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diff --git a/gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_de_aging.json b/gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_de_aging.json new file mode 100644 index 0000000..5f14f2a --- /dev/null +++ b/gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_de_aging.json @@ -0,0 +1,289 @@ +{ + "question": [ + "How do recent single-cell transcriptomics studies enhance our understanding of cellular heterogeneity in aging tissues?", + "What are the latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction?", + "How do age-related changes in chromatin architecture contribute to the decline in cellular function?", + "What insights have been gained from studying the epigenetic reprogramming of aged cells to a more youthful state?", + "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?", + "What are the therapeutic potentials and challenges of targeting the insulin/IGF-1 signaling pathway for extending healthspan and lifespan?", + "How can the integration of proteomics and metabolomics data shed light on age-associated metabolic shifts?", + "What role do long non-coding RNAs (lncRNAs) play in the regulation of aging and age-related diseases?", + "How do recent advancements in CRISPR/Cas9 technology open new avenues for studying and potentially reversing aging?", + "What is the significance of the DNA damage response (DDR) in the context of both replicative and chronological aging?", + "How do age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases?", + "How do advancements in machine learning and artificial intelligence aid in the identification of biomarkers for biological aging?", + "What recent discoveries have been made regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes?", + "How do changes in the gut microbiome composition correlate with aging and longevity?", + "What are the key molecular mechanisms through which caloric restriction exerts its lifespan-extending effects across different species?", + "How do oxidative stress and the subsequent accumulation of damaged macromolecules contribute to cellular aging?", + "How are extracellular matrix remodeling and tissue stiffness implicated in the aging process?", + "How do recent developments in autophagy research contribute to our understanding of its role in aging and longevity?", + "What are the implications of age-related shifts in stem cell niche composition and function for tissue regeneration capacity?", + "How do cross-links and advanced glycation end-products (AGEs) accumulation affect the structural integrity and function of aging tissues?" + ], + "answer": [ + "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]. Single-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]. Additionally, 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].", + "The latest findings on the role of senescence-associated secretory phenotype (SASP) factors in age-related tissue dysfunction highlight several key aspects: 1. 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]. 2. 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. 3. 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]. 4. 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]. Overall, 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.", + "Age-related changes in chromatin architecture contribute to the decline in cellular function through several mechanisms: 1. **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. 2. **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]. 3. **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]. 4. **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]. 5. **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]. These changes in chromatin architecture collectively contribute to the decline in cellular function observed with aging.", + "Studying the epigenetic reprogramming of aged cells to a more youthful state has provided several insights: 1. **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]. 2. **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]. 3. **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]. 4. **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]. 5. **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]. 6. **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]. These 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.", + "Alterations in the mitochondrial genome and bioenergetics significantly influence the aging process in humans through several mechanisms: 1. **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]. 2. **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]. 3. **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]. 4. **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]. Overall, 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.", + "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: ### Therapeutic Potentials: 1. **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. 2. **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. 3. **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. ### Challenges: 1. **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. 2. **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]. 3. **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]. Overall, 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.", + "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. 1. **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. 2. **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]. 3. **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. 4. **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. Overall, 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.", + "Long non-coding RNAs (lncRNAs) play significant roles in the regulation of aging and age-related diseases through various mechanisms: 1. **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]. 