v0", + "chunk_order": 9, + "document_id": "52f09ef3-4e4c-538f-909c-d28eb72d91f3", + "extraction_id": "2f6d20f0-addc-51e8-979d-1aac7ac26694", + "associatedQuery": "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?" + } + } + ], + "kg_search_results": null + } + } + }, + "5": { + "results": { + "completion": { + "id": "chatcmpl-AIHWdEvFttNJ6ZbP6sReC3nxIXsfz", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Alterations in the mitochondrial genome and bioenergetics significantly influence the aging process in humans through several mechanisms:\n\n1. **Mitochondrial DNA Mutations**: As humans age, there is an increase in mitochondrial DNA (mtDNA) mutations. These mutations can lead to a decline in mitochondrial function, which is a fundamental mechanism in the physiological declines associated with aging [3]. Specifically, the aged heart shows a significant increase in mtDNA mutations compared to younger hearts, which may contribute to the failure in mitochondrial metabolism observed in aging [2].\n\n2. **Respiratory Function Decline**: Aging is associated with a decline in respiratory function and increased oxidative stress, which can lead to further DNA mutations and altered gene expression in mitochondria [6]. This decline in mitochondrial respiratory function is linked to the production of reactive oxygen species (ROS), which can damage mtDNA and exacerbate mitochondrial dysfunction [7].\n\n3. **Mitochondrial Dynamics**: Changes in mitochondrial dynamics, such as increased fragmentation and decreased fusion, are observed in aging tissues like skeletal muscle, heart, and brain. These alterations can impair mitochondrial biogenesis and mitophagy, leading to reduced energy production and increased cellular stress [5].\n\n4. **Bioenergetic Shifts**: The aging process involves shifts in mitochondrial metabolism, particularly in high-energy-demand tissues. For example, the brain experiences a decline in energy production due to mitochondrial dysfunction, which can affect cognitive function and overall brain health [9].\n\nOverall, the accumulation of mtDNA mutations, decline in mitochondrial respiratory function, and alterations in mitochondrial dynamics and bioenergetics contribute to the aging process by impairing cellular energy production and increasing oxidative stress, leading to cellular and tissue dysfunction.", + "role": "assistant" + } + } + ], + "created": 1728920635, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 349, + "prompt_tokens": 1517, + "total_tokens": 1866 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "4206977e-23df-5307-8d8a-cb2ed7b33595", + "score": 0.7622008607148099, + "metadata": { + "text": "abolic regulation through mitochondrial signaling. Am J Physiol Endocrinol Metab. \n2014;306:E58191.\n 74. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial DNA \nquantity and quality in humans. BMC Genomics. 2017;18:890.\n 75. Hebert SL, Lanza IR, Nair KS.Mitochondrial DNA alterations and reduced mitochondrial \nfunction in aging. Mech Ageing Dev. 2010;131:45162.\n 76. Liu D, Li H, Lu J, Bai Y .Tissue-specific implications of mitochondrial alterations in aging.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 607, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "ef9463cd-cf21-527f-ae4a-3df211c78435", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "7853fd79-e251-5e3f-8b6f-7d1ebf8182bc", + "score": 0.7536232022271645, + "metadata": { + "text": "mechanisms that lead to mitochondrial metabolism shifts in human aging are not \ncompletely understood, the literature reports that the failure in the mitochondrial \nmetabolism of aged heart might be associated with mutations in the mtDNA.In this \nsense, the aged heart shows an increase over 15-fold on mtDNA mutations in com-\nparison to hearts from young people [101]. Mutations in genes that encode Polg-a, \nresponsible for mtDNA repair machinery, cytochrome b, and several subunits of", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 563, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "391985ac-70b7-57c9-97b2-940d8ebd2366", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "1436639f-3759-5172-9b13-b1dd9105420e", + "score": 0.741439655933402, + "metadata": { + "text": "22. Fleming JE, Miquel J, Cottrell SF, Yengoyan LS, Economos AC: Is cell aging\ncaused by respiration-dependent injury to the mitochondrial genome?Gerontology 1982, 28:, 44-53.\n23. Pak JW, Herbst A, Bua E, Gokey N, McKenzie D, Aiken JM: Mitochondrial\nDNA mutations as a fundamental mechanism in physiological declinesassociated with aging. Aging Cell 2003, 2:1-7.\n24. Jacobs HT: The mitochondrial theory of aging: dead or alive. Aging Cell\n2003, 2:11-17.", + "title": "2011 - Mitochondrial genome deletions and minicircles.pdf", + "version": "v0", + "chunk_order": 157, + "document_id": "c28cecbc-be20-54e2-afdd-afb8d25b1ab1", + "extraction_id": "8a8e649d-6689-5d6d-91b6-157abfd8f990", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "7095cdbb-852e-541e-884b-a9e67c2c790c", + "score": 0.7352016129969602, + "metadata": { + "text": "Sun., N, Youle, R. J. and Finkel, T. (2016). The mitochondrial basis of aging.\nMol. Cell 61, 654-666. doi:10.1016/j.molcel.2016.01.028\nSymer, D. E., Connelly, C., Szak, S. T., Caputo, E. M., Cost, G. J., Parmigiani, G.\nand Boeke, J. D. (2002). Human L1 retrotransposition is associated with genetic\ninstability in vivo. Cell110, 327-338. doi:10.1016/S0092-8674(02)00839-5\nSzabo, L., Morey, R., Palpant, N. J., Wang, P. L., Afari, N., Jiang, C., Parast,", + "title": "2020 - Transposable elements, circular RNAs and mitochondrial.pdf", + "version": "v0", + "chunk_order": 300, + "document_id": "7bebb41c-ac73-5917-91d3-4f59fbb3266a", + "extraction_id": "5cbace8d-e538-5531-9311-ea9726ad2f15", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "a1ea550b-8017-58c5-a80f-f22f4869f792", + "score": 0.7337075034554313, + "metadata": { + "text": "limitations to study mitochondrial metabolism in human samples, in this section \nwe briefly described the implications of mitochondrial metabolism for aging in \nthe most studied and high energy demand human tissues, such as skeletal muscle, \nheart, and brain.Table 4.1 Main mitochondrial dynamics proteins that are altered in human tissues during the \naging process\nTissue/\norgan Fission Fusion Biogenesis Mitophagy Refs\nSkeletal \nmuscleIncreased \nfragmentation\nDecreased Drp1 \nproteinIncreased \ninterconnected", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 532, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "385c192b-a416-5208-9615-20111ce782aa", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "8ec531e8-2692-5995-8f1e-246406b9de04", + "score": 0.732002485036407, + "metadata": { + "text": "96. Wei Y-H, Wu S-B, Ma Y-S, Lee H-C.Respiratory function decline and DNA mutation in \nmitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J. \n2009;32:11332.\n 97. Kates AM, Herrero P, Dence C, Soto P, Srinivasan M, Delano DG, Ehsani A, Gropler \nRJ. Impact of aging on substrate metabolism by the human heart. J Am Coll Cardiol. \n2003;41:2939.\n 98. Gmez LA, Monette JS, Chavez JD, Maier CS, Hagen TM.Supercomplexes of the mito-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 616, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "7cf75da1-3c2a-5155-84dd-0dfe77d3fe41", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "f41af83b-dd40-5128-b051-2b0f26942786", + "score": 0.729981871845499, + "metadata": { + "text": "phenotype, such as the Mitochondrial Free Radical Theory of Aging (MFRTA), and \nalthough these theories have been recently confronted, the role of mitochondria in \nthe aging process is undeniable because of their versatile roles and implications \nfor cellular function. MFRTA suggests that the oxidative damage of mtDNA is the \nkey event disturbing the respiratory chain proteins to induce its dysfunction and \nincrease ROS production in a vicious cycle [123]. However, alterations in mito-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 134, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "c7041bbd-983f-5532-8b0e-cbd5f114a75f", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "1a9d5c26-f606-5cb5-98ee-4120de3fbd1a", + "score": 0.7225154207637668, + "metadata": { + "text": "102. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial \nDNA quantity and quality in humans. BMC Genomics. 2017;18:890. https://doi.org/10.1186/\ns12864-017-4287-0.\n 103. Norddahl GL, et al. Accumulating mitochondrial DNA mutations drive premature hema-\ntopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell. \n2011;8:499510. https://doi.org/10.1016/j.stem.2011.03.009.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 783, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "c8db1d28-f6c2-5896-95ec-bb01159ba483", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "e183f824-0ca8-58aa-a06e-110a3a94c2e9", + "score": 0.7214284109217889, + "metadata": { + "text": "78\np53, which regulate the catalytic subunits of ETC complexes [103]. Unfortunately, \nthese data have only been observed in murine models of aging and require further \nverification in human samples.\n Mitochondrial Metabolism intheAged Brain\nIn normal conditions, the brain consumes around 25% of the total body glucose via \nglycolysis and mitochondrial OxPhos [104]. So besides the mitochondrial dynam-\nics dysfunctions described above, during aging there is also a decline in energy", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 566, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "d226a80b-8a07-52ea-82b8-30adce468571", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + }, + { + "id": "39019881-9b6d-5111-87ea-71c413bdf4ff", + "score": 0.720432417366958, + "metadata": { + "text": "mitochondrial DNA mutations can reduce lifespan. Sci Rep. 2014;4:6569.\n20. Ross JM, Stewart JB, Hagstrm E, Bren S, Mourier A, Coppotelli G,\nFreyer C, Lagouge M, Hoffer BJ, Olson L. Germline mitochondrial DNA\nmutations aggravate ageing and can impair brain development. Nature.\n2013;501(7467):412 5.\n21. Sondheimer N, Glatz CE, Tirone JE, Deardorff MA, Krieger AM, Hakonarson H.\nNeutral mitochondrial heteroplasmy and the influence of aging. Hum Mol\nGenet. 2011;20(8):1653 9.", + "title": "2017 - Independent impacts of aging.pdf", + "version": "v0", + "chunk_order": 126, + "document_id": "d1d0b9ce-f827-5dfb-8e39-d87a9ca52f6d", + "extraction_id": "1f0b6363-a045-53aa-a124-4cf89e61fc26", + "associatedQuery": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?" + } + } + ], + "kg_search_results": null + } + } + }, + "6": { + "results": { + "completion": { + "id": "chatcmpl-AIHWn49FE1NOTaexKIcZmCPOm6e2F", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "The insulin/IGF-1 signaling pathway has been identified as a significant target for extending healthspan and lifespan due to its role as a nutrient sensor and its control over the transcription of stress response genes [1]. Here are the therapeutic potentials and challenges associated with targeting this pathway:\n\n### Therapeutic Potentials:\n1. **Treatment of Age-Related Diseases**: Lowering IGF signaling, such as by targeting IGF receptors, has been proposed as a treatment for age-related diseases including cancer, Alzheimer's disease, and autoimmune diseases [2]. This suggests that modulating this pathway could have broad therapeutic applications in managing diseases associated with aging.\n \n2. **Lifespan Extension**: Genetic interference in the insulin-signaling pathway has been shown to prolong life in various organisms, including C. elegans, D. melanogaster, and certain mouse models [8]. This indicates a potential for extending lifespan through targeted interventions in this pathway.\n\n3. **Improved Cellular Maintenance**: The insulin/IGF-1 signaling pathway is involved in processes such as cellular senescence, protein refolding, and autophagy, which are crucial for cellular maintenance and protection against aging-related diseases [3]. Enhancing these processes could lead to slowed aging and improved healthspan.\n\n### Challenges:\n1. **Complexity of the Pathway**: The role of IGF-1 in lifespan regulation is complex, and it is not fully understood how alterations in this pathway contribute to aging phenotypes [9]. This complexity poses a challenge in developing targeted therapies without unintended consequences.\n\n2. **Balancing Growth and Longevity**: The insulin/IGF-1 pathway is also involved in regulating growth and development. Therefore, interventions that reduce IGF signaling must carefully balance the trade-offs between promoting longevity and maintaining necessary growth functions [2].\n\n3. **Species-Specific Responses**: While interventions in the insulin/IGF-1 pathway have shown promising results in model organisms, translating these findings to humans is challenging due to species-specific differences in the pathway's role and regulation [8].\n\nOverall, while targeting the insulin/IGF-1 signaling pathway holds significant promise for extending healthspan and lifespan, it requires careful consideration of the pathway's complexity and the potential trade-offs involved.", + "role": "assistant" + } + } + ], + "created": 1728920645, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 456, + "prompt_tokens": 1439, + "total_tokens": 1895 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "bc91a693-0eff-5911-ae9a-b192f1088119", + "score": 0.698900580406189, + "metadata": { + "text": "the attention of researchers as a therapeutic target for age-related diseases [109]. \nResveratrol, a phytochemical enriched in the skin of red grapes and wine, has been \nactively investigated to determine whether it promotesSIRTs activity with conse-\nquent beneficial effects on aging [110].\n IGF\nBecause insulin/IGF-1 function through signaling as a nutrient sensor and controls \nthe transcription of stress response genes, the insulin/IGF-1 pathway provides a", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 126, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "a933e419-b369-5de5-8236-a1944a486e51", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "8ac8b243-f23c-596d-add2-441df4e980a9", + "score": 0.6942377868749042, + "metadata": { + "text": "the use of lowered IGF signaling (e.g., by target-ing IGF receptors) to treat certain age-related diseasessuch as cancer (Pollak et al., 2004), Alzheimers disease(Cohen et al., 2009), and autoimmune diseases (Smith,2010). Moreover, a number of genes and pathways associ-ated with longevity and CR are part of nutrient-sensingpathways that also regulate growth and development, in-cluding the insulin/IGF1/GH pathway (Narasimhan et", + "title": "2012 - Genome-Environment Interactions That Modulate.pdf", + "version": "v0", + "chunk_order": 66, + "document_id": "b1a1997c-e9df-5dc0-9d12-a3977d0c64ec", + "extraction_id": "a01ca925-4ccf-5863-a162-7bd4c754fe89", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "759ea147-5ac2-5d48-80f2-3693f56d4afc", + "score": 0.6894049829599284, + "metadata": { + "text": "as insulinIGF-1 signalling [6], cellular senescence [4], protein refolding [4345] ,\nautophagy [41] and phase 1 and 2 detoxication [36,37,52] . These represent major\npoints of intervention against ageing-related disease. As shown here, lifespan\npathways control improved cellular maintenance, which leads to slowed ageing(e.g. slowed normal cognitive ageing) and protection against diseases of ageing\n(e.g. neurodegenerative diseases of ageing, such as Alzheimers and Parkinsons", + "title": "2006 - Beyond the evolutionary theory.pdf", + "version": "v0", + "chunk_order": 65, + "document_id": "a8da3f57-a8dc-55c3-9dc9-eb778105e680", + "extraction_id": "373c0bb8-f6b2-5c6b-b768-226b12ba6385", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "fc227aaf-85c1-553f-aa59-d9bcdd803aaf", + "score": 0.6818851232528687, + "metadata": { + "text": "ent-sensing pathways such as insulin/insulin-likegrowth factor (IGF-1) signalling (IIS) and target of\nrapamycin (TOR) signalling mediated lifespan exten-\nsion, and also the extension of lifespan by DR [ 2].\nAn interesting observation from the perspective ofhuman ageing is that, in rodents and monkeys, dietsrestricted in glucose, fat or protein uptake reduced ordelayed the risk of cancer and metabolic disease,thus extending the healthspan of the animals [ 2]. Fol-", + "title": "2011 - Genomics of human longevity.pdf", + "version": "v0", + "chunk_order": 10, + "document_id": "2e038219-fdaa-506f-9cd3-51379054130e", + "extraction_id": "89586b79-902d-5e2b-9b8a-b7a8c4971783", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "a0198ed1-1303-5652-aafc-1a1287914ac4", + "score": 0.6767085194587708, + "metadata": { + "text": "43. Svensson, J. et al. Liver-derived IGF-I regulates mean life span in mice. PLoS ONE 6, e22640 (2011).\n44. Junnila, R. K., List, E. O., Berryman, D. E., Murrey, J. W. & Kopchick, J. J. The GH/IGF-1 axis in ageing and longevity. Nat. Rev. \nEndocrinol. 9, 366376 (2013).\n45. Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. \nAging Cell 8, 277287 (2009).\n46. Zhu, H. et al. Reference ranges for serum insulin-like growth", + "title": "2023 - Genome-wide RNA polymerase stalling.pdf", + "version": "v0", + "chunk_order": 128, + "document_id": "78812a12-8d31-5159-8367-b0d38e5bc84b", + "extraction_id": "31088092-778f-59e0-a9de-5ec25c241aab", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "e3a78ec1-7f79-55db-a13d-196f718f8a1d", + "score": 0.6761923625354562, + "metadata": { + "text": "5. Piper MD, Selman C, McElwee JJ, Partridge L: Separating cause\nfrom effect: how does insulin/I GF signalling control lifespan\nin worms, flies and mice? J Intern Med 2008, 263:179-191.\n6. Holzenberger M, Kappeler L, De Magalhaes Filho C: IGF-1 signaling\nand aging. Exp Gerontol 2004, 39:1761-1764.\n7. Zahn JM, Kim SK: Systems biology of aging in four species. Curr\nOpin Biotechnol 2007, 18:355-359.\n8. McElwee JJ, Schuster E, Blanc E, Piper MD, Thomas JH, Patel DS,", + "title": "2009 - High tandem repeat content in the genome of the short-lived.pdf", + "version": "v0", + "chunk_order": 153, + "document_id": "bcc64bfb-9b7f-5f6f-83f3-861ab8f8a8e3", + "extraction_id": "fcb05f39-0821-56e1-a627-92911d4d46bc", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "bdebc11c-26ca-5ac0-bab3-503bd7d25f50", + "score": 0.6721978788552799, + "metadata": { + "text": "humans enriched for familial longevity. Aging Cell. 2016;15(6):112631.\n 44. Lee WS, Kim J.Insulin-like growth factor-1 signaling in cardiac aging. Biochim Biophys Acta \nMol basis Dis. 2018;1864(5 Pt B):19318.\n 45. Balasubramanian P, Longo VD. Growth factors, aging and age-related diseases. Growth \nHormon IGF Res. 2016;28:668.\n 46. Suzuki K, etal. Serum insulin-like growth factor-1 levels in neurodegenerative diseases. Acta \nNeurol Scand. 2019;139(6):5637.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 867, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "8f165f13-b4a5-5553-a992-f4a70b079898", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "9868d78e-6151-5383-9d52-542a8b43c50f", + "score": 0.6709864139556885, + "metadata": { + "text": "paradigms for lifespan extension (C. elegans, D. melanogaster),\ngenetic interference in the insulin-signaling pathway can\nprolong life multi-fold [47,48]. In mammals, IGF1-decient,\nAmes and Snell dwarf mice (characterized by defects in the\ndevelopment of the anterior pituitary due to mutations in the\nProp-1 and Pit1 loci and diminished levels of GH, thyroid\nstimulating hormone, and prolactin hormone) combine", + "title": "2007 - Impaired Genome Maintenance Suppresses.pdf", + "version": "v0", + "chunk_order": 129, + "document_id": "4ed9d527-4f92-51a3-a5d7-6caab655b1be", + "extraction_id": "74482eef-9eb3-5915-838e-5f1f0439c410", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "58d61a19-d5b0-501c-90a9-2eeb66866c07", + "score": 0.6700917682079011, + "metadata": { + "text": "the role of IGF-1 in life span regulation is complex. In theory,SIRT6 might play a role in insulin signaling, similar to Sir2 fac-\ntors in other lower organisms. However, as in the prematureaging mouse models described above, it remains unclear\nwhether the altered serum IGF-1/insulin levels of SIRT-6-\ndecient mice directly contribute to aging-like phenotypesor, alternatively, reect compensatory alterations. In this re-\ngard, it will be of interest to determine whether SIRT6 is", + "title": "2006 - Genomic Instability.pdf", + "version": "v0", + "chunk_order": 96, + "document_id": "c9c9a8d6-2daf-5ff2-86bd-84e087ba1a47", + "extraction_id": "634526cb-daa7-5769-a3f2-741931964ccd", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + }, + { + "id": "e51c4436-0895-5adb-8a80-a3e1ee6956dd", + "score": 0.6700788736343384, + "metadata": { + "text": "lin-like growth factors (IGFs), and receptors in theinsulin-signaling pathway has been shown to confergreater longevity in yeast (12, 16), nematodes (21, 44),fruit ies (10, 43), mutant long-lived mice (4, 11), and\ncaloric-restricted mice (40). Therefore, the as-yet un-identi ed mechanism of insulin signaling on lifespan", + "title": "2003 - Lifelong voluntary exercise in the mouse prevents.pdf", + "version": "v0", + "chunk_order": 126, + "document_id": "24d4f270-f45b-5830-84f9-b1e5bcd3c070", + "extraction_id": "b6422281-0ef4-58f3-9d43-4c8c7534e057", + "associatedQuery": "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?" + } + } + ], + "kg_search_results": null + } + } + }, + "7": { + "results": { + "completion": { + "id": "chatcmpl-AIHX1EytrrBFzyZb7piMsWydaKzhq", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "The integration of proteomics and metabolomics data can provide a comprehensive understanding of age-associated metabolic shifts by revealing changes in protein expression and metabolite profiles that occur with aging. This multi-omics approach allows for the identification of specific pathways and molecular mechanisms that are altered as organisms age.\n\n1. **Proteomics Insights**: Proteomics data can identify plasma proteins that predict age and are predominantly associated with immunity [1]. This suggests that changes in protein expression related to immune function are significant in the aging process.\n\n2. **Metabolomics Insights**: Metabolomics approaches enable the study of age-related changes in metabolite profiles, providing new insights into the physiological mechanisms of aging [1]. For example, metabolomics has identified significant alterations in glutathione metabolism, a key antioxidant pathway, which is indicative of oxidative stress associated with aging [10].\n\n3. **Integrated Analysis**: By integrating transcriptome and metabolome data, researchers have identified transcriptionally-driven alterations in metabolism during aging, such as changes in glycolysis and glycerolipid biosynthesis, and reductions in protein and polyamine biosynthesis [4], [8]. These changes can affect cellular signaling, epidermal barrier function, and skin structure and morphology, highlighting the interconnected nature of metabolic pathways and their impact on aging.\n\n4. **Functional Changes**: The integration of these datasets can also reveal age-dependent changes in the activity of metabolic enzymes, which are driven by altered gene expression [6]. This helps in understanding how mild adaptations in metabolite and transcript levels contribute to maintaining functions like epidermal homeostasis during aging.\n\nOverall, the integration of proteomics and metabolomics data provides a holistic view of the molecular changes that occur with aging, allowing for the identification of biomarkers and pathways that could be targeted to mitigate age-related decline.", + "role": "assistant" + } + } + ], + "created": 1728920659, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 359, + "prompt_tokens": 1181, + "total_tokens": 1540 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "a8194abc-51ab-5c29-a6be-f34bb24e0b47", + "score": 0.7574900388717651, + "metadata": { + "text": "learning to show that plasma proteins that predict age are predominantly associated with immunity\n[91]. State-of-the-art metabolomics approaches are also now allowing age-related changes in me-\ntabolite pro les to be studied, which provide new insights into the physiological mechanisms of age-\ning [ 92,93]. The integration of multiple datasets generated from genomes, epigenomes,\ntranscriptomes, proteomes, and metabolomes, an approach termed multi-omics , offers great", + "title": "2022 - Immunity and lifespan answering.pdf", + "version": "v0", + "chunk_order": 71, + "document_id": "a834e7ee-7bab-5c4d-a236-b570d1ae635f", + "extraction_id": "d4db0b82-40d3-5341-ad30-c70a91fdc785", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "1d8fd475-f7a7-55c6-881e-6985826c1e23", + "score": 0.7088847371603474, + "metadata": { + "text": "13. Menni C, Kastenmuller G, Petersen AK, et al. Metabolomic markers reveal novel pathways of ageing \nand early development in human populations. Int J Epidemiol 2013;42:1111- 9. \n14. Evans AM BB, Liu Q, Mitchell MW, Robinson RJ, et al. . High Resolution Mass Spectrometry Improves \nData Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in High- Throughput \nProfiling Metabolomics. Metabolomics 2014;4:132.", + "title": "2018 - Metabolomic pathways to osteoporosis in middle-aged women A genome-metabolome-wide.pdf", + "version": "v0", + "chunk_order": 67, + "document_id": "f9aa8a09-5148-5399-b6be-c3350f12c0f3", + "extraction_id": "e92950f9-a8d6-5aa5-bf83-ab1cef74627d", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "4547b6ad-efaf-509e-8e0b-5587542905fd", + "score": 0.6993709206581116, + "metadata": { + "text": "Due to the mild adaptions, the identification of func-\ntionally altered metabolic activity in aged skin interpret-\nation of significant metabolite and transcript changes of\nsmall magnitude is especially challenging. Therefore, we\nemployed the previously presented locality scoring ap-\nproach [60] to identify age-dependent transcriptional al-\nterations of enzymes that functionally effect proximal\nmetabolic activity and thus metabolite levels. This inte-\ngrated analysis revealed age-dependent, concerted me-", + "title": "2017 - An integrative metabolomics.pdf", + "version": "v0", + "chunk_order": 75, + "document_id": "cb0831f4-540a-5620-b69e-03d6127f84e5", + "extraction_id": "09a73df7-f690-5984-a498-69a8077fe327", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "3dba594a-b79b-5bc6-95f6-6e0a36193818", + "score": 0.695720094697471, + "metadata": { + "text": "matched transcriptome and metabolome data highlighted transcriptionally-driven alterations of metabolism during\naging such as altered activity in upper glycolysis and glycerolipid biosynthesis or decreased protein and polyamine\nbiosynthesis. Together, we identified several age-dependent metabolic alterations that might affect cellular\nsignaling, epidermal barrier function, and skin structure and morphology.", + "title": "2017 - An integrative metabolomics.pdf", + "version": "v0", + "chunk_order": 3, + "document_id": "cb0831f4-540a-5620-b69e-03d6127f84e5", + "extraction_id": "af201c05-daed-5cba-abc8-e714483e602f", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "ce9d4d88-2586-5071-bf9e-45b7172b0e8e", + "score": 0.6835841317672621, + "metadata": { + "text": "used to assess biological responses provides new oppor -\ntunities to understand the impact of the environment on \nthe risk of age-related diseases. For example, the multi -\nomics analysis and integration method produces a pri -\nority list of multiple sets of biomarkers, which together \nreflect the molecular responses of the exposome. Each of \nthese data warrants integration into a biomarker panel to \naid physicians in developing age-related disease diagno -\nses and prognoses [78].", + "title": "2022 - A review on the application of the exposome.pdf", + "version": "v0", + "chunk_order": 78, + "document_id": "803a14cc-d8ab-54ca-80d6-78f1677457f9", + "extraction_id": "cac0d599-4e0a-5826-b47f-e71b52203956", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "beea72ed-e213-5877-8144-d0ef000a2912", + "score": 0.6832429359410456, + "metadata": { + "text": "summary, we identified age-dependent changes in gene\nexpression in different metabolic pathways that have\nbeen associated with epidermal homeostasis and there-\nfore might be important to sustain epidermal function.\nIntegrated analysis of transcriptome and metabolome data\nSince the age-dependent adaptations of metabolite and\ntranscript levels are only mild, we set out to identify\nmetabolic enzymes that featured an age-dependent and\nfunctional change in activity driven by altered gene ex-", + "title": "2017 - An integrative metabolomics.pdf", + "version": "v0", + "chunk_order": 51, + "document_id": "cb0831f4-540a-5620-b69e-03d6127f84e5", + "extraction_id": "f9c942d2-a191-52d4-8018-1030e414649d", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "6ad38ef0-c6bd-5b6a-9fb6-53c04f18a76d", + "score": 0.6780407428741455, + "metadata": { + "text": "These high throughput prof iling experiments have gener-\nated large amounts of data for meta-analysis [24], which can \ncompare molecular functions and expression patterns that change during aging in different systems. However, such studies are far from exhaustive, as they only describe the molecular changes during aging, which could in fact be the consequence of aging, rather than the cause of aging. Thus to \nexplore the causal factors for aging, studies are increasingly", + "title": "2012 - Systems Biology in Aging Linking the Old and the Young.pdf", + "version": "v0", + "chunk_order": 31, + "document_id": "cf7a8c59-4b4d-5e04-94b6-dd97edcb47a8", + "extraction_id": "6794bfa0-86ff-506f-ac40-35a9b1e33bcf", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "554f2525-a8cb-5003-be3d-137da97ea97f", + "score": 0.6730986627222749, + "metadata": { + "text": "over, the integration of trans criptome and metabolome data\nrevealed a transcriptionally re gulated reduction in protein\nas well as polyamine biosynthesis and adaptation in upper\nglycolysis and glycerolipid biosynthesis in aged skin.\nResults\nDifferences in the epidermal skin metabolome of young\nand old human volunteers\nTo chart metabolic adaptations in human skin during\naging in vivo , we performed non-targeted metabolomicsanalysis of epidermal skin tissue samples obtained from", + "title": "2017 - An integrative metabolomics.pdf", + "version": "v0", + "chunk_order": 15, + "document_id": "cb0831f4-540a-5620-b69e-03d6127f84e5", + "extraction_id": "500f52f7-9205-5859-a156-6d30575a3d62", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "d0b9df07-f6aa-52a5-9696-81f9034d9548", + "score": 0.6728132562152602, + "metadata": { + "text": "proteomes overlap significantly with the waves of aging proteins (Supplementary Table 15). Accounting for heterogeneous and com\n-\nplex changes to the plasma proteome during life will likely improve the sensitivity and specificity of prognostic and diagnostic tests. Moreover, these results are pertinent when considering the use of \nblood or blood products to treat aging and age-related diseases\n39. \nSpecifically, identifying plasma proteins that promote or antagonize", + "title": "2019 - Undulating changes in human plasma proteome.pdf", + "version": "v0", + "chunk_order": 193, + "document_id": "53c3130f-7029-50de-8dba-8714dfa36420", + "extraction_id": "24e63f26-0bac-59d4-b325-9c8ead69a4de", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + }, + { + "id": "07a5111b-b38b-5e1a-bd76-9372499a4dd9", + "score": 0.6681016285358901, + "metadata": { + "text": "rmed using authentic standards. One of the key nodes identi ed by\nmetabolomics as signi cantly altered with accelerated and normal\naging was glutathione metabolism ( Fig. 4A), a key antioxidant and\nindex of oxidative stress [71].\nDierential MS was used for proteomics analysis to identify redox-\nrelated proteins signi cantly altered in the livers of 3 4 month-old\nprogeroid Ercc1/mice and old WT mice (> 2 years-old) vs. adult WT\nmice. Expression of catalase, SOD1 (CuZnSOD) and SOD2 (MnSOD)", + "title": "2018 - Spontaneous DNA damage to the nuclear genome promotes senescence.pdf", + "version": "v0", + "chunk_order": 98, + "document_id": "08be7274-78a3-5e93-9e8c-3d4f6dbeacf9", + "extraction_id": "40e2d528-9297-575f-82a9-178aae0bab81", + "associatedQuery": "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?" + } + } + ], + "kg_search_results": null + } + } + }, + "8": { + "results": { + "completion": { + "id": "chatcmpl-AIHX9ExmiM3mDYaf83XTHzQDSE0IN", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Long non-coding RNAs (lncRNAs) play significant roles in the regulation of aging and age-related diseases through various mechanisms:\n\n1. **Regulation of Age-Associated Cardiovascular Diseases**: LncRNAs are involved in the regulation of age-associated cardiovascular diseases by acting as non-canonical precursors for specific microRNAs, such as hsa-miR-4485 and hsa-miR-1973, which participate in tissue age-related changes [1].\n\n2. **Senescence-Associated lncRNAs**: Certain lncRNAs are associated with cellular senescence, a key process in aging. These senescence-associated lncRNAs are implicated in the regulation of aging mechanisms [2].\n\n3. **Telomere Length Regulation**: LncRNAs are involved in the regulation of telomere length by modulating TERT activity and the synthesis of telomeric repeats, which is crucial for cellular aging and longevity [3].\n\n4. **Gene Expression Regulation**: LncRNAs interact with proteins and nucleic acids to regulate gene expression through epigenetic mechanisms, acting as antisense transcripts or transcriptional coactivators. They also influence the nuclear location of transcription factors and stabilize ribonucleoprotein complexes, which are important in aging-associated mechanisms [4].\n\n5. **Disease Progression**: LncRNAs play roles in the progression of various age-related diseases, such as atherosclerosis, diabetic nephropathy, glomerular disease, and renal fibrosis. For example, lncRNA H19 is involved in the activation of signaling pathways that induce atherosclerosis [5].\n\n6. **Neurodegeneration**: LncRNAs are implicated in neurodegenerative diseases, such as Huntington's disease, by regulating transcriptional networks and chromatin states [6].\n\n7. **Impaired Learning and Senescence**: Specific lncRNAs, like Gas5, are associated with impaired learning in aged brains, and others, like H19, interact with methyl-CpG binding domains, influencing senescence and aging pathways [7].\n\n8. **Angiogenic Capacity**: The expression of lncRNA Meg3 is linked to age-related impairment of the angiogenic capacity of endothelial cells, indicating a role in vascular aging processes [9].\n\nOverall, lncRNAs are crucial regulators of aging and age-related diseases through their diverse roles in gene expression, cellular senescence, disease progression, and other aging-related mechanisms.", + "role": "assistant" + } + } + ], + "created": 1728920667, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 494, + "prompt_tokens": 1337, + "total_tokens": 1831 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "41e5a2ca-1c83-5394-8fbf-c9dcc75e6a51", + "score": 0.7691522974281148, + "metadata": { + "text": "lncRNA which overexpression participates in the regulation of age-associated car -\ndiovascular diseases as it is a non-canonical precursor for hsa-miR-4485 and hsa- \nmiR- 1973 microRNAs [62]. These studies demonstrate that not only coding genes \n(which represent only 2% of the genome sequence) are implicated in aging regula-\ntion, but also lncRNAs and microRNAs participate in tissue age-related changes.\ncircRNAs are non-coding covalently closed single-stranded transcripts produced", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 685, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "e2fc0d00-8552-5b39-830f-6df7ec7c32e4", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "cb309a6a-4566-5de2-9687-cffa2f7737d2", + "score": 0.728266260870286, + "metadata": { + "text": "(2008).\n192. K. Abdelmohsen, A. Panda, M.-J. Kang, J. Xu, R. Selimyan, J.-H. Yoon, J. L. Martindale, S. De,\nW. H. Wood III, K. G. Becker, M. Gorospe, Senescence-associated lncRNAs: Senescence-\nassociated long noncoding RNAs. Aging Cell 12, 890 900 (2013).\n193. S. Kour, P. C. Rath, Long noncoding RNAs in aging and age-related diseases. Ageing Res. Rev.\n26,1 21 (2015).\n194. R. Johnson, Long non-coding RNAs in Huntington s disease neurodegeneration. Neurobiol. Dis.\n46,2 4 5 254 (2012).", + "title": "2016 - Epigenetics and aging.pdf", + "version": "v0", + "chunk_order": 318, + "document_id": "71b206ec-81bd-5194-8b21-ae522f8cbc2d", + "extraction_id": "91434549-bda3-5154-b089-28efed9c1089", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "8fa044d2-c807-5207-8361-ea22659d8b63", + "score": 0.7174522280693054, + "metadata": { + "text": "155\nPremature ageing has been associated with altered expression of lncRNAs that \nparticipate in the regulation of the telomere length by modulating the TERT activity \nand synthesis of telomeric repeats [155, 161]. Furthermore, it has been reported that \nchanges in the expression levels of some lncRNAs are associated with the develop-\nment of AD [162].\n Circular RNAs andAgeing\nCircular RNAs (circRNAs) are highly conserved covalently closed non-coding", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1075, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "b45152cc-6626-5989-a1b0-148c137ea1f3", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "e4d9a99d-4d28-5432-8e91-09388ea4b613", + "score": 0.7167888452536568, + "metadata": { + "text": "interacting with proteins and nucleic acids in order to regulate gene expression (by \nindirect epigenetic mechanisms or by direct mechanisms acting as antisense tran-\nscripts or transcriptional coactivators), nuclear location of transcription factors and \nstabilization of ribonucleoprotein complexes [155]. It has been reported that lncRNAs \nare important in the regulation of ageing-associated mechanisms in humans and ani-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1072, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "3932ada5-6fc4-5354-b52a-60fddbd47d3e", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "85a38fea-bd20-5170-bba0-963b12633c55", + "score": 0.7063658237457275, + "metadata": { + "text": "progression. LncRNA H19 was recently reported to play \na crucial role in the activation of MAPK and the NF-kB \nsignaling pathway and the induction of atherosclero -\nsis [3]. lncRNAs play crucial roles in the progression of \ndiabetic nephropathy [12], glomerular disease [13] and \nrenal fibrosis [14]. The lncRNA Arid-IR promotes NF-\nkB-mediated kidney inflammation by targeting NLRC5 \ntranscription [15]. The cell cycle changes during aging. \nPrevious studies have shown that lncRNAs are related to", + "title": "2022 - Predict the role of lncRNA in kidney aging.pdf", + "version": "v0", + "chunk_order": 12, + "document_id": "0d3b0558-289c-5af0-843a-f288d5da3d8c", + "extraction_id": "67e3cb94-cc30-58fe-8ff7-a9790c74325f", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "36a2ed56-a0b9-589d-b178-f1515337f1ae", + "score": 0.705976503731222, + "metadata": { + "text": "expression of SIRT1 and are decreased in lymphoblastic cell lines generated from \ncentenarians compared with those of AD patients, suggesting a protective effect of \nthese miRNAs against neurodegeneration [66].\nLong noncoding RNAs are important regulators of transcriptional networks and \nthe closed or opened chromatin state [2]. One interesting example of an lncRNA \nis that associated with aging, H19. This lncRNA interacts with MBD1 (a methyl-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 98, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "cb24a361-e7b4-5d35-a507-12ef65603d1f", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "577459d5-e2fc-599f-9806-3d18ab6837e6", + "score": 0.7041338295976471, + "metadata": { + "text": "associated factors, modulating aging and senescence directly or in-directly. One such example includes a specific lncRNA, Gas5 ,w h i c h\nis highly expressed in aged mice brain and has been associated with im-paired learning ( 189). Another bona fide example is H19lncRNA, a dif-\nferentially spliced product from the H19gene located at the IGF2/H19\nimprinted locus, which interacts with methyl-CpG binding domain", + "title": "2016 - Epigenetics and aging.pdf", + "version": "v0", + "chunk_order": 161, + "document_id": "71b206ec-81bd-5194-8b21-ae522f8cbc2d", + "extraction_id": "5221f1f8-1c53-590f-86c2-23ab47ac0cbc", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "ab28b2fc-4144-5b86-92af-d6054794a0b1", + "score": 0.7032895441902277, + "metadata": { + "text": "tempting to speculate that these lncRNAs may exert some\nregulatory control of this locus, possibly contributing to\nsenescent phenotypes. Together, these findings point to-\nwards a host of age-related ncRNAs as regulators of aging\npathways and networks.