2. **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]. 3. **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]. 4. **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]. 5. **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]. 6. **Neurodegeneration**: LncRNAs are implicated in neurodegenerative diseases, such as Huntington's disease, by regulating transcriptional networks and chromatin states [6]. 7. **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]. 8. **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]. Overall, 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.", + "Recent advancements in CRISPR/Cas9 technology have opened new avenues for studying and potentially reversing aging in several ways: 1. **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]. 2. **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]. 3. **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]. 4. **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]. These 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.", + "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: 1. **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. 2. **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. 3. **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. 4. **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]. 5. **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]. Overall, 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.", + "Age-dependent changes in the immune system, such as immunosenescence, contribute to increased susceptibility to diseases through several mechanisms: 1. **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]. 2. **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. 3. **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]. 4. **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]. These 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.", + "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].", + "Recent discoveries regarding the impact of systemic factors, such as circulating microvesicles, on aging phenotypes include the following: 1. 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]. 2. 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]. These 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.", + "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]. Research 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]. Additionally, 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]. Overall, maintaining a healthy gut microbiome is crucial for promoting longevity and mitigating some of the negative effects associated with aging.", + "Caloric restriction extends lifespan across various species through several key molecular mechanisms: 1. **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]. 2. **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]. 3. **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]. 4. **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]. These mechanisms highlight the complex interplay of genetic and metabolic pathways through which caloric restriction can extend lifespan across diverse species.", + "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]. Oxidative 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]. Overall, 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].", + "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]. Additionally, 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]. The 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]. Overall, 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].", + "Recent developments in autophagy research have significantly enhanced our understanding of its role in aging and longevity. Here are some key contributions: 1. **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]. 2. **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]. 3. **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]. 4. **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]. 5. **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]. 6. **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]. These 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.", + "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: 1. **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]. 2. **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]. 3. **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]. 4. **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]. 5. **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]. Overall, 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].", + "The accumulation of cross-links and advanced glycation end-products (AGEs) significantly impacts the structural integrity and function of aging tissues in several ways: 1. **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. 2. **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. 3. **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]. 4. **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. 5. **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. Overall, 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." + ], + "contexts": [ + [ + "Single-cell sequencing has helped to support several hypotheses about the cel- lular and genetic origin of age-related dysfunctions. Since single-cell sequencing allows us to study small populations of cells, it has been possible to find low repre- sented mutations as well as transcriptional events that alter cellular identity. This newly generated data suggests that aging could be the result of mutational accumu- lation, epigenetic errors, and transcriptional noise that occurs in cells altering the", + "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 changes during aging, several studies have applied machine-learn- ing models to single-cell transcriptomics and DNA methylation", + "within whole tissues or individual cell types