\nInteraction network analysis\nThe increased accuracy and breadth of our RNA-seq\ndata sets allowed us to generate networks of gene func-\ntional change in aging liver, above and beyond what was\nobserved using DAVID or GOrilla. Using Ingenuity", + "title": "2015 - Comprehensive transcriptional landscape.pdf", + "version": "v0", + "chunk_order": 53, + "document_id": "6f223b7b-d0ed-55d3-be91-a9e704149a94", + "extraction_id": "45ff5315-7500-5641-9c1a-e03b8aafc2d5", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "90c36562-0443-5100-b710-d750bd365b46", + "score": 0.7004715204238892, + "metadata": { + "text": "RNAs interact with proinflammatory signaling pathways and regulate senescence; however, their role on regulation of vas-cular aging processes is virtually unknown.\n151 Interestingly, \nthere is initial evidence linking the expression of the long \nnoncoding RNA Meg3 (maternally expressed 3) to age-related \nimpairment of angiogenic capacity of endothelial cells.152\nFurther studies are definitely needed to understand the", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 106, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "e308005e-d6ef-5492-a9a9-95256bb9ccee", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + }, + { + "id": "c2978dcd-0bab-5ca9-8130-0cdca1cc9330", + "score": 0.6980729103088379, + "metadata": { + "text": "Page 2 of 11 Lietal. BMC Genomics (2022) 23:254 \nmechanism of kidney aging will be of great significance \nfor delaying the occurrence and development of renal \naging. Although a small number of studies have been \nconducted on renal aging, it is still meaningful to com -\nprehend the mechanism of renal aging.\nLong chain noncoding RNAs (lncRNAs) are more than \n200 nucleotides in length. LncRNAs regulate transcrip -\ntional and posttranscriptional RNA processing, transla -", + "title": "2022 - Predict the role of lncRNA in kidney aging.pdf", + "version": "v0", + "chunk_order": 10, + "document_id": "0d3b0558-289c-5af0-843a-f288d5da3d8c", + "extraction_id": "67e3cb94-cc30-58fe-8ff7-a9790c74325f", + "associatedQuery": "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?" + } + } + ], + "kg_search_results": null + } + } + }, + "9": { + "results": { + "completion": { + "id": "chatcmpl-AIHXK8F2Ohi1RX10guI90pglYXyhM", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Recent advancements in CRISPR/Cas9 technology have opened new avenues for studying and potentially reversing aging in several ways:\n\n1. **Development of New Research Models**: CRISPR/Cas9 is significantly impacting research by enabling the creation of new models for studying age-related diseases. This includes manipulating disease-associated gene pathways, which can lead to a better understanding of the cellular and molecular origins of these diseases [1], [2].\n\n2. **Understanding Aging Processes Across Species**: The technology is beneficial in clarifying aging processes across different species. This improved understanding, particularly of epigenetic mechanisms affecting longevity, is crucial for identifying new potential therapeutic targets [3], [9].\n\n3. **Targeting Non-Proliferating Cells**: One notable contribution of CRISPR/Cas9 to aging research is its ability to target non-proliferating cells. This capability is important for studying cellular senescence, which is a key factor in both physiological aging and age-associated diseases [4].\n\n4. **Molecular Pathogenesis of Neurodegenerative Diseases**: CRISPR/Cas technologies have significantly contributed to studies on the molecular pathogenesis of age-related neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. This includes developing new tools to study the molecular mechanisms underlying these diseases using patient-derived cell lines with pathogenic mutations [10].\n\nThese advancements suggest that CRISPR/Cas9 technology not only aids in understanding the mechanisms of aging but also holds potential for developing interventions that could reverse or mitigate age-related conditions.", + "role": "assistant" + } + } + ], + "created": 1728920678, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 306, + "prompt_tokens": 930, + "total_tokens": 1236 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "9e4d48fb-e942-52a6-8e7e-57313d567a72", + "score": 0.7790865302085876, + "metadata": { + "text": "models of ageing, but it will also drastically accelerate the generation of refined ver -\nsions of those models or even allow the development of new research approaches in \nnon-model organisms. Moreover, CRISPR-based genome editing is already having \na significant impact in research aiming to understand the cellular and molecular \norigins of age-related diseases, as well as developing potential treatments against 11 Applications ofCRISPR-Cas inAgeing Research", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1551, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "fcc88af4-1949-59fe-8111-200ec0dcb7d6", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "d7a12958-6d0b-546f-b0aa-152b6812e2fd", + "score": 0.7558349370956421, + "metadata": { + "text": "of ageing. Finally, we will review how CRISPR-Cas has been used for creating new \nmodels for the study of age-related diseases, as well as for manipulating disease- \nassociated gene pathways.\nS. Haston et al.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1470, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "c072d600-8450-5842-ade1-aefd03854312", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "093e7604-5108-5fda-850e-007817090a9a", + "score": 0.7537974265934584, + "metadata": { + "text": "ularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9) will be beneficial in clari-\nfying aging-processes across species. \nAn improved understanding of epigenetic mechanisms affecting longevity will be \ndeciding crucial step towards the identification of new potential therapeutic targets. In \nfact, epigenetic drugs are of particular interest to the clinic due to their reversible and \ntransient effect. \nA limitation of manifold epigenetic studies, however, are the variations among sin-", + "title": "2021 - Epigenetics of Aging and Aging-Associated Diseases.pdf", + "version": "v0", + "chunk_order": 153, + "document_id": "70945353-4808-539a-80f9-5632c27913e5", + "extraction_id": "8db25d5e-25bd-5873-a53d-3815badbfd32", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "9a06df0b-a5b6-52d8-82c1-9dda446f9132", + "score": 0.7460278424008, + "metadata": { + "text": "224\nhigh-throughput assays able to further delineate important molecular pathways \ninvolved in inducing and maintaining cellular senescence in both physiological \nageing and age-associated diseases.\n Applications ofCRISPR-Cas intheStudy ofAgeing-Related \nDisease\n Cardiovascular Disease\nOne of the most notable contributions of CRISPR-Cas to ageing research is its \nability to target non-proliferating cells (contrary to HDR-directed gene targeting),", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1538, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "267468ed-0f9f-5a55-9334-9630792f300d", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "49c65d89-ec44-5412-a5bf-d94649e4afc3", + "score": 0.7414271235466003, + "metadata": { + "text": "219\n Applications ofCRISPR-Cas inBasic Research oftheMolecular \nCauses ofAgeing\n Investigating theMechanisms ofLongevity\nCurrently there have been no studies exploring the utility of the CRISPR-Cas sys-\ntem on experimentally extending the lifespan of physiologically aged laboratory \nanimals. A main issue in this regard is that established vertebrate models already \npossess relatively long lifespans that make longevity extension studies economi-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1500, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "625c559f-9ef6-5bef-8b4c-c57a72d421ed", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "a5ffc379-24d5-5c73-8435-41ca43af6347", + "score": 0.7320237159729004, + "metadata": { + "text": "CRISPR-Cas genome- editing tools will provide feasible implementation of 11 Applications ofCRISPR-Cas inAgeing Research", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1537, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "7d0ed573-4d0a-5de2-8be2-1ec0fb3a5800", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "7387d1f6-323a-52ea-90d4-6821fea31bf9", + "score": 0.729721188545227, + "metadata": { + "text": "the basis for future investigations into the spatio-temporal dynamics of the telom-\nerase protein invivo.11 Applications ofCRISPR-Cas inAgeing Research", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1521, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "1caf6ac0-0409-5b28-8fcf-bdffff2738a8", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "a02244c8-44da-595f-8a61-42bae541d784", + "score": 0.7277640104293823, + "metadata": { + "text": "induced by telomere erosion. Protein Cell. 2019;10:3705.11 Applications ofCRISPR-Cas inAgeing Research", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1583, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "5f85264a-a5cd-5ef6-a4c9-900dcb7b07ad", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "4eb34c07-921b-55bb-98eb-ff013bb2ace0", + "score": 0.7236873672194871, + "metadata": { + "text": "using bulk mRNA or even analyzing single cells (scRNA-seq). In addition, advances in\nmolecular biology and cell culture approaches (for instance Clustered Regularly Interspaced\nShort Palindromic Repeats (CRISPR)/Cas9) will be benecial in clarifying aging-processes\nacross species.\nAn improved understanding of epigenetic mechanisms affecting longevity will be\ndeciding crucial step towards the identication of new potential therapeutic targets. In", + "title": "2021 - Epigenetics of Aging and Aging-Associated Diseases.pdf", + "version": "v0", + "chunk_order": 146, + "document_id": "70945353-4808-539a-80f9-5632c27913e5", + "extraction_id": "e2bc9b8e-2349-509b-a148-fbd86f0455f4", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + }, + { + "id": "c6c119e6-362e-5ae7-a1f1-a5e75eb456ba", + "score": 0.7211248874664307, + "metadata": { + "text": "In recent years, CRISPR-Cas technologies have significantly contributed to studies \naddressing the molecular pathogenesis of age-related neurodegenerative conditions \nsuch as Alzheimers disease (AD) and Parkinsons disease (PD). Currently, it has \nmostly been utilised for developing new or improved tools in which to study the \nmolecular mechanisms underlying these diseases, such as in patient-derived cell \nlines carrying pathogenic mutations.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1542, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "267468ed-0f9f-5a55-9334-9630792f300d", + "associatedQuery": "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?" + } + } + ], + "kg_search_results": null + } + } + }, + "10": { + "results": { + "completion": { + "id": "chatcmpl-AIHXSI5xx8VWq2TPqps22AUgX04Pq", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "The DNA damage response (DDR) plays a crucial role in both replicative and chronological aging by maintaining genomic stability and influencing cell fate in response to DNA damage. Here are the key points regarding its significance:\n\n1. **Premature Aging and DDR Impairment**: Impaired DDR is directly correlated with premature aging phenotypes, as evidenced by studies on certain genetic models like Ercc1 [1]. This suggests that a functional DDR is essential for normal aging processes.\n\n2. **Cellular Senescence and DDR**: Persistent DDR signaling is a shared mechanism that triggers cellular senescence, which is a hallmark of aging [4]. This indicates that DDR not only repairs damage but also influences aging by promoting senescence when damage is irreparable.\n\n3. **Replicative Senescence**: DDR activation at telomeres, especially when they are critically short or damaged, triggers replicative cellular senescence or apoptosis [5]. This highlights the role of DDR in controlling the replicative lifespan of cells.\n\n4. **Age-related DNA Damage Accumulation**: As organisms age, DNA damage accumulates, and the DDR pathway becomes increasingly important in managing this damage to prevent mutations and maintain cellular function [6].\n\n5. **Tumor Suppression and Aging**: While DDR mechanisms like apoptosis and senescence are potent tumor suppressors, they also contribute to aging by removing or halting the proliferation of damaged cells [7].\n\nOverall, the DDR is significant in aging as it balances repair and cell fate decisions, influencing both the replicative capacity of cells and the overall aging process by managing DNA damage and maintaining genomic integrity.", + "role": "assistant" + } + } + ], + "created": 1728920686, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 325, + "prompt_tokens": 1225, + "total_tokens": 1550 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "42a07dfa-c5ac-535f-9a65-8c53b8f10aec", + "score": 0.7411069869995117, + "metadata": { + "text": "Chromatin Remodeling, DNA Damage Repair and Aging Current Genomics, 2012 , Vol. 13, No. 7 539 \nErcc1 also show premature aging phenotypes, providing evi-\ndence of a direct correlation between impaired DDR and premature aging [137, 138]. \n The relationship between DNA damage accumulation \nand aging has gained maximum credibility through studies", + "title": "2012 - Chromatin Remodeling, DNA Damage Repair and Aging.pdf", + "version": "v0", + "chunk_order": 96, + "document_id": "594e5dbe-b92a-5b0c-9f65-2a10670f9517", + "extraction_id": "d9a12bd9-c65e-547a-89aa-4e0231558ddc", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "86bd9226-94dc-5186-984e-3dd140de9af3", + "score": 0.728931725025177, + "metadata": { + "text": "genome is being transcribed or replicated, the threshold of damage needed to activate DDRs,\nand the choice of cell fate in response to genotoxic stress. It is important to point out that cross-sectional studies, which are largely all we have to date, yield information about the burden of DNA\ndamage and cannot inform as to whether lesions accumulate over time. Longitudinal studies on\ntissues that can be serially accessed are desperately needed.\nDNA Repair Capacity Decreases with Aging", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 74, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "e3e52327-4a23-5003-b418-dafdcdcae82c", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "79535f3c-51b2-5696-9081-3fdf146e8e61", + "score": 0.7221173048019409, + "metadata": { + "text": "INTRODUCTION\nDamage to DNA occurs with surprising frequency. DNA lesions can cause mutations, blocktranscription and replication, and trigger the DNA damage response (DDR). The DDR arrests\ncell cycle progression and activates signaling pathways that impact cell fate: repair, apoptosis, or\ncellular senescence. DNA damage is widely recognized as a cause of cancer, and strong evidencenow links DNA damage to aging and diseases associated with aging.", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 11, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "3da50120-f7fd-5256-ae05-4ffd57876a5c", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "6b4d2b61-4c6b-5b9e-a175-7a3c53a923a5", + "score": 0.7206555175390544, + "metadata": { + "text": "DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence andageing. Curr. Opin. Genet. Dev. 26:8995\n103. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, et al. 2009. Persistent DNA damage\nsignalling triggers senescence-associated inammatory cytokine secretion. Nat. Cell Biol. 11:97379\n104. Garinis GA, Uittenboogaard LM, Stachelscheid H, Fousteri M, van Ijcken W, et al. 2009. Persistent", + "title": "2016 - Genome Integrity in Aging.pdf", + "version": "v0", + "chunk_order": 154, + "document_id": "85d5fcbb-5385-5a01-8139-d11fc8b1fe3a", + "extraction_id": "fdd9c5d5-2cca-5fe1-baed-c672f464dab0", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "609e97e2-babd-5a49-9451-1a6162eb01e4", + "score": 0.7086535692214966, + "metadata": { + "text": "persistent DNA damage response (DDR) at telomeres and that even long telomeres may be a target for the accu-mulation of irreparable DNA damage. Therefore, DDR activation either at critically short telomeres or caused by persistent telomeric DNA damage represents the trigger of replicative cellular senescence or apoptosis\n48, 50. The \nanalysis of apoptosis by TUNEL assay showed that leukocytes from untrained T2D subjects were more sensitive to H", + "title": "2017 - Regular exercise participation improves genomic stability in diabetic patients an exploratory study to analyse telomere length and DNA damage.pdf", + "version": "v0", + "chunk_order": 51, + "document_id": "dcaf7b09-2d54-5cbf-b061-e3c4e6c6c518", + "extraction_id": "a5caef7f-f1c1-55af-8807-3c9db425df7b", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "9fac0777-2bcb-528c-9c16-cbcd85e28522", + "score": 0.7073437397088862, + "metadata": { + "text": "E) (2931) and have alleviated the dependency on invitro and \ninvivo models by using direct human samples.\nAGe-ReLATeD DNA DAMAGe AND DNA \nDAMAGe ReSPONSe (DDR) ACTiviTY\nAge-related accumulation of DNA damage has been studied \nthoroughly, showing correlation between age and damage levels \nor mutation frequency (32, 33). In the presence of DNA lesions \nor abnormalities, the DDR, a complex multigenic pathway, is", + "title": "2018 - Genomic Instabilities, Cellular Senescence, and Aging In Vitro, In Vivo and Aging-Like Human Syndromes.pdf", + "version": "v0", + "chunk_order": 38, + "document_id": "7de8d462-8a3c-5625-8cbb-374f3bb46425", + "extraction_id": "4cd1741b-c96f-592f-af69-95f3a10a157b", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "b9de772a-53c5-5128-a595-9baf9420e534", + "score": 0.7070512771606445, + "metadata": { + "text": "Spontaneous damage is stochastic. But the response to DNA damage is highly conserved, geneti-cally controlled, and with evolution exceedingly more complex. DNA damage triggers activation\nof signaling pathways termed the DDR, which facilitates repair and arrests cell cycle progression\nuntil repair is complete. If DNA damage is extensive or irreparable, DDR effectors trigger celldeath (apoptosis) or cell senescence. These are potent tumor suppressor mechanisms. However,", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 115, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "2b1396d1-ea5d-5708-a6b1-2adf1712c7b4", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "1d1662ae-28d6-514d-a600-8860b061a504", + "score": 0.7031606049287502, + "metadata": { + "text": "to senescence. Genetic attenuation of the DDR enables reversal of cellular senescence (81). Incontrast, introduction of DSBs in mouse liver, using a tetracycline-inducible SacI restriction\nendonuclease system, increases the burden of senescent cells in vivo and triggers hallmarks of liver\naging (82), illustrating a clear path for how DNA damage can play a causal role in aging.\nMarkers of senescence are detected at higher levels in tissues of older mice, humans, and other", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 118, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "2b1396d1-ea5d-5708-a6b1-2adf1712c7b4", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "43c4d87f-c0ce-5148-b601-77e6fd8956b2", + "score": 0.7019306421279907, + "metadata": { + "text": "mechanisms. In general, it appears that DDR signaling enhances DNA repair and autophagy tocontrol the level of damage in the cell.