in aging (Rodwellet al. 2004; Jonker et al. 2013; Cosgrove et al. 2014; O Brown et al. 2015; Su et al. 2015; White et al. 2015; Keyes et al. 2016; Benayoun et al. 2019). However, it remains unclear to what degree age-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.", + "populations. Furthermore, single cell analysis should allow us to relate prospective profiles of HSCs that have just been isolated with known heterogeneity in their retrospective functional capacity in transplantation assays. Here, we leveraged single cell RNA-seq to directly assess transcriptional heterogeneity within the HSCs and how it may change with age in the steady-state unperturbed hematopoiesis. Given that HSCs are", + "cells. Here, we used single-cell RNA-seq to investigate aging across a diverse set of murine cell identities in three tissues. We found that cell identities differentially express unique genes with aging, consistent with previous reports of cell-identi- ty-specific aging phenotypes (Angelidis et al. 2019). Similar celltypes (e.g., kidney capillary endothelial cells and lung endothelial cells) showed broadly similar aging trajectories across tissues, and", + "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", + "Genomics 114 (2022) 110379 2have been observed in multiple species and tissues [7,8]. Transcriptome analysis using aged oocyte samples have confirmed the impact of aging on transcriptome landscapes [9,10]. Advances in single-cell sequencing technology promote our understanding of intrinsic complexity to another level [11]. Recently, we have successfully applied single-cell transcriptome technique to reveal cellular and molecular transitions in", + "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 inherent characteristics of cell types play an important role in shaping cell aging patterns, even when situated in different tissue environments. Discussion Here we show that tissue-specific aging programs can be learnedfrom scRNA-seq data and applied to describe aging heterogeneity", + "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. Results Single-cell RNA-sequencing identifies a diversity of cell types and states in young and old mouse tissue We collected transcriptional profiles of young and old cells of many identities by isolating single cells from the kidney, lung,", + "during the last decades. However, different types of cells in the cardiovascular system may be highly heterogeneous dur - ing aging and disease progression. Single-cell genomics, such as massively parallel single-cell RNA-seq, facilitate detailed transcriptome analysis to identify variants of key epigen-etic enzymes/pathways in specific diseased cohorts or cell types. 54,57,58,146 Altogether, new sequencing technologies have" + ], + [ + "SASP (senescence-associated secretoryphenotype):cytokines, chemokines,proteases, and otherfactors secreted bysenescent cells, whichare inammatory anddisrupt tissuehomeostasis viaparacrine mechanisms ATM (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-", + "SASP is one of the most representative features of senescent cells and may explain the organismal expression of aging and age-related diseases. Senescent cells pro- duce a deleterious microenvironment through the production and secretion of pro- liferative and proinflammatory molecules such as IL-1 and -1, IL-6, IL-8, the chemotactic cytokine GRO, IGBP-7, growth factors, VEGF, TGF-, serine prote- ases, and matrix remodeling enzymes [146]. It has been determined that the activa-", + "context. For example, SASP likely contributes to early tumorigenesis (84), chemoresistance (94),and potentially neurodegenerative diseases (95). However, SASP is also important for mammalian development (96), tissue repair (97), and wound healing (98). SASP plays an important role in stimulating 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 chronic inammation of aging.", + "many tissues, where theSASP promotes chronic inflammation and exacerbates age-associated degeneration and hyperplasia. Recent evidence suggests that neurological aging and neurode- generation areaccompanied byanaccumulation ofsecretory cells inbrain, suggesting that cel- lular senescence may contribute tobrain aging [2]through ashared mechanism. Overlapping mechanisms canbedetected using functional genomics studies ofboth thebiology ofcellular senescence and cognitive aging.", + "senescence-associated with the secretory phenotype (SASP) are other markers of cellular senescence. Inflammation andIntercellular Communication While senescent cells no longer replicate, they are still metabolically active and secrete proteins in a recognizable pattern known as SASP.This is a widely heteroge- neous group of proteins with autocrine and paracrine effects [47], including soluble signaling factors, such as interleukins, chemokines, and growth factors, as well as", + "matory mediators. This particular phenotype is termed the senescence- associated secretory phenotype (SASP). Replicative cellular aging includes biochemical, mor - phological, and functional modifications that lead to the irreversible impairment of cell proliferation associated with DNA damage, shortening of the telomeres, and changes in chromatin architecture, as previously described [135, 136]. The molecular mechanisms that drive cellular senescence in proliferative and", + "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, IL6, IL8, and various matrix metalloproteases (MMPs), all of which individually are thought to drive 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", + "senescent cells [150]. SASP factors exert their functions in either an autocrine or a paracrine manner and are responsible for the induction of the chronic inflammation and cell proliferation that contributes to cell dysfunction and cancer. Thus, the accu- mulation of senescent cells in tissue is closely associated with aging-related dis- eases. Recently, it was determined that senescent fibroblasts significantly increase the expression of HLA-E, which inhibits the receptor NKG2A in killer cells, and", + "Role of L1 and Alu in cellular senescence and age-related inflammation A key feature of cellular senescence is the senescence-associatedsecretory phenotype (SASP), whereby senescent cells secretenumerous proinflammatory cytokines, chemokines, growth factors, and proteases (Campisi, 2013). This altered secretome", + "8. Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous func- tions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol2008; 6:285368. 9. Wiley CD, Liu S, Limbad C, et al. SILAC analysis reveals increased secretion of hemostasis-related factors by senes- cent cells. Cell Rep 2019; 28:33293337 e3325. 10. Basisty N, Kale A, Jeon OH, et al. A proteomic atlas of senescence-associated secretomes for aging biomarker" + ], + [ + "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- ed functional decline. Age-dependent changes in chromatin marks (e.g., DNA meth- ylation, histone modifications) have been observed in multiple species and tissues (Benayoun et al. 2015; Booth and Brunet", + "contributes to the onset of tissue dysfunction and the eventual demise of organisms as they age. During replicative senescence of human fibroblasts chromatin is subject to extensive changes in the global distribution of euchromatin and heterochromatin [25,35]. We found that the fundamental architecture of the genome undergoes profound alterations: an overall closing of chromatin in euchromatic gene-rich regions, which is", + "impaired function of histone modifying activ-ities, which in turn lead to structural chroma- tin changes. The number of known diseasesOrganismal agingAging-associated gene expression programsCellular stress DNA damageChromatin remodelingEpigenetic status SusceptibilityHistone modifier redistribution Non-specific gene expression events Figure 3. Chromatin effects in aging. A complex network of interactions links chromatin structure to aging.", + "by Pelicci and colleagues in this issue). However, it could also be argued that chromatin structure is directly affected by the ageing process through an as-yet-unknown mecha - nism that leads to increased DNA damage and a perma - nent damage response that alters gene-expression patterns in a similar way to the model proposed in this review. o ver the coming years, as researchers use mammalian models to map the global pattern of chromatin modifi -", + "and peripheral heterochromatin blocks are lost during aging (Haithcock et al. 2005). The aging-associated defects in chromatin structure have various functional consequences.T o start with, aged genomes are characterized by increased DNA damage and high levels of per-sistent DNA breaks, possibly brought about by structural changes, which increase the suscepti- bility of the genome to damage. Furthermore,probably as a consequence of loss of pericentro- meric heterochromatin structure, physiologi-", + "related changes in gene expression and the ageing process4,5. Changes in gene expression were already known to contribute to cellular senescence6, a possible cause of ageing7, and may provide an explanation for the age-related decline in organ and tissue function in complex organisms.Although chromatin reorganization was linked to ageing in budding yeast over 10 years ago8,9, these ideas have remained untested. Recently, a growing appre - ciation for the importance of chromatin in regulating", + "tone loss in the ageing process has been attributed to alterations in heterochromatin, which are characterized by a decrease in its distribution in the genome and the content of characteristic heterochromatin histone marks (such as H3K9me3 and H3K27me3) as evidenced in fibroblasts cells from a HGS patient and healthy aged individuals [59, 60]. Interestingly, it has been suggested that the increase in chroma- tin opening in T cells from aged people could be related to histone loss, which in", + "long lifespan (Dang et al. 2009). Given theseextensive changes in histone modications, not surprisingly, aged cells show dramatic and global misregulation of gene expression. Al-though some of these changes are likely part of specic aging-related gene expression pro- grams including inammation and cellularstress responses, others likely occur largely sto- chastically because of random changes in epi- genetic modications and chromatin structure. The mechanisms that drive chromatin and", + "general loss of histones coupled with local and global chromatinremodeling, an imbalance of activating and repressive histone modications, and transcriptional change in all aging models. Additionally, particularly in mammalian systems, there is globaland local change in DNA methylation, site-specic loss and gain in heterochromatin, and signicant nuclear reorganization (Figure 1 ). It is as yet unclear whether changes in the activity of epigenetic", + "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" + ], + [ + "experiments suggest that epigenetic features associated withaging can be reversed. In successfully reprogrammed iPSCs, the chromatin state of CDKN2A locus associated with aging is erased and restored to that of youthful cells ( Meissner, 2010 ). The requirement for proper epigenetic gene silencing for longevity has been observed in multiple model organisms, sug- gesting an evolutionarily conserved process ( Lin et al., 2000; Chen et al., 2005; Greer et al., 2010 ). The function of Polycomb", + "apparent rewinding of the aging clock without loss of differenti-ation. Formal demonstration will require clear epigenetic signa- tures of young and old cells and evidence that the aged cells have regained a youthful signature. It should be noted thatreprogramming of the epigenome to a youthful state in an aged cell has inherent risks and uncertainties. For example, the", + "et al., 2010 ). Clearly, inhibiting single signaling pathways (NF-k B and mTOR) is sufcient to restore some features of youthful cells, but the number of transcriptional regulatorsthat need to be modulated to result in full rejuvenation is unknown. Third, is the youthful state or the aged state domi- nant? It would be interesting to determine which epigeneticand transcriptional prole is more robust in experiments of fusion of young and old cells. Concluding Remarks", + "Rejuvenation: Is It Epigenetic Reprogramming?By analogy to the attainment of a pluripotent state by epigenetic reprogramming of a differentiated cell, is cellular rejuvenation byheterochronic parabiosis, NF- kB inhibition, or inhibition of mTOR signaling ( Figure 1 ) a form of epigenetic reprogramming from an aged state to a youthful state? If so, then these would be examples of an uncoupling of the differentiation program from the aging clock, with cells in each case manifesting an", + "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 addition to epigenetic drift, telomere shortening has been associated with", + "tion through the lens of epigenetic reprogramming. By dening youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges. Introduction The inexorable tolls of aging are evident in almost all living beings. From the onset of reproductive maturity, organismalaging is generally characterized by a decline in fecundity, an increased susceptibility to disease and tissue dysfunction, and increased risk of mortality ( Kirkwood, 2005; Hayick, 2007; Kirk-", + "others (i.e. DNA methylation influences chromatin structures, histones PTMs). Several important conclusions emerge from the presented findings: there are at least two ways to reverse or inhibit senescence by epigenetic mechanisms, whereby a healthy life expectancy could be prolonged. The first way involves rejuvenation through effective epigenetic reprogramming in cells undergoing senescence or cells derived from very aged patients or patients with progeroid syndromes, by which the", + "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 mechanisms of rejuvenation. If so, it should be possible to char- acterize young and old cells by specic transcriptional andepigenetic proles and states. Furthermore, the processes that underlie aging and rejuvenation should be identiable in terms", + "determinants of the aged state by genetically manipulatingspecic biochemical pathways. A recent example demonstratesthe power of transcriptional proling and bioinformatic analysis to reveal an aging signature that can be genetically engineered to reect a more youthful state ( Adler et al., 2007 ). In a compar- ison of old and young tissues from mice and humans, old tissues were found to express at signicantly higher levels a set of genes that contained sequences in their 5 0regulatory regions, indica-", + "Recently, studying the direct relationship between epigeneticmechanisms and the aging process itself is gaining increasing attention. The potential reversibility of these epigenetic changes that occur as a hallmark of aging offers excitingopportunities to alter the trajectory of age-related diseases. 8 This is especially important given the remarkable plasticityof aging. 9,10In the literature, age-associated epigenetic alter- ations have been identified by epigenome-wide association" + ], + [ + "abolic regulation through mitochondrial signaling. Am J Physiol Endocrinol Metab. 2014;306:E58191. 74. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial DNA quantity and quality in humans. BMC Genomics. 2017;18:890. 75. Hebert SL, Lanza IR, Nair KS.Mitochondrial DNA alterations and reduced mitochondrial function in aging. Mech Ageing Dev. 2010;131:45162. 76. Liu D, Li H, Lu J, Bai Y .Tissue-specific implications of mitochondrial alterations in aging.", + "mechanisms that lead to mitochondrial metabolism shifts in human aging are not completely understood, the literature reports that the failure in the mitochondrial metabolism of aged heart might be associated with mutations in the mtDNA.In this sense, the aged heart shows an increase over 15-fold on mtDNA mutations in com- parison to hearts from young people [101]. Mutations in genes that encode Polg-a, responsible for mtDNA repair machinery, cytochrome b, and several subunits of", + "22. Fleming JE, Miquel J, Cottrell SF, Yengoyan LS, Economos AC: Is cell aging caused by respiration-dependent injury to the mitochondrial genome?Gerontology 1982, 28:, 44-53. 23. Pak JW, Herbst A, Bua E, Gokey N, McKenzie D, Aiken JM: Mitochondrial DNA mutations as a fundamental mechanism in physiological declinesassociated with aging. Aging Cell 2003, 2:1-7. 24. Jacobs HT: The mitochondrial theory of aging: dead or alive. Aging Cell 2003, 2:11-17.", + "Sun., N, Youle, R. J. and Finkel, T. (2016). The mitochondrial basis of aging. Mol. Cell 61, 654-666. doi:10.1016/j.molcel.2016.01.028 Symer, D. E., Connelly, C., Szak, S. T., Caputo, E. M., Cost, G. J., Parmigiani, G. and Boeke, J. D. (2002). Human L1 retrotransposition is associated with genetic instability in vivo. Cell110, 327-338. doi:10.1016/S0092-8674(02)00839-5 Szabo, L., Morey, R., Palpant, N. J., Wang, P. L., Afari, N., Jiang, C., Parast,", + "limitations to study mitochondrial metabolism in human samples, in this section we briefly described the implications of mitochondrial metabolism for aging in the most studied and high energy demand human tissues, such as skeletal muscle, heart, and brain.Table 4.1 Main mitochondrial dynamics proteins that are altered in human tissues during the aging process Tissue/ organ Fission Fusion Biogenesis Mitophagy Refs Skeletal muscleIncreased fragmentation Decreased Drp1 proteinIncreased interconnected", + "96. Wei Y-H, Wu S-B, Ma Y-S, Lee H-C.Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J. 2009;32:11332. 97. Kates AM, Herrero P, Dence C, Soto P, Srinivasan M, Delano DG, Ehsani A, Gropler RJ. Impact of aging on substrate metabolism by the human heart. J Am Coll Cardiol. 