\nInterestingly, evidence, albeit early evidence, has been found that DNA damage is linked to\nproteostasis. Expression of proteins containing polyglutamine tracts that drive protein aggrega-\ntion linked to neurodegeneration activates the DDR and H2AX foci (148). Interestingly, DNA\nbreaks in cells and H2AX foci in brain of a murine model of Huntington disease are detected", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 172, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "0a7a0a01-a262-51bf-bfaf-4f301a0a467b", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + }, + { + "id": "0acc43f6-5d5b-53f5-af2f-53077b26591a", + "score": 0.6958593726158142, + "metadata": { + "text": "its relevance to age -related functional decline at the molecular and cellular level. \nThe importance of oxidative stress and key DNA damage response (DDR) pathways \nin cellular aging is discussed, with a special focus on poly (ADP -ribose) polymerase \n1, whose persistent activation depletes cellular energy reserves, leading to \nmitochondrial dysfunction, loss of energy homeostasis , and altered cellular \nmetabolism. Elucidation of the relationship between genomic instability ,", + "title": "2019 - Towards Understanding Genomic Instability, Mitochondrial.pdf", + "version": "v0", + "chunk_order": 5, + "document_id": "9b34514d-3d0e-52b5-8e5e-2f3c0708fd82", + "extraction_id": "93dbd5fc-d568-5b19-a9cd-fa192ed94ca7", + "associatedQuery": "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?" + } + } + ], + "kg_search_results": null + } + } + }, + "11": { + "results": { + "completion": { + "id": "chatcmpl-AIHXbfIiqBOfJAG67WB3RBf5qTOVk", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases through several mechanisms:\n\n1. **Functional Decline of the Adaptive Immune System**: Immunosenescence is characterized by a decline in the adaptive immune system's function, which leads to reduced protection against infections and decreased effectiveness of vaccinations [1]. This decline is primarily due to changes in T and B lymphocytes, which are crucial for adaptive immunity [2].\n\n2. **Loss of Diversity in Immune Receptors**: There is a loss of diversity in the T-cell receptor (TCR) and B-cell receptor repertoire as people age. This is due to the accumulation of dysfunctional cells and decreased output from the thymus and bone marrow, which are essential for generating new immune cells [9]. This loss of diversity impairs the immune system's ability to recognize and respond to new pathogens effectively.\n\n3. **Chronic Inflammation (Inflammaging)**: Aging is also associated with a state of low-grade chronic inflammation, known as inflammaging. This chronic inflammation can further compromise immune function and contribute to the development of age-related diseases [1], [4].\n\n4. **Overall Immune System Alterations**: All components of the immune system are affected by aging, not just the adaptive immune system. This widespread alteration can lead to a compromised defense against pathogens, making the elderly more susceptible to infectious diseases and less responsive to vaccinations [2], [9].\n\nThese changes collectively lead to an increased susceptibility to diseases in the elderly, highlighting the importance of understanding and potentially intervening in these age-related immune alterations to improve health outcomes in older populations.", + "role": "assistant" + } + } + ], + "created": 1728920695, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 331, + "prompt_tokens": 1134, + "total_tokens": 1465 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "65fe4bdc-890e-53bf-ad11-2d9c67adac7f", + "score": 0.74183189868927, + "metadata": { + "text": "immune system are one of the hallmarks of the aging\nbody. Immunosenescence is the functional decline of the\nadaptive immune system brought on by natural agingwhereby protection against infection by pathogens and\nthe effectiveness of vaccination decline [45,46]. The sec-\nond aging-induced change in the immune system iscalled inflammaging which is characterized by a low-\ngrade chronic inflammation process that contributes to", + "title": "2012 - Structural, functional and molecular analysis.pdf", + "version": "v0", + "chunk_order": 100, + "document_id": "0e803003-d6e5-570e-a810-1aea89d7ea63", + "extraction_id": "d9ef944b-b9a5-5b45-aaa6-c48f6fe54893", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "0c2a9ad8-054d-5a03-af43-704d2b7722d0", + "score": 0.7318152189254761, + "metadata": { + "text": "the increased susceptibility of the elderly to infectious disease and tothe poor outcome of vaccination. Defence against pathogens is com-promised mainly because of changes in adaptive immunity mediatedby T and B lymphocytes; however, all components of the immunesystem are affected (Fig 1). Dissecting the crucial alterations responsi-ble for dysfunctional immunity in old age will facilitate the develop-ment of rational interventions to reconstitute appropriate immunefunction. Given the increasing", + "title": "2007 - Immunosenescence comes of age.pdf", + "version": "v0", + "chunk_order": 1, + "document_id": "22313267-b0be-572f-8170-dcb814fe6140", + "extraction_id": "1ec3aae0-b171-511c-8250-fc0731aa3ec8", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "a8f4f7d2-85f9-5097-b588-614c7973c3b5", + "score": 0.7281038761138916, + "metadata": { + "text": "[39] C. Castelo-Branco, I. Soveral, The immune system and aging: a review, Gynecol. \nEndocrinol. 30 (2014) 1622. \n[40] S.A. Johnson, S.J. Rozzo, J.C. Cambier, Aging-dependent exclusion of antigen-in\n-\nexperienced cells from the peripheral B cell repertoire, J. Immunol. 168 (2002) \n50145023\n. \n[41] D.P. Shanley, D. Aw, N.R. Manley, D.B. Palmer, An evolutionary perspective on the \nmechanisms of immunosenescence, Trends Immunol. 30 (2009) 374381.", + "title": "2020 - Age-related gene expression and DNA methylation changes in rhesus.pdf", + "version": "v0", + "chunk_order": 108, + "document_id": "0f1fe2f6-b9c8-514d-ac1c-4e7c07a19ff0", + "extraction_id": "245e6d14-fa43-5af6-92d3-c5d7bf0235c2", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "6822e1b6-b9bc-5e26-b6d5-d0d141854dd4", + "score": 0.7085440158843994, + "metadata": { + "text": "immunosenescence: the decline in immune efficacy of both the innate and the adaptive immune systems. Age-relatedimmune decline also links to the concept of inflamm-aging, whereby aging is accompanied by sterile chronic\ninflammation. Along with a decline in immune function, aging is accompanied by a widespread of omics remodeling.", + "title": "2022 - Functional genomics of inflamm-aging.pdf", + "version": "v0", + "chunk_order": 1, + "document_id": "435dc081-e3d1-52c5-93a1-caa11206422f", + "extraction_id": "1635dbe1-1dcb-5213-9446-74129d50c5f8", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "c0eedfc9-fd74-51f8-ace9-dfd79ad16b71", + "score": 0.703385966814402, + "metadata": { + "text": "ence the development of inflamm-aging and immunosenes-\ncence phenotypes.\nFinally, although discussed studies have reported age-related\nchanges in innate immune cell processes, there is still little\nknown about how these changes are influenced by biologicalsex. Indeed, both the adult mammalian immune system [ 80,125]\nand the aging process [ 126] are sex-dimorphic, suggesting that", + "title": "2022 - Functional genomics of inflamm-aging.pdf", + "version": "v0", + "chunk_order": 87, + "document_id": "435dc081-e3d1-52c5-93a1-caa11206422f", + "extraction_id": "72b29fff-be72-5ede-85c9-7dc81894c956", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "c4f7a0e2-0d13-5928-aaf2-8fc70dc9face", + "score": 0.6911636775038447, + "metadata": { + "text": "tion has also been implicated in ageing across a range of non-model organisms, including mice,nematode worms ( Caenorhabditis elegans ), and primates [ 4042].\nThe damage caused by the ageing adaptive and innate immune systems gives us insights into\nhow these different arms of the immune system may in uence longevity. In general, adaptive im-\nmune function diminishes with age, whereas innate immune function is maintained [ 34,4346].", + "title": "2022 - Immunity and lifespan answering.pdf", + "version": "v0", + "chunk_order": 31, + "document_id": "a834e7ee-7bab-5c4d-a236-b570d1ae635f", + "extraction_id": "b7467732-698f-5ca4-be08-08b011b0d343", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "1683b89a-86bd-5439-9a6f-df120b67d0e8", + "score": 0.6838449443532513, + "metadata": { + "text": "development to senescence, innate immunity to adaptive immunity,and genes to environments, in organisms ranging from mice to monkeys and humans. Understanding and eventually modulatingimmune dysfunction in the elderly now beckons.\nLymphocyte development and ageing", + "title": "2007 - Immunosenescence comes of age.pdf", + "version": "v0", + "chunk_order": 3, + "document_id": "22313267-b0be-572f-8170-dcb814fe6140", + "extraction_id": "1ec3aae0-b171-511c-8250-fc0731aa3ec8", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "fb4173c8-cf14-59d2-804c-3c2824a3fdc5", + "score": 0.6819573234345137, + "metadata": { + "text": "an age-related decline in the capacity of adaptive immunity,consisting of more specic responses carried out by B andT cells [ 7]. Thus, with advanced age, the immune system\nundergoes a gradual remodeling in the attempt to reestablisha new balance that assures survival, however, favoring thedevelopment of chronic inammatory conditions [ 5,6,8,9].\nDNA damage and inammation are inevitably linked by", + "title": "2012 - Pleiotropic Cellular Functions of PARP1 in Longevity.pdf", + "version": "v0", + "chunk_order": 12, + "document_id": "e67324c0-474b-5280-8cbc-3778c6c0e5f0", + "extraction_id": "f12b7e5c-29bc-5f56-9303-ab9286f22d88", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "f16127b0-68dc-50bc-b39e-8ead81d723ee", + "score": 0.6773538589477539, + "metadata": { + "text": "All components of the immune system are altered as ageing pro-ceeds (Fig 1); however, the T-cell and B-cell compartments seem tobe particularly susceptible. The most severe clinical impact is proba-bly a result of the loss of diversity in the TCR and B-cell-receptorrepertoire, owing to the accumulation of dysfunctional cells, anddecreased thymic and bone-marrow output. Several interventionsdiscussed at the meeting could conceivably contribute to therestoration of appropriate immune function in the near", + "title": "2007 - Immunosenescence comes of age.pdf", + "version": "v0", + "chunk_order": 62, + "document_id": "22313267-b0be-572f-8170-dcb814fe6140", + "extraction_id": "170e6d89-2624-5b49-a6d1-95d4f35f73f3", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + }, + { + "id": "ba9fdb3c-b9c2-57a2-9bb7-df5472d20e73", + "score": 0.6744434043433323, + "metadata": { + "text": "more susceptible to DNA damage. One of the major rea-sons are the impaired DNA repair mechanisms which havebeen described in several studies and have been associated\nwith the initiation of age-associated diseases and progeroidsyndromes ( Hasty et al., 2003; Lieber and Karanjawala,\n2004). Furthermore, dysregulated immune and inamma-\ntory responses have been already documented both inhumans and mouse with increasing age ( Badawi et al.,\n2004; Kovaiou et al., 2007 ).", + "title": "2007 - The skin as a mirror of the aging process in the human organism.pdf", + "version": "v0", + "chunk_order": 69, + "document_id": "c429b80b-ad40-5fd3-b189-3982e5a8ab23", + "extraction_id": "daf4bb0f-4be5-5c47-baa5-686cd61adc1a", + "associatedQuery": "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?" + } + } + ], + "kg_search_results": null + } + } + }, + "12": { + "results": { + "completion": { + "id": "chatcmpl-AIHXkz3iFRslvxy1Jaw30l5EF9v8O", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Advancements in machine learning and artificial intelligence significantly aid in the identification of biomarkers for biological aging by enabling the development of predictive models and personalized medical treatments. These technologies allow for the integration and analysis of complex biological data, which can be used to forecast an individual's lifespan and potential age-related diseases, thereby facilitating personalized medical interventions [2]. Machine learning algorithms, such as linear regression and its variants, are employed to select aging-related biomarkers and construct aging clocks, which are predictors of chronological and biological age based on various omics datasets [3]. Additionally, computational methods have been developed to predict biological age from gene expression data, which can help in evaluating lifestyle changes and therapeutic strategies aimed at promoting healthy aging [8].", + "role": "assistant" + } + } + ], + "created": 1728920704, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 141, + "prompt_tokens": 1171, + "total_tokens": 1312 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "8139ed83-471f-5aa8-a6e1-2294b106ffd7", + "score": 0.6753724410907971, + "metadata": { + "text": "tifications of biological aging: do they measure the same thing? Am J Epidemiol. \n2018;187(6):122030.\n 74. Putin E, etal. Deep biomarkers of human aging: application of deep neural networks to bio-\nmarker development. Aging (Albany NY). 2016;8(5):102133.\n 75. Rehkopf DH, etal. Leukocyte telomere length in relation to 17 biomarkers of cardiovascular \ndisease risk: a cross-sectional study of US adults. PLoS Med. 2016;13(11):e1002188.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1795, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "660d608e-8333-590f-8183-31b51779cec3", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "eeed3c27-9717-5592-8d69-937eca35bfff", + "score": 0.6621368334130294, + "metadata": { + "text": "studied (Table 13.1). Thus, due to the generation of these data and technological \nadvances, possibly in the future, artificial intelligence programs will be able to \nreliably forecast the life of an individual, as well as the possible diseases that he \nmay suffer in ageing; so these advances and discoveries will allow us to achieve \na personalized medical treatment as a result of to the integration of biomarkers \nof ageing.\n Ageing Is aTreatable Condition", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1763, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "1af20df8-561f-59cb-9996-106a3be3f82f", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "b545cd47-00c7-5bd8-bd25-8d2bf59be62e", + "score": 0.6620581347363634, + "metadata": { + "text": "the data. However, construction of such models is often highlydegenerate, yielding little overlap of identified biomarkers be-tween studies and thus making results difficult to interpret(Thompson et al. 2018; Galkin et al. 2020).\nAmong the many computational algorithms, linear regres-\nsion and its variants have been widely used to select aging-relatedbiomarkers and build aging clocks, namely, predictors of chro-\nnological age and biological age, in various omics data sets and ag-", + "title": "2023 - A transcriptome-based single-cell biological age model.pdf", + "version": "v0", + "chunk_order": 10, + "document_id": "9be234b7-f37d-5cd5-8895-bfe676441b2f", + "extraction_id": "f9312bd9-9f67-5e36-9986-f01d66d4b7ac", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "4b418218-07f6-5103-a9f4-4a28be7247c8", + "score": 0.6509723275320346, + "metadata": { + "text": "states, which can be monitored using various biomarkers (Belskyet al. 2015). These markers are usually measurable indicators of aparticular outcome or source of aging, such as phenotypical mea-sures like frailty and molecular measures like DNA methylation dy-\nnamics (Schumacher et al. 2021; Lpez-Otn et al. 2023). Although\ninformative, they are not always quantitatively predictive of anindividual s true biological age, nor are they easy to obtain. The ad-", + "title": "2023 - A transcriptome-based single-cell biological age model.pdf", + "version": "v0", + "chunk_order": 7, + "document_id": "9be234b7-f37d-5cd5-8895-bfe676441b2f", + "extraction_id": "f9312bd9-9f67-5e36-9986-f01d66d4b7ac", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "11d9e838-e4a1-50d4-92e8-658d4ff57b68", + "score": 0.6488766670227051, + "metadata": { + "text": "biomarkers of the aging process.", + "title": "2007 - Biological Aging Is No Longer.pdf", + "version": "v0", + "chunk_order": 58, + "document_id": "efef1c11-52f9-5b95-878a-07980080f0f8", + "extraction_id": "5362f054-bb14-53fd-8d6d-9fb7aa41b3f3", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "71a04373-81b9-5219-bbde-6f9cd1935491", + "score": 0.6426215980874551, + "metadata": { + "text": "supervisedmachinelearningappliedtoageingresearch.\nBiogerontology\n,18,171188.\n47. Kriete,A.,Lechner,M.,Clearfield,D.andBohmann,D.(2011)\nComputationalsystemsbiologyofaging. WileyInterdiscip.Rev.Syst.\nBiol.Med. ,3,414428.Downloaded from https://academic.oup.com/nar/article/46/D1/D1083/4599180 by guest on 14 October 2023", + "title": "2018 - Human Ageing Genomic Resources new and updated.pdf", + "version": "v0", + "chunk_order": 80, + "document_id": "82726cea-f77c-5a92-9f2e-ecccc369953a", + "extraction_id": "62ff5c38-25a5-5729-a160-ce89e2ceb1c8", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "ed814cb1-4fd3-5586-bd75-131d2a3ae96b", + "score": 0.637718677520752, + "metadata": { + "text": "associated with age, such as mouth width, nose width, and eye corner droop. This \ntype of bioimage analysis has rendered relatively accurate calculations of the actual \nage, although this accuracy tended to fall with increasing age after 40years [71].\n Integration ofBiomarkers ofAgeing\nBiomarkers of ageing allow estimating the biological age of an organism (Table 13.1) \nwhile providing information on their health status. Different studies are looking for", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1752, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "5a07784a-755c-598d-9d2d-3eb2ab8285cc", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "bb3a61fd-7137-5735-b65c-8aabab7eb971", + "score": 0.637002310931546, + "metadata": { + "text": "Background\nThere is a marked heterogeneity in human lifespan and\nhealth outcomes for people of the same chronological\nage. Thus, one fundamental challenge is to identify mo-\nlecular and cellular biomarkers of aging that could pre-\ndict lifespan and be useful in evaluating lifestyle changes\nand therapeutic strategies in the pursuit of healthy aging.\nHere, we developed a computational method to predict\nbiological age from gene expression data in skin fibro-", + "title": "2018 - Predicting age from the transcriptome.pdf", + "version": "v0", + "chunk_order": 2, + "document_id": "73128c69-30e0-5b7a-9504-1502e3f062c7", + "extraction_id": "be79444e-743f-5289-9607-db6bc3b35493", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "c2ea0dae-b466-5c5b-babb-bfa74243bd34", + "score": 0.6301597952842712, + "metadata": { + "text": "Background\nAgeing is a major risk for diseases and mortality [ 1,2].\nChronological age has been widely used as a marker of\nageing due to ease and accuracy of measurement [ 1].\nHowever, it is not necessarily a good predictor of\nbiological ageing since individuals with the same\nchronological age can vary in health, especially in later\nlife [ 3]. Therefore, researchers have attempted to search\nfor biomarkers of ageing that can predict functional cap-\nability at a later age [ 4,5]. In 2013, Hannum et al. and", + "title": "2019 - Improved precision of epigenetic clock.pdf", + "version": "v0", + "chunk_order": 8, + "document_id": "556d0179-023f-581f-9c2d-febe4e75722f", + "extraction_id": "6e048749-b423-54c0-9505-439db5595254", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + }, + { + "id": "96135704-e84c-53fc-9b57-b1e7b8dcd81f", + "score": 0.6267950161221625, + "metadata": { + "text": "discriminate between adverse aging-related events,\nsuch as frailty (Mitnitski et al. 2002 ), immobility\n(Simonsick et al. 2001 ), and propensity to fall (Lord et\nal.1994 ).\nThere are additional considerations when choosing\nbiomarkers to characterize aging. First, biomarkers\nmeasured at a given age are merely snapshots of\nimportant regulatory systems (Seeman et al. 2004 );\nthere is no information on system dynamics if each\nbiomarker is measured only once. Having longitudinal", + "title": "2011 - How pleiotropic genetics of the musculoskeletal system.pdf", + "version": "v0", + "chunk_order": 17, + "document_id": "ed31486c-a651-5894-bd96-21fbd78f2646", + "extraction_id": "1b0806b9-729c-581f-9e3f-a98a5e0ce7eb", + "associatedQuery": "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?" + } + } + ], + "kg_search_results": null + } + } + }, + "13": { + "results": { + "completion": { + "id": "chatcmpl-AIHXpT1Oa9sduYt2d6yF1iu8bJvoN", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Recent discoveries regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes include the following:\n\n1. The importance of progeronic (aging-promoting) and antigeronic (aging-delaying) circulating factors in the development of vascular aging phenotypes has been discussed. This highlights the role of systemic factors in contributing to age-related vascular pathologies and suggests potential interventions to prevent or delay these conditions by targeting fundamental cellular and molecular aging processes [1].