2003;41:2939. 98. Gmez LA, Monette JS, Chavez JD, Maier CS, Hagen TM.Supercomplexes of the mito-", + "phenotype, such as the Mitochondrial Free Radical Theory of Aging (MFRTA), and although these theories have been recently confronted, the role of mitochondria in the aging process is undeniable because of their versatile roles and implications for cellular function. MFRTA suggests that the oxidative damage of mtDNA is the key event disturbing the respiratory chain proteins to induce its dysfunction and increase ROS production in a vicious cycle [123]. However, alterations in mito-", + "102. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial DNA quantity and quality in humans. BMC Genomics. 2017;18:890. https://doi.org/10.1186/ s12864-017-4287-0. 103. Norddahl GL, et al. Accumulating mitochondrial DNA mutations drive premature hema- topoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell. 2011;8:499510. https://doi.org/10.1016/j.stem.2011.03.009.", + "78 p53, which regulate the catalytic subunits of ETC complexes [103]. Unfortunately, these data have only been observed in murine models of aging and require further verification in human samples. Mitochondrial Metabolism intheAged Brain In normal conditions, the brain consumes around 25% of the total body glucose via glycolysis and mitochondrial OxPhos [104]. So besides the mitochondrial dynam- ics dysfunctions described above, during aging there is also a decline in energy", + "mitochondrial DNA mutations can reduce lifespan. Sci Rep. 2014;4:6569. 20. Ross JM, Stewart JB, Hagstrm E, Bren S, Mourier A, Coppotelli G, Freyer C, Lagouge M, Hoffer BJ, Olson L. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature. 2013;501(7467):412 5. 21. Sondheimer N, Glatz CE, Tirone JE, Deardorff MA, Krieger AM, Hakonarson H. Neutral mitochondrial heteroplasmy and the influence of aging. Hum Mol Genet. 2011;20(8):1653 9." + ], + [ + "the attention of researchers as a therapeutic target for age-related diseases [109]. Resveratrol, a phytochemical enriched in the skin of red grapes and wine, has been actively investigated to determine whether it promotesSIRTs activity with conse- quent beneficial effects on aging [110]. IGF Because insulin/IGF-1 function through signaling as a nutrient sensor and controls the transcription of stress response genes, the insulin/IGF-1 pathway provides a", + "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", + "as insulinIGF-1 signalling [6], cellular senescence [4], protein refolding [4345] , autophagy [41] and phase 1 and 2 detoxication [36,37,52] . These represent major points of intervention against ageing-related disease. As shown here, lifespan pathways control improved cellular maintenance, which leads to slowed ageing(e.g. slowed normal cognitive ageing) and protection against diseases of ageing (e.g. neurodegenerative diseases of ageing, such as Alzheimers and Parkinsons", + "ent-sensing pathways such as insulin/insulin-likegrowth factor (IGF-1) signalling (IIS) and target of rapamycin (TOR) signalling mediated lifespan exten- sion, and also the extension of lifespan by DR [ 2]. An 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-", + "43. Svensson, J. et al. Liver-derived IGF-I regulates mean life span in mice. PLoS ONE 6, e22640 (2011). 44. 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. Endocrinol. 9, 366376 (2013). 45. Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277287 (2009). 46. Zhu, H. et al. Reference ranges for serum insulin-like growth", + "5. Piper MD, Selman C, McElwee JJ, Partridge L: Separating cause from effect: how does insulin/I GF signalling control lifespan in worms, flies and mice? J Intern Med 2008, 263:179-191. 6. Holzenberger M, Kappeler L, De Magalhaes Filho C: IGF-1 signaling and aging. Exp Gerontol 2004, 39:1761-1764. 7. Zahn JM, Kim SK: Systems biology of aging in four species. Curr Opin Biotechnol 2007, 18:355-359. 8. McElwee JJ, Schuster E, Blanc E, Piper MD, Thomas JH, Patel DS,", + "humans enriched for familial longevity. Aging Cell. 2016;15(6):112631. 44. Lee WS, Kim J.Insulin-like growth factor-1 signaling in cardiac aging. Biochim Biophys Acta Mol basis Dis. 2018;1864(5 Pt B):19318. 45. Balasubramanian P, Longo VD. Growth factors, aging and age-related diseases. Growth Hormon IGF Res. 2016;28:668. 46. Suzuki K, etal. Serum insulin-like growth factor-1 levels in neurodegenerative diseases. Acta Neurol Scand. 2019;139(6):5637.", + "paradigms for lifespan extension (C. elegans, D. melanogaster), genetic interference in the insulin-signaling pathway can prolong life multi-fold [47,48]. In mammals, IGF1-decient, Ames and Snell dwarf mice (characterized by defects in the development of the anterior pituitary due to mutations in the Prop-1 and Pit1 loci and diminished levels of GH, thyroid stimulating hormone, and prolactin hormone) combine", + "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- tors in other lower organisms. However, as in the prematureaging mouse models described above, it remains unclear whether the altered serum IGF-1/insulin levels of SIRT-6- decient mice directly contribute to aging-like phenotypesor, alternatively, reect compensatory alterations. In this re- gard, it will be of interest to determine whether SIRT6 is", + "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 caloric-restricted mice (40). Therefore, the as-yet un-identi ed mechanism of insulin signaling on lifespan" + ], + [ + "learning to show that plasma proteins that predict age are predominantly associated with immunity [91]. State-of-the-art metabolomics approaches are also now allowing age-related changes in me- tabolite pro les to be studied, which provide new insights into the physiological mechanisms of age- ing [ 92,93]. The integration of multiple datasets generated from genomes, epigenomes, transcriptomes, proteomes, and metabolomes, an approach termed multi-omics , offers great", + "13. Menni C, Kastenmuller G, Petersen AK, et al. Metabolomic markers reveal novel pathways of ageing and early development in human populations. Int J Epidemiol 2013;42:1111- 9. 