\n\n2. Studies using heterochronic parabiosis, which involves connecting the circulatory systems of young and aged mice, have demonstrated the impact of circulating factors on aging phenotypes. This research provides initial evidence that circulating factors can influence cerebromicrovascular density, which typically declines with advanced age [3].\n\nThese findings underscore the significant role that systemic factors, including circulating microvesicles, play in influencing aging phenotypes, particularly in the context of vascular aging and potential rejuvenation strategies.", + "role": "assistant" + } + } + ], + "created": 1728920709, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 193, + "prompt_tokens": 1367, + "total_tokens": 1560 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "c4c7b861-6d13-5814-818d-a79ddabd742c", + "score": 0.6523131728172302, + "metadata": { + "text": "in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented. (Circ", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 13, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "bfeb5c38-4fa6-5df5-90ce-63204deba3a8", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "9d96fdeb-3b94-57d2-8025-db47be7c52ad", + "score": 0.6351242065429688, + "metadata": { + "text": "pression of numerous mRNAs, some of which directly influence aging and age-related diseases. Jung and Suh describe what we know about the importance of microRNAs in aging and how this exciting new field is just starting to become explored. \n The last review in this special issue by Hou et al. brings things together nicely with a systems biology perspective of aging. \nIn order to model the immense complexity of aging, we require systems-level approaches. This review describes how several", + "title": "2012 - Genomics and Genetics of Aging.pdf", + "version": "v0", + "chunk_order": 6, + "document_id": "3c2efc4d-b5a8-5843-be7e-44c3b52f3d9b", + "extraction_id": "726bbaa2-97e8-5f62-a731-a1ba3cf1778f", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "e9ddeedc-70ba-516f-ad9b-77e2b45cd01f", + "score": 0.6344840148398878, + "metadata": { + "text": "autoregulation of blood flow,218 vascular structural remodel-\ning, atherogenesis,219 and angiogenic processes.220\nThe impact of circulating factors on aging phenotypes \nwas also demonstrated by studies using mice with heter -\nochronic parabiosis, which involves surgically connecting the circulatory system of a young and an aged mouse.\n221 \nCerebromicrovascular density typically declines with ad-vanced age,\n222 and there is initial evidence that circulating an-", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 143, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "4b0673e0-fb5e-5212-ba68-417de0e867b7", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "415a6dd6-0e64-5aef-8561-289d728ad721", + "score": 0.6310828704287343, + "metadata": { + "text": "components, particularly chemokines and cytokines, in theblood and tissues ( Villeda et al., 2011 ). In addition to illuminating\nthe inuence of the systemic environment on cellular function,such heterochronic studies emphasize the potential role of envi-ronmental factors in rejuvenating aged cells.\nMolecular signatures of aging have been directly tested as", + "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf", + "version": "v0", + "chunk_order": 46, + "document_id": "bde26feb-f423-51b0-89ec-6f079bfc8b17", + "extraction_id": "7f8f4ca0-9b27-55e3-a889-030af08dc84b", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "729ae0a3-95f3-50c7-8c00-d1ce0673ea08", + "score": 0.6283429861068726, + "metadata": { + "text": "related diseases. Ageing Res Rev. 2018;47:21477.\n 115. Kumar S, Vijayan M, Bhatti JS, Reddy PH.MicroRNAs as peripheral biomarkers in aging \nand age-related diseases. Prog Mol Biol Transl Sci. 2017;146:4794.\n 116. Smith-Vikos T, Liu Z, Parsons C, Gorospe M, Ferrucci L, Gill TM, etal. A serum miRNA \nprofile of human longevity: findings from the Baltimore Longitudinal Study of Aging \n(BLSA). Aging (Albany NY). 2016;8(11):297187.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1140, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "575a9f30-8504-5526-90e0-e558bfc29c02", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "571e50a8-c009-59a5-b01c-0f01c4b5e163", + "score": 0.627212643623352, + "metadata": { + "text": "in the endothelium and the VSMCs and specific disease pro-cesses. There is evidence that the senescence-associated se-cretory phenotype can also induce paracrine senescence and \nalter the function of neighboring cells, and the role of this \nmechanism in vascular aging should be further evaluated. \nThe possibility of paracrine transmission of senescence from \nmicrovascular endothelial cells to parenchymal cells also requires further investigations. It should be noted that many", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 89, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "fe270a46-7f2f-5a25-b98f-a782511801fb", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "ab32705e-4e02-59ab-986d-4552a4a522b9", + "score": 0.6239165663719177, + "metadata": { + "text": "protein VSIG4 as a biomarker of aging in murine adiposetissue. Aging Cell 2020; 19:e13219.\n128. Angelidis I, Simon LM, Fernandez IE, et al. An atlas of the\naging lung mapped by single cell transcriptomics and deeptissue proteomics. Nat Commun 2019; 10:963.\n129. Clark D, Brazina S, Yang F, et al. Age-related changes to\nmacrophages are detrimental to fracture healing in mice.\nAging Cell 2020; 19:e13112.\n130. Tabula Muris Consortium. A single-cell transcriptomic", + "title": "2022 - Functional genomics of inflamm-aging.pdf", + "version": "v0", + "chunk_order": 137, + "document_id": "435dc081-e3d1-52c5-93a1-caa11206422f", + "extraction_id": "14dbffca-9dc8-5d8c-bb23-98bc80b77e86", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "55a6fe97-29cd-5969-8ea8-3b350b8e0554", + "score": 0.6122685074806213, + "metadata": { + "text": "Ungvari et al Mechanisms of Vascular Aging 861\nmechanisms of vascular aging and identify translationally \nrelevant treatments for the promotion of vascular health in older adults.\nThe same cellular and molecular aging processes that af-\nfect arterial vessels and capillaries also affect veins and the lymphatic/glymphatic system, likely contributing to various \ndisease pathologies. Examples include the potential role of \ncerebral venules in neuroinflammation, Alzheimer disease, and cerebral microhemorrhages", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 166, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "2836777b-037b-52e4-a160-9cb02dd98b92", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "3914af93-b251-54ae-b7bf-9c8243a24f74", + "score": 0.6107358336448669, + "metadata": { + "text": "et al., Plasma proteomic signature of age in healthy humans, Aging Cell 17 (2018). \n[17] D. Mari, P.M. Mannucci, R. Coppola, B. Bottasso, K.A. Bauer, R.D. Rosenberg, \nHypercoagulability in centenarians - the paradox of successful aging, Blood 85 \n(1995) 31443149. \n[18] S.A. Phillips, The vasculature in cardiovascular diseases: will the vasculature tell us what the future holds? Prog. Cardiovasc. Dis. 57 (2015) 407408. \n[19] R.A. Gibbs, J. Rogers, M.G. Katze, R. Bumgarner, G.M. Weinstock, E.R. Mardis,", + "title": "2020 - Age-related gene expression and DNA methylation changes in rhesus.pdf", + "version": "v0", + "chunk_order": 99, + "document_id": "0f1fe2f6-b9c8-514d-ac1c-4e7c07a19ff0", + "extraction_id": "245e6d14-fa43-5af6-92d3-c5d7bf0235c2", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + }, + { + "id": "d2ce22fd-6c12-56cf-948d-fc6604cf0f23", + "score": 0.6083986163139343, + "metadata": { + "text": "16Lidzbarsky et al.\nGenomic Instabilities, Cellular Senescence, and Aging\nFrontiers in Medicine | www.frontiersin.org April 2018 | Volume 5 | Article 104\n177. Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci (2012) \n125:717. doi:10.1242/jcs.099200 \n178. Lanceta J, Prough RA, Liang R, Wang E. MicroRNA group disorganiza-\ntion in aging. Exp Gerontol (2010) 45:26978. doi:10.1016/j.exger.2009. \n12.009", + "title": "2018 - Genomic Instabilities, Cellular Senescence, and Aging In Vitro, In Vivo and Aging-Like Human Syndromes.pdf", + "version": "v0", + "chunk_order": 228, + "document_id": "7de8d462-8a3c-5625-8cbb-374f3bb46425", + "extraction_id": "d3686eba-0aa4-5c56-b60d-bf76c3ab433b", + "associatedQuery": "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?" + } + } + ], + "kg_search_results": null + } + } + }, + "14": { + "results": { + "completion": { + "id": "chatcmpl-AIHXx0hXjoPni1lj2qiHnS6BLuSSU", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Changes in the gut microbiome composition are closely linked to aging and longevity. As individuals age, the composition and function of the gut microbiome undergo significant modifications. These changes are thought to contribute to various age-related processes, including immunosenescence and inflammaging, which are associated with the aging immune system [6]. \n\nResearch has shown that a healthy microbiota can promote survival and is linked to longevity. Specifically, certain bacterial families such as Christensenellaceae, Akkermansia, and Bifidobacterium have been associated with immunological and metabolic regulation, which may contribute to increased lifespan [1]. \n\nAdditionally, the gut microbiota of older adults differs in type and number of microorganisms compared to younger adults, with Bacteroidetes and Firmicutes being the most prevalent species in older individuals [4]. These changes in microbial composition can be influenced by both intrinsic and extrinsic factors, which play a significant role in the health and function of the microbiome as people age [8]. \n\nOverall, maintaining a healthy gut microbiome is crucial for promoting longevity and mitigating some of the negative effects associated with aging.", + "role": "assistant" + } + } + ], + "created": 1728920717, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 225, + "prompt_tokens": 1456, + "total_tokens": 1681 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "1bcfcf33-d9b4-55b7-a384-bc8e08893a22", + "score": 0.7504067420959473, + "metadata": { + "text": "the adaptation of the microbiota to the physiological changes of the long aging \nprocess. It has been demonstrated that the microbiota on this population maintains \nthe health and promotes the survival. Additionally, a relationship between a healthy \nmicrobiota and longevity had been proposed [44]. A possible pathway is an immu-\nnological and metabolic regulation linked to the increase of bacterial compounds \nlike Christensenellaceae, Akkermansia, and Bifidobacterium [44, 45].", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1207, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "07a2b9a1-d683-568d-b2e6-c2cc1fcffba5", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "f4ec4435-00f7-5477-984a-68d1eff9e7a0", + "score": 0.7143480777740479, + "metadata": { + "text": "Marchesi JR, Falush D, Dinan T, Fitzgerald G, et al:Composition, variability,\nand temporal stability of the intestinal microbiota of the elderly. Proc\nNatl Acad Sci USA 2011, 108(Suppl 1):4586 4591.\n21. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S,\nDonehower LA, Issa JP: Widespread and tissue specific age-related DNA\nmethylation changes in mice. Genome Res 2010, 20(3):332 340.\n22. Englander EW: Gene expression changes reveal patterns of aging in the", + "title": "2012 - Structural, functional and molecular analysis.pdf", + "version": "v0", + "chunk_order": 124, + "document_id": "0e803003-d6e5-570e-a810-1aea89d7ea63", + "extraction_id": "faae2e40-6de8-5285-8410-ac1ef5dac6ad", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "393bd8fc-14c6-5fc3-be3b-3ddf1c218531", + "score": 0.7123257264702697, + "metadata": { + "text": "microbiota present in infants, adults, and the elderly. Appl. Environ. Microbiol. 73, \n77677770 (2007).\n40. Kong, F. et al. Gut microbiota signatures of longevity. Curr. Biol. 26, R832R833 \n(2016).\n41. Tremaroli, V. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce \nlong-term changes on the human gut microbiome contributing to fat mass regulation. \nCell Metab. 22, 228238 (2015).\n42. Everard, A. et al. Microbiome of prebiotic-treated mice reveals novel targets involved", + "title": "2017 - Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug.pdf", + "version": "v0", + "chunk_order": 120, + "document_id": "448d68d1-19a8-5f4c-a48b-8d33597bd03b", + "extraction_id": "b2654364-b3e8-5e26-9664-d19ca8f5605e", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "0856bafc-06ce-5716-af52-f65dc3abfafe", + "score": 0.7113192677497864, + "metadata": { + "text": "Therefore, research in the field has demonstrated that aging is a potential modi-\nfier of the composition and function of the human microbiome. Figure 9.3 shows the \nlocal composition of the microbiome in an average older adult. It can be seen that \nBacteroidetes and Firmicutes species are the most prevalent in this age.\nRecent data has shown that older people hide a microbiota that differs in the \ntype and number of microorganisms from that of younger adults [38]. Young people", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1202, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "c50b343b-3eef-548c-88cd-d5bda6605619", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "3742fdda-bdba-5c09-bf7c-732b2554c5fe", + "score": 0.7079554200172424, + "metadata": { + "text": "related malnutrition. Furthermore, it has been shownthat aging can cause bacterial overgrowth in the smallintestine [16,17] and promote changes in microbial com-\nposition in the colon [18-20]. In addition, reported age-\nrelated changes in DNA methylation of the mouseintestine [21] might play a role in the altered gene\nexpression levels observed in the duodenum and colon\nof aging mice [22]. Together these observations demon-strate that although certain aspects of the aging intestine", + "title": "2012 - Structural, functional and molecular analysis.pdf", + "version": "v0", + "chunk_order": 13, + "document_id": "0e803003-d6e5-570e-a810-1aea89d7ea63", + "extraction_id": "66edc533-58a4-5ad1-96c4-7e0c05462de5", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "bb367137-9186-53aa-8765-af837b7b4242", + "score": 0.6961455345153809, + "metadata": { + "text": "detectable.\nChanges in the gut microbiota in terms of compos-\nition and functionality during the process of aging\nhave previously been reported [19,20,51] and it hasbeen postulated that these changes might contribute\nto the development of immunosenescence and inflam-\nmaging [18,52]. To establish whether the enhanced\nexpression of genes playing a role in the immune sys-\ntem are due to modifications in the microbiota wemeasured the total number of all bacteria and of the", + "title": "2012 - Structural, functional and molecular analysis.pdf", + "version": "v0", + "chunk_order": 104, + "document_id": "0e803003-d6e5-570e-a810-1aea89d7ea63", + "extraction_id": "d9ef944b-b9a5-5b45-aaa6-c48f6fe54893", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "a6a78000-8744-5f89-bcbb-d26781ece651", + "score": 0.6960152387619019, + "metadata": { + "text": "37. Li H, Qi Y , Jasper H.Preventing age-related decline of gut compartmentalization limits micro-\nbiota Dysbiosis and extends lifespan. Cell Host Microbe. 2016;19(2):24053.\n 38. Mihajlovski A, Dor J, Levenez F, Alric M, Brugre J.Molecular evaluation of the human gut \nmethanogenic archaeal microbiota reveals an age-associated increase of the diversity. Environ \nMicrobiol Rep. 2010;2(2):27280.\n 39. Quercia S, Candela M, Giuliani C, Turroni S, Luiselli D, Rampelli S, etal. From lifetime to", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1276, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "307ac6d0-46d2-50e8-a618-d640136d4131", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "39564137-871b-5464-b364-ba63cbf9cc31", + "score": 0.6929019689559937, + "metadata": { + "text": "[26], but at advanced ages, dramatic changes in its composition are associated with \nvarious diseases and frailty [27, 28].\nRegarding pathological processes, it is known that cancer, obesity, diabetes, and \ninflammatory bowel disease (IBD) are associated with specific microbial alterations \n[29, 30]. In older ages, a burden of intrinsic and extrinsic factors affects the compo-\nsition of the microbiome and plays a determining role in every tract and tissue. Such \nmentioned factors can be seen in Fig.9.2.", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1197, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "a0bb2ab8-44b4-5409-814c-22005b259479", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "7a775400-f8f2-5758-af40-b461adc83aa3", + "score": 0.6868119239807129, + "metadata": { + "text": "Osawa R. Age-related changes in gut microbiota composition from\nnewborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90.\n14. Dugue PA, Bassett JK, Joo JE, Jung CH, Ming Wong E, Moreno-Betancur M,\nSchmidt D, Makalic E, Li S, Severi G, et al. DNA methylation-based biological\naging and cancer risk and survival: pooled analysis of seven prospective\nstudies. Int J Cancer. 2018;142(8):1611 9.\n15. Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S. DNA", + "title": "2020 - Blood-based epigenetic estimators.pdf", + "version": "v0", + "chunk_order": 92, + "document_id": "2673299f-21e5-5746-9c33-84b99b373355", + "extraction_id": "062e4ac3-ef28-5bfa-be8c-770757083cfb", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + }, + { + "id": "35f973f6-2ca0-5d89-98b2-8e28a67323c5", + "score": 0.6831619739532471, + "metadata": { + "text": "survival advantage that is age- and site-specific: Results from a large multi-site study. Aging Cell \n18, e12905 (2019). [PubMed: 30801953] \n51. Houtkooper RHet al.The metabolic footprint of aging in mice. Sci. Rep. 1, 134 (2011). [PubMed: \n22355651] \n52. Morrison KE, Jaarevi E, Howard CD & Bale TL Its the fiber, not the fat: significant effects of \ndietary challenge on the gut microbiome. Microbiome 8, 15 (2020). [PubMed: 32046785]", + "title": "2021 - Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.pdf", + "version": "v0", + "chunk_order": 148, + "document_id": "4d082da4-fa48-5170-8147-c4fea47a5d4b", + "extraction_id": "bca61863-81b3-5ef7-850d-10cc9577a9e1", + "associatedQuery": "How do changes in the gut microbiome composition correlate with aging and longevity?" + } + } + ], + "kg_search_results": null + } + } + }, + "15": { + "results": { + "completion": { + "id": "chatcmpl-AIHY3hgOmiQgttq4BdrpX79X5LkzF", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Caloric restriction extends lifespan across various species through several key molecular mechanisms:\n\n1. **Sirtuin Activation**: Caloric restriction may exert some of its effects through the sirtuin family of genes, particularly SIR2, which is known to prolong lifespan in organisms like yeast, worms, and flies [3], [4]. Sirtuins are involved in chromatin regulation and promoting DNA stability, which are crucial for maintaining cellular health and longevity [4].\n\n2. **Insulin-like Signaling Pathways**: In mammals, caloric restriction is thought to modulate aging through the insulin-like signaling pathways. This mechanism is also observed in organisms like C. elegans and Drosophila, where it plays a role in regulating lifespan [6].\n\n3. **Oxidative Stress Reduction**: Caloric restriction is associated with reduced oxidative damage, which is a significant factor in aging. This reduction in oxidative stress is a common mechanism observed across different species [9].\n\n4. **AMPK Activation**: In mammals, caloric restriction has been linked to the activation of AMP-activated protein kinase (AMPK), which plays a role in energy homeostasis and has protective effects on the aged myocardium [10].\n\nThese mechanisms highlight the complex interplay of genetic and metabolic pathways through which caloric restriction can extend lifespan across diverse species.", + "role": "assistant" + } + } + ], + "created": 1728920723, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 270, + "prompt_tokens": 1293, + "total_tokens": 1563 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "b516b1a9-d0f2-5d1e-9015-4799c902770b", + "score": 0.7854373689126187, + "metadata": { + "text": "Metabolism\nStudies show that calorie restriction is the most consistent means to prolong life \nexpectancy and health across several experimental models [55], ranging from yeasts \nto primates. It not only increases life expectancy, but it also delays the onset of many \nfeatures and hallmarks of ageing, including age-related diseases. Transcriptional \nprofiles are currently being applied and investigated. One of them is a caloric restric-", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1732, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "5d1905a8-536e-5efd-a92b-21053093d956", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "6870f741-be38-5d34-aafd-25da39e1ff68", + "score": 0.757936381040108, + "metadata": { + "text": "Keywords: caloric restriction; hepatic expression\nprofiling; lifespan prolongation; metabolic signaling;microarray analysis; nutrition response.\nIntroduction", + "title": "2004 - Linking nutrition to genomics.pdf", + "version": "v0", + "chunk_order": 6, + "document_id": "99891ef7-0589-5c41-a61f-1ab1fe1c8939", + "extraction_id": "b193c536-dc9e-5ea6-9a01-064243a6cbf3", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "c5b37b9a-1ffa-516b-9681-22fecc5aee5b", + "score": 0.7539928330781241, + "metadata": { + "text": "(154, 155).\nCaloric restriction has been shown to sig-\nnicantly increase life span and promote resis-tance to a broad range of age-related pathol-ogy in worms, ies, and mice. Some of theeffects of caloric restriction may be mediatedthrough the sirtuin family of genes, as exem-plied by SIR2, which prolongs life span in", + "title": "2008 - The Aging Brain.pdf", + "version": "v0", + "chunk_order": 158, + "document_id": "874f5d02-35c9-5233-8ded-6e06c7570ca9", + "extraction_id": "f63ffca5-2418-5683-9958-558c46b48def", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "e01c4c58-342d-5369-89e6-98344af55000", + "score": 0.7516640052695279, + "metadata": { + "text": "Calorie restriction, a dietary regimen that extends \nthe lifespan of numerous organisms, also delays the \nmajority of age-related gene-expression changes in \nmice and, to a certain extent, in flies45,50. It is currently \nunclear whether the effect of calorie restriction on gene \nexpression underlies its beneficial effect on lifespan or is merely a consequence thereof. Findings in yeast suggest \nthat there may be a causal link: Sir2 not only facilitates \nheterochromatin and promotes DNA stability, but is", + "title": "2007 - The role of nuclear architecture.pdf", + "version": "v0", + "chunk_order": 76, + "document_id": "578e2f7d-ddd4-56c8-a5b0-670969f8ff1e", + "extraction_id": "9655c555-838e-5cdf-85cf-13736c3cf028", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "b990eb0a-709a-500c-836e-83e202e0d6a6", + "score": 0.7479555829750179, + "metadata": { + "text": "life-span extension by calorie restriction in Saccharomyces cerevisiae. Science\n289:21262128.\nMair W, Goymer P, Pletcher SD, and Partridge L (2003) Demography of dietary\nrestriction and death in Drosophila. Science 301:17311733.\nMasoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev\n126:913922.\nMathers JC (2006) Nutritional modulation of ageing: genomic and epigenetic ap-\nproaches. Mech Ageing Dev 127:584589.\nMeric-Bernstam F and Gonzalez-Angulo AM (2009) Targeting the mTOR signaling", + "title": "2012 - Genome-Environment Interactions That Modulate.pdf", + "version": "v0", + "chunk_order": 214, + "document_id": "b1a1997c-e9df-5dc0-9d12-a3977d0c64ec", + "extraction_id": "5745c701-a549-51c3-adcc-b19c47436740", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "ffe5fc40-f6d4-5066-9e07-424f7b8e3dc9", + "score": 0.7476480229988108, + "metadata": { + "text": "that caloric restriction also regulates mammalian aging, perhaps via the modulationof insulin-like signaling pathways. The nervous system has been implicated as a keytissue where insulin-like signaling and free radical protective pathways regulate lifespan inC. elegans andDrosophila . Genes that determine the life span could act in", + "title": "2001 - The genetics of aging.pdf", + "version": "v0", + "chunk_order": 3, + "document_id": "aa9a9193-b6f3-5ef8-aefd-e01ec44abb46", + "extraction_id": "713d3122-d856-5dbc-a3bf-d8cd836830cb", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "2b081115-d36e-57ec-aedc-2fd9691bc5e9", + "score": 0.7473168595825693, + "metadata": { + "text": "extension by dietary restriction. Annu Rev Biochem 2008,\n77:727-54.\n8. Harper JM, Leathers CW, Austad SN: Does caloric restriction\nextend life iin wild mice? Aging Cell 2006, 5:441-9.\n9. Forster MJ, Morris P, Sohal RS: Genotype and age influence the\neffect of caloric intake on mortality in mice. FASEB J 2003,\n17:690-2.\n10. Spindler SR, Mote PL: Screening candidate longevity therapeu-\ntics using gene-e xpression arrays. Gerontology 2007, 53:306-21.", + "title": "2009 - Genes and gene expression modules associated with caloric.pdf", + "version": "v0", + "chunk_order": 276, + "document_id": "893ba204-2e69-563f-9046-7246ca61494f", + "extraction_id": "0b45ae60-562c-5e48-a1c1-9eb29614a63c", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "03196bec-4ae2-5408-b90c-12dcb38e5831", + "score": 0.742712237158056, + "metadata": { + "text": "Corton JC, Apte U, Anderson SP, Limaye P, Yoon L. Mimetics of caloric restriction include agonists\nof lipid-activated nuclear receptors. J Biol Chem 2004;279:4620446212. [PubMed: 15302862]\nFerguson M, Sohal BH, Forster MJ, Sohal RS. Effect of long-term caloric restriction on oxygen\nconsumption and body temperature in two different strains of mice. Mech Ageing Dev\n2007;128:539545. [PubMed: 17822741]\nForster MJ, Morris P, Sohal RS. Genotype and age influence the effect of caloric intake on mortality in", + "title": "2010 - Genetic Dissection of Dietary Restriction in Mice Supports the Metabolic Efficiency Model of Life Extension.pdf", + "version": "v0", + "chunk_order": 130, + "document_id": "92419d8a-27ed-5142-8a87-189c1ba5459b", + "extraction_id": "da7abebd-f7c0-5b9c-b0f2-e29871326855", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "2cf68c41-aa60-5dca-8aa1-04bc0d7a4db3", + "score": 0.7404902798083511, + "metadata": { + "text": "A key question still unresolved is to what extent the\nmechanisms of aging are conserved between species with\nvastly different lifespans. Some studies suggest that similar\nmechanisms are involved in aging in many species. Forexample, caloric restriction extends lifespan in yeast, worms,ies, mice, and primates (Weindruch 2003). Additionally,signaling through the insulin-like growth factor pathway,chromatin regulation by sir2,and oxidative damage have each", + "title": "2004 - A Transcriptional Profile of Aging.pdf", + "version": "v0", + "chunk_order": 11, + "document_id": "4ab656a7-9656-526b-94e1-422875409b44", + "extraction_id": "b382fe8a-0267-5515-ac4b-07be55420040", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + }, + { + "id": "51a448cf-6015-53f7-a949-f247b71efcef", + "score": 0.7371145706508929, + "metadata": { + "text": "10.1111/acel.12103\n 241. Edwards AG, Donato AJ, Lesniewski LA, Gioscia RA, Seals DR, Moore \nRL. Life-long caloric restriction elicits pronounced protection of the \naged myocardium: a role for AMPK. Mech Ageing Dev. 2010;131:739\n742. doi: 10.1016/j.mad.2010.09.007\n 242. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch \nR, Anderson RM. Caloric restriction reduces age-related and all-\ncause mortality in rhesus monkeys. Nat Commun. 2014;5:3557. doi: \n10.1038/ncomms4557", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 303, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "fddca610-97a6-5f2c-88b4-dc6e96c60cf3", + "associatedQuery": "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?" + } + } + ], + "kg_search_results": null + } + } + }, + "16": { + "results": { + "completion": { + "id": "chatcmpl-AIHY9RBdJPzHPCH0uE5dG6bbj0z6D", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Oxidative stress contributes to cellular aging through the accumulation of oxidative damage in various macromolecules, which leads to a decline in cellular function. This process occurs due to an imbalance between prooxidants and antioxidants, resulting in a steady-state accumulation of oxidative damage that increases with age [1]. The oxidative stress theory of aging posits that damage caused by reactive oxygen species (ROS) plays a critical role in determining lifespan, as it leads to the deterioration of biochemical and physiological processes [4]. \n\nOxidative damage affects all cellular macromolecules, including lipids, proteins, and DNA, and this damage increases with age [3]. The accumulation of such damage is a key hallmark of aging physiology [5]. Specifically, oxidative damage to mitochondrial DNA (mtDNA) and the generation of ROS from the mitochondrial electron transport chain are significant contributors to this process [6]. \n\nOverall, the accumulation of oxidative damage is causally linked to aging and death, as it impairs cellular processes and bioenergetics, leading to the progressive loss of functional efficiency in cells [2], [8].", + "role": "assistant" + } + } + ], + "created": 1728920729, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_e5e4913e83", + "usage": { + "completion_tokens": 220, + "prompt_tokens": 1147, + "total_tokens": 1367 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "b39d86ef-3c6a-561f-b8eb-f90ac124c12c", + "score": 0.7463477405102421, + "metadata": { + "text": "under normal physiological conditions because of an imbal-ance between prooxidants and antioxidants. The imbalanceleads to a steady-state accumulation of oxidative damage in avariety of macromolecules t hat increases during aging,\nresulting in a progressive loss in the functional efficiency ofvarious cellular processes. In a recent review, Beckman andAmes made a useful addition to this debate by dividing the", + "title": "2007 - Trends in oxidative aging theories.pdf", + "version": "v0", + "chunk_order": 22, + "document_id": "0d752c1a-706a-5b9e-88ef-ba7c51735c3c", + "extraction_id": "9994d4e6-e53d-5381-af9c-e811afe7a802", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "091ca29b-5c85-5d0d-8fbb-e829bb71bd0c", + "score": 0.7439146194508912, + "metadata": { + "text": "tributing to impaired bioenergetics in aged cells include oxida-tion/nitration of mitochondrial proteins, destabilization of the macromolecular organization of electron transport chain com-plexes, and impaired mitophagy (a mitochondria-specific form of autophagy). The combination of increased mitochondrial \nFigure 2. Proposed scheme for mechanisms and pathological consequences of age-related oxidative stress in vascular endothelial cells. The", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 43, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "6dcd5550-7f8d-5668-bb82-b6040cbf1e61", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "69365543-2760-5376-8e90-9a922a9759a7", + "score": 0.7431315932791489, + "metadata": { + "text": "over the years to become the oxidative stress theory of aging, but the principle is the same, inthat the accumulation of oxidative damage drives aging. In support of this theory, a large body\nof literature indicates that oxidative damage to all cellular macromolecules increases with age.\nFurthermore, overexpression of antioxidant enzymes that detoxify ROS, such as copper- andzinc-containing superoxide dismutase (SOD), manganese-containing SOD, or catalase, increase", + "title": "2018 - Nuclear Genomic Instability.pdf", + "version": "v0", + "chunk_order": 47, + "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36", + "extraction_id": "b934a2a9-a672-5d65-9d0d-bbc36652a148", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "9713b3c5-cd67-57d1-8c17-b3a4db7f911f", + "score": 0.7227561804346824, + "metadata": { + "text": "predicted from the oxidative stress theory of aging. Thistheory,whichisbasedonthetenetthatdamagecausedbyROSplays a critical role in determining life span, has been one ofthe most popular theories to explain the deterioration in bio-chemical and physiological processes that occur during theaging process. A large number of studies have producedcorrelative data in support of this theory, e.g., an increase inoxidativedamagetolipid,protein,andDNAwithagehasbeendemonstrated in a variety of tissues and organisms", + "title": "2003 - Life-long reduction in MnSOD activity results.pdf", + "version": "v0", + "chunk_order": 80, + "document_id": "0cef9dec-dbbe-5b5d-bb43-1a21a601fde2", + "extraction_id": "f0a1875a-9969-598b-a670-e6f61bf11898", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "4bab1bd2-05a4-5c8e-897d-e456be8c8998", + "score": 0.7122546434402517, + "metadata": { + "text": "during\tthe\taging\tprocess\t(Yi,\tChang,\t&\tShong,\t2018).\tOxidative\tdam -\nage to cellular macromolecules, or stress arising from mitochondrial DNA\t(mtDNA)\tmutation\tand\tincreased\treactive\toxygen\tspecies\t\n(ROS),\tis\ta\tkey\thallmark\tof\taging\tphysiology\t(Yi\tet\tal.,\t2018).\tAlthough", + "title": "2020 - Growth differentiation factor 15 protects against the aging\u2010mediated systemic inflammatory response in humans and mice.pdf", + "version": "v0", + "chunk_order": 11, + "document_id": "0ceff9cf-2b2b-5fe8-b844-f3f8ee7704ad", + "extraction_id": "cebd8a1c-01ea-5c43-a2f1-96ea3c304259", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "d99e64c1-2fe1-50c5-8a75-a2390ed0eac0", + "score": 0.7102594721007977, + "metadata": { + "text": "radical theory of aging, which argues that oxidative damageplays a key role in senescence. Among the numerousmechanisms known to generate oxidants, leakage of super-oxide anion and hydrogen peroxide from the mitochondrialelectron transport chain are the chief candidates. Increased\ndamage to mtDNA could exacerbate this leakage of reactive\noxygen species (ROS) (4).\nIt is not known how mtDNA deletions accumulate during", + "title": "2002 - Human mitochondrial DNA with large deletions.pdf", + "version": "v0", + "chunk_order": 6, + "document_id": "35de1e32-95eb-5b1d-acf9-2c37ea1cc3c4", + "extraction_id": "14f137b3-20cf-5b34-a3dd-4b550a3dec92", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "0f1d7692-a2c0-5def-9545-c2c16019536e", + "score": 0.7093930417661058, + "metadata": { + "text": "most plausible explanation for aging. But, as we have discussed, not all types of damage contribute equally to aging. From this point of view, it seems that ROS generated by complex I (at sulfur iron clusters or flavin sites) may damage specific targets that can alter homeosta -\nsis in a significant enough way to influ -\nence aging. The most obvious target for this damage is mtDNA. The generation of ROS specifically by complex I corre -\nlates with levels of oxidative damage in mtDNA.", + "title": "2011 - Mitochondrial complex I.pdf", + "version": "v0", + "chunk_order": 37, + "document_id": "6943c112-611d-5108-9d0f-d52c1138871b", + "extraction_id": "c195a6a2-d6a9-53f3-a0dd-abe76ae29588", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "fec5b83b-cd2c-51ea-83c9-45efdcbff83d", + "score": 0.7084904486840709, + "metadata": { + "text": "increase lifespan also confer resistance to oxidative stress (1).This finding supports the free-radical hypothesis of aging, whichsuggests that reactive oxygen species that accumulate withincreasing age cause oxidative damage to macromolecules (in-cluding nucleic acids, proteins, and lipids) and are causally linkedto aging and death (8, 9). Free radicals have been found toregulate the expression of a number of genes that includeantioxidant defense genes involved in repairing oxidative dam-age, as well as", + "title": "2000 - Genome-wide study of aging and oxidative stress.pdf", + "version": "v0", + "chunk_order": 5, + "document_id": "3fc2266c-d677-54f9-b3a2-5129eedf214a", + "extraction_id": "ac5d00c0-f445-5c6a-b248-12c82c985d9a", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "cbfc2dc4-99ae-5177-955f-4bc243689419", + "score": 0.7079625899814028, + "metadata": { + "text": "Molecular Biomarkers forOxidative Stress\nThere are many theories that try to explain the nature of aging; however, none of \nthem can explain every aspect of the biology of aging. One of the most accepted and \nstudied is the one proposed by Denham Harman in 1956. This theory proposed that \nduring lifespan organisms accumulate oxidative damage in their biomolecules. \nOxidative damage is generated by reactive oxygen species (ROS), which are the", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 811, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "7f1594a3-120c-5982-aa4d-babd6ab70265", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + }, + { + "id": "6d58996a-1250-5eaa-bc6f-bd1057ccca88", + "score": 0.7078255589112319, + "metadata": { + "text": "production by mitochondria and increased 8-oxo-dG con-tent in the mtDNA are frequently detected in aged tissues\n[40,4750], suggesting that progressive accumulation of\noxidative DNA damage is a contributory factor to the agingprocess. Consistently, many studies have found that increasedoxidative damage in cells is associated with aging [ 5153].\nFurthermore, genetic studies in worm, y, and mouse havelinked enhanced stress resistance or reduced free radical", + "title": "2012 - Oxidative Stress, Mitochondrial Dysfunction, and Aging.pdf", + "version": "v0", + "chunk_order": 16, + "document_id": "24277eba-69dd-5e12-9aa4-bbb6f0a88f52", + "extraction_id": "32c4c0b2-d44c-5121-8975-196040fb2a1d", + "associatedQuery": "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?" + } + } + ], + "kg_search_results": null + } + } + }, + "17": { + "results": { + "completion": { + "id": "chatcmpl-AIHYGBcI0VJ8rQxINM8Z5Fqy6gz6y", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Extracellular matrix (ECM) remodeling and tissue stiffness are significant factors in the aging process. As we age, several changes occur in the ECM that contribute to increased tissue stiffness. These changes include decreased elastin synthesis, elastin degradation and fragmentation, and alterations in the cross-linking of ECM components, such as increased presence of advanced glycation end products (AGEs) [1]. AGEs can interfere with collagenolysis by forming cross-links that confer resistance to enzymatic degradation, thereby contributing to increased arterial stiffness [2].\n\nAdditionally, the activity of transforming growth factor-beta (TGF-\u03b2) increases with age, stimulating the synthesis of interstitial collagen by vascular smooth muscle cells (VSMCs), which further augments arterial stiffness [2]. The renin-angiotensin-aldosterone system (RAAS) also plays a role in this process by augmenting collagen synthesis and promoting elastolysis [2].\n\nThe ECM is crucial for providing mechanical scaffolding and mediating biomechanical and biochemical signals necessary for tissue homeostasis and cell differentiation [4]. However, with aging, ECM stiffness increases, affecting various organs, including the larynx [6]. This increased stiffness is associated with a decline in tissue health, as seen with the accumulation of damage in long-lived proteins like collagens, which become resistant to proteolysis and affect their turnover [8].\n\nOverall, these changes in ECM remodeling and tissue stiffness contribute to the aging process by affecting vascular and tissue elasticity, leading to conditions such as arterial stiffening and vascular remodeling [1], [3], [9].", + "role": "assistant" + } + } + ], + "created": 1728920736, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 320, + "prompt_tokens": 1293, + "total_tokens": 1613 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "9f768c0d-8518-5ac9-9d66-9ffdba704a84", + "score": 0.7314896045466908, + "metadata": { + "text": "208 Additional features that contribute to increased ar -\nterial stiffness include decreased elastin synthesis, elastin degradation and fragmentation, elastin calcification, al-terations in cross-linking of extracellular matrix compo-nents (eg, by increased presence of advanced glycation end products).