14. Evans AM BB, Liu Q, Mitchell MW, Robinson RJ, et al. . High Resolution Mass Spectrometry Improves Data Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in High- Throughput Profiling Metabolomics. Metabolomics 2014;4:132.", + "Due to the mild adaptions, the identification of func- tionally altered metabolic activity in aged skin interpret- ation of significant metabolite and transcript changes of small magnitude is especially challenging. Therefore, we employed the previously presented locality scoring ap- proach [60] to identify age-dependent transcriptional al- terations of enzymes that functionally effect proximal metabolic activity and thus metabolite levels. This inte- grated analysis revealed age-dependent, concerted me-", + "matched transcriptome and metabolome data highlighted transcriptionally-driven alterations of metabolism during aging such as altered activity in upper glycolysis and glycerolipid biosynthesis or decreased protein and polyamine biosynthesis. Together, we identified several age-dependent metabolic alterations that might affect cellular signaling, epidermal barrier function, and skin structure and morphology.", + "used to assess biological responses provides new oppor - tunities to understand the impact of the environment on the risk of age-related diseases. For example, the multi - omics analysis and integration method produces a pri - ority list of multiple sets of biomarkers, which together reflect the molecular responses of the exposome. Each of these data warrants integration into a biomarker panel to aid physicians in developing age-related disease diagno - ses and prognoses [78].", + "summary, we identified age-dependent changes in gene expression in different metabolic pathways that have been associated with epidermal homeostasis and there- fore might be important to sustain epidermal function. Integrated analysis of transcriptome and metabolome data Since the age-dependent adaptations of metabolite and transcript levels are only mild, we set out to identify metabolic enzymes that featured an age-dependent and functional change in activity driven by altered gene ex-", + "These high throughput prof iling experiments have gener- ated large amounts of data for meta-analysis [24], which can compare 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 explore the causal factors for aging, studies are increasingly", + "over, the integration of trans criptome and metabolome data revealed a transcriptionally re gulated reduction in protein as well as polyamine biosynthesis and adaptation in upper glycolysis and glycerolipid biosynthesis in aged skin. Results Differences in the epidermal skin metabolome of young and old human volunteers To chart metabolic adaptations in human skin during aging in vivo , we performed non-targeted metabolomicsanalysis of epidermal skin tissue samples obtained from", + "proteomes overlap significantly with the waves of aging proteins (Supplementary Table 15). Accounting for heterogeneous and com - plex 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 blood or blood products to treat aging and age-related diseases 39. Specifically, identifying plasma proteins that promote or antagonize", + "rmed using authentic standards. One of the key nodes identi ed by metabolomics as signi cantly altered with accelerated and normal aging was glutathione metabolism ( Fig. 4A), a key antioxidant and index of oxidative stress [71]. Dierential MS was used for proteomics analysis to identify redox- related proteins signi cantly altered in the livers of 3 4 month-old progeroid Ercc1/mice and old WT mice (> 2 years-old) vs. adult WT mice. Expression of catalase, SOD1 (CuZnSOD) and SOD2 (MnSOD)" + ], + [ + "lncRNA which overexpression participates in the regulation of age-associated car - diovascular diseases as it is a non-canonical precursor for hsa-miR-4485 and hsa- miR- 1973 microRNAs [62]. These studies demonstrate that not only coding genes (which represent only 2% of the genome sequence) are implicated in aging regula- tion, but also lncRNAs and microRNAs participate in tissue age-related changes. circRNAs are non-coding covalently closed single-stranded transcripts produced", + "(2008). 192. K. Abdelmohsen, A. Panda, M.-J. Kang, J. Xu, R. Selimyan, J.-H. Yoon, J. L. Martindale, S. De, W. H. Wood III, K. G. Becker, M. Gorospe, Senescence-associated lncRNAs: Senescence- associated long noncoding RNAs. Aging Cell 12, 890 900 (2013). 193. S. Kour, P. C. Rath, Long noncoding RNAs in aging and age-related diseases. Ageing Res. Rev. 26,1 21 (2015). 194. R. Johnson, Long non-coding RNAs in Huntington s disease neurodegeneration. Neurobiol. Dis. 46,2 4 5 254 (2012).", + "155 Premature ageing has been associated with altered expression of lncRNAs that participate in the regulation of the telomere length by modulating the TERT activity and synthesis of telomeric repeats [155, 161]. Furthermore, it has been reported that changes in the expression levels of some lncRNAs are associated with the develop- ment of AD [162]. Circular RNAs andAgeing Circular RNAs (circRNAs) are highly conserved covalently closed non-coding", + "interacting with proteins and nucleic acids in order to regulate gene expression (by indirect epigenetic mechanisms or by direct mechanisms acting as antisense tran- scripts or transcriptional coactivators), nuclear location of transcription factors and stabilization of ribonucleoprotein complexes [155]. It has been reported that lncRNAs are important in the regulation of ageing-associated mechanisms in humans and ani-", + "progression. LncRNA H19 was recently reported to play a crucial role in the activation of MAPK and the NF-kB signaling pathway and the induction