\n208,210,211\nThe pathophysiological consequences of age-related \nECM remodeling and arterial stiffening have been the sub-ject of a recent comprehensive review by AlGhatrif and Lakatta.", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 139, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "4b0673e0-fb5e-5212-ba68-417de0e867b7", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "e7f8f5f2-9102-56bf-b579-43ad3c8d6b84", + "score": 0.7306935408918128, + "metadata": { + "text": "collagen. AGE-mediated cross-links can confer resis-tance to enzymatic degradation, and thus interferewith collagenolysis (56). In addition, increased ac-\ntivity of TGF-\nbwith aging stimulates the synthesis of\ninterstitial collagen by vascular smooth muscle cells(VSMCs), and thereby augments arterial stiffness (57).\nLikewise, increased activity of the RAAS may\naugment collagen synthesis and heighten elastolysis\n(58).\nEndothelial dysfunction and arterial stiffness are", + "title": "2017 - The Aging Cardiovascular System.pdf", + "version": "v0", + "chunk_order": 40, + "document_id": "d3ff8471-986b-5fa0-b9c4-96eaaa8fce7c", + "extraction_id": "d60f1e7d-cde2-5c66-8863-507065ed5c7f", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "b7cd7044-b2fe-5dd2-b7b4-6388b9f4765d", + "score": 0.708830931519543, + "metadata": { + "text": "that many of these age-related ECM alterations are governed by circulating factors and factors produced in the vascular wall, including the extended renin-angiotensin-aldosterone system (see above) and an age-related decline in circulating IGF-1.\n209\nCollagen synthesis is also dysregulated with age in the \nvascular wall likely because of the effects of increased para-crine action of TGF- (transforming growth factor- ),\n123 \nwhich contributes to vascular fibrosis and arterial stiffen-ing.", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 138, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "4b0673e0-fb5e-5212-ba68-417de0e867b7", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "ab8d8d0e-f91a-538a-bd84-beafa1fe8ce8", + "score": 0.7016867190096788, + "metadata": { + "text": "Ungvari et al Mechanisms of Vascular Aging 859\nRole of Extracellular Matrix Remodeling in \nVascular Aging\nThe extracellular matrix (ECM) is an important contribu-\ntor to health and longevity. This noncellular compartment, ubiquitous to all tissues and organs does not only provide es-sential mechanical scaffolding but mediates highly dynamic \nbiomechanical and biochemical signals required for tissue \nhomeostasis, morphogenesis, and cell differentiation. Studies", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 133, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "4b0673e0-fb5e-5212-ba68-417de0e867b7", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "e7121d85-7538-5cdd-8b2d-6d3d536439b9", + "score": 0.688574077657528, + "metadata": { + "text": "1996;25(3):20915.\n 79. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in \ndevelopment and disease. Nat Rev Mol Cell Biol. 2014;15(12):786801.\n 80. Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PCDP , Pinter J, et al. \nNuclear Lamin-A scales with tissue stiffness and enhances matrix-\ndirected differentiation. Science. 2013;341(6149):1240104.\n 81. Vogel C, Marcotte EM. Insights into the regulation of protein abun-\ndance from proteomic and transcriptomic analyses. Nat Rev Genet.", + "title": "2022 - Proteomic analysis reveals that aging rabbit.pdf", + "version": "v0", + "chunk_order": 189, + "document_id": "f6c524a5-acf9-5a07-8bbf-31091443cab3", + "extraction_id": "a099ce3c-cdff-5971-b3d5-f31e03aace96", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "cf5f0034-c806-52d6-bd26-137fb9d8a418", + "score": 0.686365228078677, + "metadata": { + "text": "result in extracellular matrix stiffness in aging larynx and \nother organs [59, 79]. Finally, Lamin A was upregulated \nby dehydration, by a smaller magnitude, especially when \nobserving the mean difference within the young groups. \nPrevious data has identified that Lamin proteins A and \nC are important for imparting the nucleus with its stiff -\nness, and their expression has been reported to scale with", + "title": "2022 - Proteomic analysis reveals that aging rabbit.pdf", + "version": "v0", + "chunk_order": 95, + "document_id": "f6c524a5-acf9-5a07-8bbf-31091443cab3", + "extraction_id": "c738a4b2-0aea-5157-bed4-fecdac9863b9", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "58e94400-b0f0-5757-b964-83a6b2b6f98f", + "score": 0.6824693287154835, + "metadata": { + "text": "aging. Annu Rev Biomed Eng. 2015;17:113141. doi: 10.1146/ \nannurev-bioeng-071114-040829\n 208. Jacob MP. Extracellular matrix remodeling and matrix metalloprotein-\nases in the vascular wall during aging and in pathological conditions. \nBiomed Pharmacother. 2003;57:195202.\n 209. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop \nGA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, \nUngvari Z. Insulin-like growth factor 1 deficiency exacerbates hyperten-", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 284, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "e91c9a2a-a797-59d5-8565-91b45b0113a1", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "4dfd7818-9111-5bf9-bbcf-e917b1c9b9fc", + "score": 0.6723205452251925, + "metadata": { + "text": "able human diseases such as osteoporosis and musculo-\nskeletal diseases [53]. Collagens are long-lived proteins\nknown to accumulate damage during aging, leading to a\ndecline in tissue health [54]. Also, type I collagens be-\ncome resistant to proteolysis upon age [55, 56], affecting\ntheir turnover. Interestingly, mice expressing cleavage-\nresistant type I collagen go through an accelerated aging\nprocess [57]. Thus, cellular aging can be affected by the\nstate of the extracellular matrix in mammals.", + "title": "2016 - The genome-wide role of HSF-1.pdf", + "version": "v0", + "chunk_order": 122, + "document_id": "e3c48474-21da-51d2-b378-200138fda0d3", + "extraction_id": "b2c1c466-d4b3-5c01-a8a4-2f49e9f246a2", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "d5cd4d54-b051-5638-ba76-39c385f3e423", + "score": 0.6651890875230129, + "metadata": { + "text": "the characteristics of endothelial dysfunction and pheno-\ntypic transition of smooth muscle cells, resulting in in-\ncreased vascular stiffness and increased thickness of\nvascular walls. It has been reported that the age-\nassociated phenotypic transition of VSMCs is a crucial\ncontributor to vascular remodeling [ 17,25]. However,\nthe mechanism that drives phenotypic transition ofVSMCs with aging remains unclarified. In this study,\nusing RNAs extracted from the in vitro cultured VSMCs,", + "title": "2019 - Downregulation of miR-542-3p promotes.pdf", + "version": "v0", + "chunk_order": 45, + "document_id": "527e562f-f7c3-5a01-b70b-5737d63e2457", + "extraction_id": "32322971-f8f4-53d3-8104-ac44cf03ebef", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + }, + { + "id": "479ae037-3dd5-57f7-9bf7-78a3a45ac47f", + "score": 0.6571096377703443, + "metadata": { + "text": "downregulation with aging of genes involved in the synthesisof the ECM and in particular of different forms of collagen(Table 2). In addition, aging males but not females showed adecrease in collagen type III. Interestingly, collagen type IIIdecreases the size of collagen bundles and thereby increasesvascular elasticity (11). Therefore, a decreased expression ofcollagen type III can participate in the increased stiffness thatcharacterizes the aging aorta (23). An interesting observationfrom our study that", + "title": "2007 - Sex-specific regulation of gene expression in the aging monkey aorta.pdf", + "version": "v0", + "chunk_order": 100, + "document_id": "6c2a7135-31ed-57e3-89fa-42856979ea1a", + "extraction_id": "1d889462-37d6-5cb5-b0df-8ae9c50560b7", + "associatedQuery": "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?" + } + } + ], + "kg_search_results": null + } + } + }, + "18": { + "results": { + "completion": { + "id": "chatcmpl-AIHYO1XLJbUnaqsOWyFh9a97rwIzB", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Recent developments in autophagy research have significantly enhanced our understanding of its role in aging and longevity. Here are some key contributions:\n\n1. **Energy Metabolism and Lifespan Extension**: Research has shown that the depletion of acetyl-coenzyme A, an energy metabolite, can stimulate autophagy and prolong lifespan. This suggests that autophagy is closely linked to energy metabolism and can be a mechanism for extending lifespan [1].\n\n2. **Autophagy as an Anti-Aging Mechanism**: Autophagy is increasingly recognized as an emerging anti-aging mechanism. It plays a crucial role in maintaining cellular homeostasis by degrading and recycling damaged cellular components, which is essential for longevity [1].\n\n3. **Genetic Regulation and Dietary Restriction**: Studies have identified autophagy genes as important for lifespan extension, particularly in the context of dietary restriction. This indicates that genetic regulation of autophagy is a key factor in promoting longevity [2].\n\n4. **Pharmacological Activation**: There is evidence that pharmacological activation of autophagy can increase lifespan in animal models, including mice. This highlights the potential for therapeutic interventions targeting autophagy to promote healthy aging [3].\n\n5. **Impaired Autophagy and Cellular Aging**: Impaired autophagy is considered a principal determinant of cellular aging. The decline in autophagy with age is linked to various age-related diseases, emphasizing the importance of maintaining autophagic activity for longevity [4].\n\n6. **Spermidine and Longevity**: The induction of autophagy by compounds like spermidine has been shown to promote longevity, further supporting the role of autophagy in extending lifespan [7].\n\nThese findings collectively underscore the critical role of autophagy in aging and longevity, suggesting that enhancing autophagic processes could be a viable strategy for promoting healthy aging and extending lifespan.", + "role": "assistant" + } + } + ], + "created": 1728920744, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_a20a4ee344", + "usage": { + "completion_tokens": 381, + "prompt_tokens": 1775, + "total_tokens": 2156 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "603183d9-d22c-5008-bfa5-147ee5df4198", + "score": 0.7353694438934378, + "metadata": { + "text": "D. Carmona-Gutierrez, C. Ruckenstuhl, J. Ring, W. Reichelt, K. Schimmel, T. Leeb,C. Moser, S. Schatz, L.-P. Kamolz, C. Magnes, F. Sinner, S. Sedej, K.-U. Frhlich,G. Juhasz, T. R. Pieber, J. Dengjel, S. J. Sigrist, G. Kroemer, F. Madeo, Nucleocytosolic de-pletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs\nlifespan. Cell Metab. 19, 431 444 (2014).\n225. S. Gelino, M. Hansen, Autophagy An emerging anti-aging mechanism. J. Clin. Exp. Pathol.\n(Suppl. 4), pii: 006 (2012).", + "title": "2016 - Epigenetics and aging.pdf", + "version": "v0", + "chunk_order": 339, + "document_id": "71b206ec-81bd-5194-8b21-ae522f8cbc2d", + "extraction_id": "9b7b806c-cac3-549e-9ae9-424cc3e5f869", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "a6d18c4e-632c-52a2-b3f9-6296025e0ce7", + "score": 0.7156161835422419, + "metadata": { + "text": "[73] Vellai, T. Autophagy genes and ageing . Cell Death Differ. , 2009 , \n16(1), 94-102. \n[74] Kaeberlein, M.; Kapahi, P. Cell signaling. Aging is RSKy business . \nScience , 2009 , 326(5949), 55-6. \n[75] Hansen, M.; Chandra, A.; Mitic, L.L.; Onken, B.; Driscoll, M.; \nKenyon, C. A role for autophagy genes in the extension of lifespan \nby dietary restriction in C. elegans. PLoS Genet. , 2008 . \n[76] Hansen, M.; Taubert, S.; Crawford, D.; Libina, N.; Lee, S.J.;", + "title": "2012 - Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans.pdf", + "version": "v0", + "chunk_order": 149, + "document_id": "7589fec2-e893-5a4d-9f0c-09abb35858ab", + "extraction_id": "f160f818-03bf-5b4e-b1f4-bfbd3b0bfb99", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "d43449f1-2d90-5e0e-8ba8-8afdc306f32d", + "score": 0.7129322632631941, + "metadata": { + "text": "chinery and upstream regulators provide evidence for\na transcriptional decline in autophagy gene expression\nwith age in human monocytes. The identification of\nkey genes contributing to a decline in autophagy are\nof great interest, as pharmacologic activation of au-\ntophagy has been linked with increasing lifespan in\nanimal models, including mice [45]. Further, dysfunc-\ntional autophagy is now widely implicated in patho-\nphysiological processes of many age-related diseases", + "title": "2015 - Transcriptomic profiles of aging in purified.pdf", + "version": "v0", + "chunk_order": 47, + "document_id": "50f357a3-e0f2-5e32-a6b2-771fb4b1e1c6", + "extraction_id": "a972e2fb-b73f-51bf-980a-85c9db1482be", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "ca8ae9e1-f598-56b9-952e-bb5bea62d8fe", + "score": 0.7100938346954065, + "metadata": { + "text": "invasive pathogens, and to transport these cargos to the\nlysosomes for degradation [25]. In the aging field, im-\npaired autophagy is considered one of the principal de-\nterminants of cellular aging, which is supported by\nin vitro and animal study findings that autophagy de-\nclines with age [26]. However, studies of autophagy and\nage in humans are sparse.\nOne of the most significant age-gene expression asso-\nciations we observed in monocytes from 1,264 individ-", + "title": "2015 - Transcriptomic profiles of aging in purified.pdf", + "version": "v0", + "chunk_order": 37, + "document_id": "50f357a3-e0f2-5e32-a6b2-771fb4b1e1c6", + "extraction_id": "a972e2fb-b73f-51bf-980a-85c9db1482be", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "581ca468-d3f3-5846-9fba-7f1f860df956", + "score": 0.7099761539711873, + "metadata": { + "text": "226. F. Madeo, N. Tavernarakis, G. Kroemer, Can autophagy promote longevity? Nat. Cell Biol.\n12, 842 846 (2010).\n227. J. Fllgrabe, M. A. Lynch-Day, N. Heldring, W. Li, R. B. Struijk, Q. Ma, O. Hermanson,\nM. G. Rosenfeld, D. J. Klionsky, B. Joseph, The histone H4 lysine 16 acetyltransferase\nhMOF regulates the outcome of autophagy. Nature 500, 468 471 (2013).\n228. F. Ng, B. L. Tang, Sirtuins modulation of autophagy. J. Cell. Physiol. 228, 2262 2270 (2013).", + "title": "2016 - Epigenetics and aging.pdf", + "version": "v0", + "chunk_order": 340, + "document_id": "71b206ec-81bd-5194-8b21-ae522f8cbc2d", + "extraction_id": "9b7b806c-cac3-549e-9ae9-424cc3e5f869", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "a2effd64-3d9d-5bdf-8fc6-0cd72762763d", + "score": 0.7057594411659907, + "metadata": { + "text": "(2013) The hallmarks of aging. Cell 153(6):11941217. doi: 10.\n1016/j.cell.2013.05.039\n3. Vellai T, Takacs-Vellai K, Sass M, Klionsky DJ (2009) The\nregulation of aging: does autophagy underlie longevity? TrendsCell Biol 19(10):487494. doi: 10.1016/j.tcb.2009.07.007\n4. Kirkwood TB (2008) A systematic look at an old problem. Nature\n451(7179):644647. doi: 10.1038/451644a\n5. Koubova J, Guarente L (2003) How does calorie restriction\nwork? Genes Dev 17(3):313321. doi: 10.1101/gad.1052903", + "title": "2015 - The mechanism of ageing primary role of transposable elements.pdf", + "version": "v0", + "chunk_order": 60, + "document_id": "de558db9-dc04-5bbd-83bf-3e3368ff906b", + "extraction_id": "20245b79-fa8f-52fc-832e-1478a080d6e1", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "f82ef429-c823-5173-a93b-5c476df110f5", + "score": 0.6964636625967239, + "metadata": { + "text": "Eisenberg, T., Knauer, H., Schauer, A., Bu ttner, S., Ruckenstuhl, C., Carmona-\nGutierrez, D., Ring, J., Schroeder, S., Magnes, C., Antonacci, L., et al. (2009).Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11,\n13051314.\nEnns, L.C., Morton, J.F., Treuting, P.R., Emond, M.J., Wolf, N.S., Dai, D.F.,\nMcKnight, G.S., Rabinovitch, P.S., and Ladiges, W.C. (2009). Disruption of\nprotein kinase A in mice enhances healthy aging. PLoS ONE 4, e5963.", + "title": "2012 - Replicative and Chronological Aging.pdf", + "version": "v0", + "chunk_order": 168, + "document_id": "496e387e-4278-5f74-8ecc-4edc1cee7dfe", + "extraction_id": "8bc194af-6e9d-51c5-8116-6d4186a885dd", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "949f7420-bfb6-564d-8537-18c47e40bbc6", + "score": 0.6928066794391478, + "metadata": { + "text": "its essential part in the anti-aging mechanism of caloric restriction.\nAnn N Y Acad Sci. 2007;1114:69 78.\n41. Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A.\nAutophagy and aging: the importance of maintaining clean cells.\nAutophagy. 2005;1:131 40.\n42. Terman A. The effect of age on formation and elimination of autophagic\nvacuoles in mouse hepatocytes. Gerontology. 1995;41 Suppl 2:319 26.\n43. Donati A, Recchia G, Cavallini G, Bergamini E. Effect of aging and anti-aging", + "title": "2015 - Transcriptomic profiles of aging in purified.pdf", + "version": "v0", + "chunk_order": 169, + "document_id": "50f357a3-e0f2-5e32-a6b2-771fb4b1e1c6", + "extraction_id": "e5fd1ff0-8df5-577f-9f2d-31b0941d5ce5", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "8ede28e5-ed8e-5c68-bd03-18c3c96bb31b", + "score": 0.6868521757810023, + "metadata": { + "text": "103 Experimental findings showing increased oxidative \nstress, impaired bioavailability of NO, and upregulation of in-flammatory mediators in autophagy-deficient endothelial cells \nsupport this view.\n104 Further, pharmacological interventions \nthat stimulate autophagy (eg, trehalose or spermidine treat-ment) were reported to reverse aspects of arterial aging.\n105,106 \nProteasomes degrade unneeded or damaged proteins by pro-teolysis. There is evidence that proteasome activity declines in \nadvanced aging", + "title": "2018 - Mechanisms of Vascular Aging.pdf", + "version": "v0", + "chunk_order": 72, + "document_id": "659b84b6-63dd-5bb1-80ee-7478ed3c47e3", + "extraction_id": "0d4cd402-e032-5edd-98eb-170357a3092e", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + }, + { + "id": "82060e66-87b7-5ac2-9877-fc7b26325b73", + "score": 0.6832387040115188, + "metadata": { + "text": "Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects\nenergy sensing to mitophagy. Science. 2011;331:456 61.\n38. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, et al.\nStructure of mammalian AMPK and its regulation by ADP. Nature.\n2011;472:230 3.\n39. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al.\nEndogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190:881 92.\n40. Bergamini E, Cavallini G, Donati A, Gori Z. The role of autophagy in aging:", + "title": "2015 - Transcriptomic profiles of aging in purified.pdf", + "version": "v0", + "chunk_order": 168, + "document_id": "50f357a3-e0f2-5e32-a6b2-771fb4b1e1c6", + "extraction_id": "e5fd1ff0-8df5-577f-9f2d-31b0941d5ce5", + "associatedQuery": "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?" + } + } + ], + "kg_search_results": null + } + } + }, + "19": { + "results": { + "completion": { + "id": "chatcmpl-AIHYWWczI6kl71Lbbg4Wx4xLfOmE6", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "Age-related shifts in stem cell niche composition and function have significant implications for tissue regeneration capacity. As individuals age, the stem cell niche, which is crucial for maintaining stem cell function, undergoes changes that can adversely affect the regenerative potential of stem cells. Here are some key implications based on the provided context:\n\n1. **Deterioration of the Stem Cell Niche**: The aging process leads to the deterioration of the stem cell niche, which can result in a failure to support the balance between stem cell self-renewal and differentiation. This is evident in the spermatogonial stem cell niche, which deteriorates with age, affecting its ability to maintain stem cell function [1].\n\n2. **Functional Impairments of Stem Cells**: The regenerative potential diminishes with age due to functional impairments in adult stem cells. This is linked to the phenomenon of replicative senescence, where cells lose their ability to proliferate after a certain number of divisions [3].\n\n3. **Changes in Gene Expression**: Age-related changes in gene expression have been observed in stem cells, such as mesenchymal stem cells (MSCs) and hematopoietic progenitor cells (HPCs). These changes can lead to declines in stem cell function and, consequently, a reduction in tissue regeneration capacity [6].\n\n4. **Loss of Stem Cell Pool Division Potential**: Aging is associated with a loss of stem cell pool division potential, which directly impacts the regenerative capacity of tissues. This loss can also indirectly affect adult stem and progenitor cells by altering the tissue microenvironment essential for stem cell support [8].\n\n5. **Reduction in Stem Cell Numbers**: There is evidence of a decline in the number of MSCs in the bone marrow with age, which can further hinder the ability of these cells to participate in tissue regeneration processes such as osteogenesis and chondrogenesis [10].\n\nOverall, these age-related shifts in stem cell niche composition and function contribute to a decline in the body's ability to repair and regenerate tissues, which is a hallmark of aging and is linked to various degenerative conditions [9].", + "role": "assistant" + } + } + ], + "created": 1728920752, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 426, + "prompt_tokens": 1208, + "total_tokens": 1634 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "cade861a-f60d-51fd-bfac-edce8860b395", + "score": 0.7382577061653137, + "metadata": { + "text": "into old versus young recipients (Liang et al., 2005 ). Further experiments demonstrated that the muscle stem cell niche adversely effects stem cell function as evidenced by the restoration of old stem cell regenerative potential upon expos ure to a young systemic microenvironment (Conboy et al., 2005; Conboy and Rando, 2005). It has also been reported that the spermatogoni al stem cell niche deteriorates with age, causing the failure to suppor t an appropriate balance between stem cell self-renewal and", + "title": "2008 - GENETIC REGULATION OF HEMATOPOIETIC STEM CELL AGING (3).pdf", + "version": "v0", + "chunk_order": 71, + "document_id": "7412a162-ee3b-5f09-9886-8e9172dd3ee8", + "extraction_id": "fca849bb-6e08-5200-8c66-5250e902dca3", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "7fcd630b-0f09-5947-8a28-f72d4418d8f8", + "score": 0.723791198504497, + "metadata": { + "text": "matopoietic stem cells is regulated by the stemcell niche. Exp Gerontol. 2008;43(11):974-980.\n18. Geiger H, Rudolph KL. Aging in the lympho-\nhematopoietic stem cell compartment. Trends\nImmunol. 2009;30(7):360-365.\n19. Muller-Sieburg C, Sieburg HB. Stem cell aging:\nsurvival of the laziest? Cell Cycle. 2008;7(24):\n3798-3804.\n20. Beerman I, Maloney WJ, Weissmann IL,\nRossi DJ. Stem cells and the aging hematopoieticsystem. Curr Opin Immunol. 2010;22(4):500-506.\n21. Teschendorff AE, Menon U, Gentry-Maharaj A,", + "title": "2011 - Genome-wide promoter DNA methylation dynamics of human hematopoietic.pdf", + "version": "v0", + "chunk_order": 95, + "document_id": "30081f4e-7189-5c9f-abf2-895250c0173e", + "extraction_id": "3be2a7fa-1d97-5280-ba37-cc3d311cfb75", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "8f53ce05-7527-52f2-8a25-9c3ee9a38861", + "score": 0.7134526968002319, + "metadata": { + "text": "Abstract\nThe regenerative potential diminishes with age and this has been ascribed to functional impairments of adult stem cells.\nCells in culture undergo senescence after a certain number of cell divisions whereby the cells enlarge and finally stop\nproliferation. This observation of replicative senescence has been extrapolated to somatic stem cells in vivo and might", + "title": "2009 - Aging and Replicative Senescence Have Related Effects.pdf", + "version": "v0", + "chunk_order": 2, + "document_id": "0703ba80-b7a5-5873-9ab0-5d66d57f4750", + "extraction_id": "f5b29cc7-fe8b-5230-adb1-0531fb1c3187", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "ccf7dace-b7d8-576f-bb59-c6707e5180f5", + "score": 0.6983357251682458, + "metadata": { + "text": "Because of their plasticity and accessibility these cells are also prime candidates for regenerative medicine. The \ncontribution of stem cell aging to organismal aging is un der debate and one theory is that reparative processes \ndeteriorate as a consequence of stem cell aging and/or de crease in number. Age has been linked with changes in \nosteogenic and adipogen ic potential of MSCs.\nResults: Here we report on changes in global gene expression of cultured MSCs isolated from the bone marrow of", + "title": "2010 - Age-related molecular genetic changes of murine.pdf", + "version": "v0", + "chunk_order": 2, + "document_id": "a69ce6db-4a5e-58a5-9dc5-d529768edcb1", + "extraction_id": "d39327b0-59b1-5e24-813d-099a48a8de85", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "f8e0e878-451b-519d-b6e5-e9834d5d3b77", + "score": 0.6977025270462036, + "metadata": { + "text": "suggesting that stem cells are not likely to be a factor limiting\nhematopoietic regeneration with age. However, their func-tional decits do show that HSCs are impacted by the forces\nof aging in a manner similar to that of differentiated cells\n[3134].\nIn our molecular analysis, we identied global age-related\nchanges in gene expression in murine HSCs, with a view to\nidentifying mechanisms that could be responsible for these\nage-associated declines in HSC function. Genes involved in", + "title": "2007 - Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation.pdf", + "version": "v0", + "chunk_order": 64, + "document_id": "a6fabf0c-e4a5-59f6-82c5-ebabce24fd0a", + "extraction_id": "188bdad0-f63b-5e4c-8eed-73cd01b8d66f", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "de67cf90-712a-5c28-9f6b-404d84a06d22", + "score": 0.6905411297405452, + "metadata": { + "text": "Discussion\nThe deterioration of the regenerative potential upon aging\nmight be due to functional changes in adult stem cells. To test this\nhypothesis we have investigated differential gene expression in\nprimary, human MSC and HPC derived from different agegroups. In this study, we demonstrate for the first time age-related\ngene expression changes in human MSC and HPC and that there", + "title": "2009 - Aging and Replicative Senescence Have Related Effects.pdf", + "version": "v0", + "chunk_order": 51, + "document_id": "0703ba80-b7a5-5873-9ab0-5d66d57f4750", + "extraction_id": "23921b67-8911-5086-a2e4-a909394a6df4", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "e6bb4c40-7fe8-5ff7-af36-1c2b749ed1fb", + "score": 0.6867024507135886, + "metadata": { + "text": "cells, which may explain the observed decline of stem cell function with age. Age-associated increases inDNAm target developmental genes, overlapping those associated with environmental disease risk factors\nand with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated", + "title": "2013 - Age-associated epigenetic drift implications.pdf", + "version": "v0", + "chunk_order": 3, + "document_id": "8513121f-71f3-5bb0-9433-feece9fd9fbc", + "extraction_id": "24500f0a-0e60-574e-9039-e9dd3b5be569", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "01740a78-e141-56f0-8f34-7c02c5602344", + "score": 0.6859941482543945, + "metadata": { + "text": "tion associated with age: loss of stem cell pool division\npotential (loss of regenerative capacity) and loss ofdierentiated somatic cell function, which directly leads\nto loss of organ function. Loss of dierentiated somatic\ncell function can additionally indirectly aect adult stem\nand progenitor cells by altering the tissue microenviron-\nment that is essential for stem cell support (the stem cellniche). In general, loss of stem cell pool division potential", + "title": "2007 - Two faces of p53 aging and tumor suppression.pdf", + "version": "v0", + "chunk_order": 8, + "document_id": "b1ef905a-c145-5270-9110-ae6954ea3d72", + "extraction_id": "270c5516-f5b2-54d3-8865-b84d8a9506c1", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "ae2ad88f-6e02-5541-b6be-966fef7712f1", + "score": 0.6849208661961051, + "metadata": { + "text": "1. Introduction\nStem cell aging is regarded as one of the contributors to several\ndegenerative conditions af icting the elderly because it underlies\nthe physiological decline in tissue maintenance and regenerative\ncapacity of many organs ( Rossi et al., 2008 ). The brain is one such\norgan that contains discrete populations of stem cells and their\nprecursors (collectively referred to as neural progenitor cells\n[NPCs]) that continue to generate new neurons throughout life", + "title": "2013 - Effects_of_age_and_strain_on_cell_prolif.pdf", + "version": "v0", + "chunk_order": 4, + "document_id": "d7e861e7-cdee-5145-9403-ef05e2d532c0", + "extraction_id": "b0fb2185-a2ee-5174-94d0-877ad2d87158", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + }, + { + "id": "1dffbbdb-f76d-581b-8384-751ce5f41e90", + "score": 0.6800036835672679, + "metadata": { + "text": "spective of tissue regeneration and repair because there isevidence that these beneficial functions may becomehandicapped with age. Age-related decline in the numberof MSCs in the bone marrows of rodents, monkeys, andhumans have been reported [26-33]. Most studies to datefocused on the effects of aging on the ability of MSCs toenter osteogenic, chondrogenic and adipogenic pro-grams. Some, but not all studies suggest that agingreduces osteogenesis and chondrogenesis while enhanc-", + "title": "2010 - Age-related molecular genetic changes of murine.pdf", + "version": "v0", + "chunk_order": 9, + "document_id": "a69ce6db-4a5e-58a5-9dc5-d529768edcb1", + "extraction_id": "d39327b0-59b1-5e24-813d-099a48a8de85", + "associatedQuery": "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?" + } + } + ], + "kg_search_results": null + } + } + }, + "20": { + "results": { + "completion": { + "id": "chatcmpl-AIHYkQV1s8mGJ0u0OlIT1WoCFkj8X", + "choices": [ + { + "finish_reason": "stop", + "index": 0, + "message": { + "content": "The accumulation of cross-links and advanced glycation end-products (AGEs) significantly impacts the structural integrity and function of aging tissues in several ways:\n\n1. **Inflammation and Oxidative Stress**: AGEs accumulation leads to inflammation and oxidative stress, which can cause long-term vascular and end-organ damage [1], [4]. This is partly due to the interaction of AGEs with specific receptors such as RAGE, which perpetuates these adverse processes.\n\n2. **Vascular Changes**: AGEs contribute to vascular hypertrophy, stiffening of collagen, and reduced arterial compliance, which are associated with aging and are accelerated by hyperglycemia [2]. This stiffening of collagen and reduction in arterial compliance can lead to decreased vascular function and increased risk of vascular complications.\n\n3. **Cross-linking of Proteins**: AGEs cause cross-linking of proteins, which affects the structural integrity of tissues. For example, the cross-linking of collagen is associated with increased susceptibility to atherosclerosis, osteoporosis, decreased joint elasticity, and the formation of cataracts [10].\n\n4. **Endothelial Dysfunction**: AGEs impair endothelial function and vascular reactivity, which can lead to complications such as atherosclerosis and diabetic complications [5]. This impairment is due to the modification of lipoproteins and the release of cytokines and growth factors upon AGE interaction with receptors.\n\n5. **Pathological Changes in Tissues**: AGEs induce various pathological changes, including increased basement membrane thickening, arterial stiffness, and glomerular sclerosis [7]. These changes contribute to the decline in tissue function and structure as they age.\n\nOverall, the accumulation of AGEs and the resulting cross-links compromise the structural integrity and function of tissues, contributing to the aging process and the development of age-related diseases.", + "role": "assistant" + } + } + ], + "created": 1728920766, + "model": "gpt-4o-2024-08-06", + "object": "chat.completion", + "system_fingerprint": "fp_6b68a8204b", + "usage": { + "completion_tokens": 366, + "prompt_tokens": 1188, + "total_tokens": 1554 + } + }, + "search_results": { + "vector_search_results": [ + { + "id": "388d90ef-1bfc-572d-b783-af945ab9519b", + "score": 0.765750527381897, + "metadata": { + "text": "vascular and kidney diseases [47].\nAdvanced glycation end-products (AGE) are the result of nonenzymatic glyca-\ntion, which produces heterogeneous bioactive molecules, such as lipids, proteins, \nand nucleic acids [59]. The accumulation of AGEs in aged tissues leads to several \nprocesses, such as inflammation, obesity, apoptosis, and other adverse processes \nrelated to ageing [47]. These AGEs are detected by various techniques, such as", + "title": "2020 - Clinical Genetics and Genomics of Aging.pdf", + "version": "v0", + "chunk_order": 1739, + "document_id": "62b635c3-040e-512a-b016-6ef295308a1e", + "extraction_id": "a3427d8a-366e-5edc-9a9d-fa1da5d9e800", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "aad43b5f-c345-53c4-a37e-4b59e54082bb", + "score": 0.7629441618919373, + "metadata": { + "text": "and leading to vascular hypertrophy and stiffening of collagen with \nsubsequent reduction of arterial compliance. These are processes that are \nassociated with aging but seem to be accelerated by hyperglycemia. These \ncross-linked macromolecules, called advanced glycosylation end products \n(AGEs), are implicated in the pathogenesis of vascular complications. Once", + "title": "2004 - Diabetes Genes a.pdf", + "version": "v0", + "chunk_order": 1668, + "document_id": "805ad0d5-6a3d-5e5f-b1ba-121e10c6daaa", + "extraction_id": "60ec7e90-7c38-5bda-a94e-ef15369c710c", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "edfb3091-1629-53bc-9f0b-88d552862fd9", + "score": 0.7581884120815059, + "metadata": { + "text": "proposed mechanisms are the development of advanced glycosylation end \nproducts and sorbitol accumulation. \nAdvanced glycosylation end products (AGEs) comprise a \nheterogeneous group of molecules that accumulate in plasma and tissues \nwith advancing age, diabetes and renal failure. They are characterized by \nbrowning, fluorescence, cross-linking and biological response through \nspecific AGE receptors and were first described in 1912 by French chemist \nL.C. Maillard (Fig. 5).", + "title": "2004 - Diabetes Genes b.pdf", + "version": "v0", + "chunk_order": 136, + "document_id": "da2f2624-e3e6-5e2d-b406-941db2fe7671", + "extraction_id": "272b3625-6f21-51f5-a83b-cfdbf4ddc841", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "3d613e0f-9ab0-575f-88cc-2b35f51f9d9d", + "score": 0.7527935729263301, + "metadata": { + "text": "the accumulation of AGEs which can further perp etuate and amplify local inflammation and 197 \noxidant stress through irreversible glycation of the various protei ns and lipids to promote long 198 \nterm vascular and end-organ damage. Thus AGEs, acting through receptors such as RAGE, 199 \ncould also contribute to hyperglycemic memo ry (18, 96, 147). These studies have begun to 200", + "title": "2010 - The Role of Epigenetics in the Pathology of Diabetic Complications.pdf", + "version": "v0", + "chunk_order": 40, + "document_id": "766edfd5-4756-51bf-b636-c94b041d030c", + "extraction_id": "cc350a5a-f474-597d-93c8-4359b9ddcc38", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "34533770-24ba-57b7-95f9-06b201c92aa5", + "score": 0.7425909638404846, + "metadata": { + "text": "AGEs are taken up by specific AGE receptors (RAGE), cytokines, growth \nfactors, and adhesion factors are released, leading to further cellular changes. \nAGEs also can impair endothelial function and vascular reactivity, such as \nin response to nitric oxide. Modification of LDL as a result of glycation may \ncontribute to foam cell formation.4 Thus, AGEs appear to be main players \nnot only in the development of diabetic complications and atherosclerosis,", + "title": "2004 - Diabetes Genes a.pdf", + "version": "v0", + "chunk_order": 1669, + "document_id": "805ad0d5-6a3d-5e5f-b1ba-121e10c6daaa", + "extraction_id": "f5f2abef-9ccd-5147-a433-489c7225017c", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "e1c2f05b-b04a-5c74-98ad-69af532d2ae9", + "score": 0.7370566443137407, + "metadata": { + "text": "geneous group of macromolecules that are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids. Overproduction of AGEs is considered the most important pathophysiological mechanism that induces diabetic complications (Semba etal. 2010). On one hand, AGEs mediate intracellular glycation of mitochondrial respiratory chain proteins and increase ROS levels, thus triggering oxidative stress (Coughlan etal. 2009) and endoplasmic reticulum stress (Piperi etal. 2012). On the", + "title": "2019 - Bioinformatic prediction of critical genes and pathways.pdf", + "version": "v0", + "chunk_order": 87, + "document_id": "01201944-11f2-52d9-ac3e-7af685d4a4c4", + "extraction_id": "98c7d4f6-45b7-53d4-979d-5503e91b1415", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "50a3dd44-9747-5456-91e3-ebeb2b6a9248", + "score": 0.7351436614990234, + "metadata": { + "text": "Introduction\nIn individuals with diabetes, nonenzymatic\nglycation of proteins leads to the formation of\nadvanced glycation end products (AGE) and\nthis process occurs at an accelerated rate in\nchronic hyperglycaemia1, and also the levels are\nfound to be increased in complications of\ndiabetes, such as diabetic retinopathy (DR).2\nAGE induces a variety of pathological changes,\nsuch as increased basement membrane\nthickening, arterial stiffness, and glomerular\nsclerosis.3,4AGEs bind to a specic receptor", + "title": "2007 - Rage gene promoter polymorphisms and diabetic retinopathy in a clinic-based population from South India.pdf", + "version": "v0", + "chunk_order": 4, + "document_id": "de5a5a08-3a63-587c-b835-41c74b37f570", + "extraction_id": "2903bc47-30d8-5e1c-acd9-5db4908f5ee9", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "a8fe389d-7249-50d5-8c4a-2f9d62fa73f6", + "score": 0.7340881982989206, + "metadata": { + "text": "AGEs accelerate atherosclerosis through cross-linking of proteins, \nplatelet aggregation, defective vascular relaxation, and abnormal lipoprotein \nmetabolism. 30 \nAGEs have a vital role in pathogenesis of diabetic nephropathy and \nprogression of renal failure. Renal failure, in turn, results in decreased \nexcretion and increased generation of AGEs (Figure 6). \n629", + "title": "2004 - Diabetes Genes b.pdf", + "version": "v0", + "chunk_order": 141, + "document_id": "da2f2624-e3e6-5e2d-b406-941db2fe7671", + "extraction_id": "26eeaac7-6846-51ee-a69b-51a75402a1bf", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "94f15877-0b3a-5dee-8d1f-d0a034f14220", + "score": 0.7306285500526428, + "metadata": { + "text": "vessels show enhanced subintimal protein and lipoprotein deposition; \nincreased vascular permeability, e.g. to albumin; \ninactivation of nitric oxide; \nactivation of endothelial receptors, leading to vasoconstriction and \nthrombosis; \naltered proteoglycan milieu; \naltered basement membrane cellular structure; \nproliferation of matrix. \nStrategies directed at the prevention of formation or the disruption of \nAGE cross-links may be promising. \nREFERENCES:", + "title": "2004 - Diabetes Genes a.pdf", + "version": "v0", + "chunk_order": 1715, + "document_id": "805ad0d5-6a3d-5e5f-b1ba-121e10c6daaa", + "extraction_id": "f6de03c3-cbbd-5963-ab23-e934f6ff1d56", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + }, + { + "id": "0b6eb47a-1fd1-58d2-81db-3a17b967f2d6", + "score": 0.7291850286236435, + "metadata": { + "text": "proteins and nucleic acids, leads to modification and then decline in structure \nand function of these molecules, as the cross-links accumulate both \nextracellularly and intracellularly over time. A prime example would be the \ncrosslinking of collagen, which is thought to lead to typical phenomena \nobserved in aging, such as increased susceptibility to atherosclerosis, \nosteoporosis, decreased joint elasticity, the formation of cataracts, and", + "title": "2004 - Diabetes Genes a.pdf", + "version": "v0", + "chunk_order": 1664, + "document_id": "805ad0d5-6a3d-5e5f-b1ba-121e10c6daaa", + "extraction_id": "60ec7e90-7c38-5bda-a94e-ef15369c710c", + "associatedQuery": "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + } + } + ], + "kg_search_results": null + } + } + } +}
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