of atherosclero - sis [3]. lncRNAs play crucial roles in the progression of diabetic nephropathy [12], glomerular disease [13] and renal fibrosis [14]. The lncRNA Arid-IR promotes NF- kB-mediated kidney inflammation by targeting NLRC5 transcription [15]. The cell cycle changes during aging. Previous studies have shown that lncRNAs are related to", + "expression of SIRT1 and are decreased in lymphoblastic cell lines generated from centenarians compared with those of AD patients, suggesting a protective effect of these miRNAs against neurodegeneration [66]. Long noncoding RNAs are important regulators of transcriptional networks and the closed or opened chromatin state [2]. One interesting example of an lncRNA is that associated with aging, H19. This lncRNA interacts with MBD1 (a methyl-", + "associated factors, modulating aging and senescence directly or in-directly. One such example includes a specific lncRNA, Gas5 ,w h i c h is highly expressed in aged mice brain and has been associated with im-paired learning ( 189). Another bona fide example is H19lncRNA, a dif- ferentially spliced product from the H19gene located at the IGF2/H19 imprinted locus, which interacts with methyl-CpG binding domain", + "tempting to speculate that these lncRNAs may exert some regulatory control of this locus, possibly contributing to senescent phenotypes. Together, these findings point to- wards a host of age-related ncRNAs as regulators of aging pathways and networks. Interaction network analysis The increased accuracy and breadth of our RNA-seq data sets allowed us to generate networks of gene func- tional change in aging liver, above and beyond what was observed using DAVID or GOrilla. Using Ingenuity", + "RNAs interact with proinflammatory signaling pathways and regulate senescence; however, their role on regulation of vas-cular aging processes is virtually unknown. 151 Interestingly, there is initial evidence linking the expression of the long noncoding RNA Meg3 (maternally expressed 3) to age-related impairment of angiogenic capacity of endothelial cells.152 Further studies are definitely needed to understand the", + "Page 2 of 11 Lietal. BMC Genomics (2022) 23:254 mechanism of kidney aging will be of great significance for delaying the occurrence and development of renal aging. Although a small number of studies have been conducted on renal aging, it is still meaningful to com - prehend the mechanism of renal aging. Long chain noncoding RNAs (lncRNAs) are more than 200 nucleotides in length. LncRNAs regulate transcrip - tional and posttranscriptional RNA processing, transla -" + ], + [ + "models of ageing, but it will also drastically accelerate the generation of refined ver - sions of those models or even allow the development of new research approaches in non-model organisms. Moreover, CRISPR-based genome editing is already having a significant impact in research aiming to understand the cellular and molecular origins of age-related diseases, as well as developing potential treatments against 11 Applications ofCRISPR-Cas inAgeing Research", + "of ageing. Finally, we will review how CRISPR-Cas has been used for creating new models for the study of age-related diseases, as well as for manipulating disease- associated gene pathways. S. Haston et al.", + "ularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9) will be beneficial in clari- fying aging-processes across species. An improved understanding of epigenetic mechanisms affecting longevity will be deciding crucial step towards the identification of new potential therapeutic targets. In fact, epigenetic drugs are of particular interest to the clinic due to their reversible and transient effect. A limitation of manifold epigenetic studies, however, are the variations among sin-", + "224 high-throughput assays able to further delineate important molecular pathways involved in inducing and maintaining cellular senescence in both physiological ageing and age-associated diseases. Applications ofCRISPR-Cas intheStudy ofAgeing-Related Disease Cardiovascular Disease One of the most notable contributions of CRISPR-Cas to ageing research is its ability to target non-proliferating cells (contrary to HDR-directed gene targeting),", + "219 Applications ofCRISPR-Cas inBasic Research oftheMolecular Causes ofAgeing Investigating theMechanisms ofLongevity Currently there have been no studies exploring the utility of the CRISPR-Cas sys- tem on experimentally extending the lifespan of physiologically aged laboratory animals. A main issue in this regard is that established vertebrate models already possess relatively long lifespans that make longevity extension studies economi-", + "CRISPR-Cas genome- editing tools will provide feasible implementation of 11 Applications ofCRISPR-Cas inAgeing Research", + "the basis for future investigations into the spatio-temporal dynamics of the telom- erase protein invivo.11 Applications ofCRISPR-Cas inAgeing Research", + "induced by telomere erosion. Protein Cell. 2019;10:3705.11 Applications ofCRISPR-Cas inAgeing Research", + "using bulk mRNA or even analyzing single cells (scRNA-seq). In addition, advances in molecular biology and cell culture approaches (for instance Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9) will be benecial in clarifying aging-processes across species. An improved understanding of epigenetic mechanisms affecting longevity will be deciding crucial step towards the identication of new potential therapeutic targets. In", + "In recent years, CRISPR-Cas technologies have significantly contributed to studies addressing the molecular pathogenesis of age-related neurodegenerative conditions such as Alzheimers disease (AD) and Parkinsons disease (PD). Currently, it has mostly been utilised for developing new or improved tools in which to study the molecular mechanisms underlying these diseases, such as in patient-derived cell lines carrying pathogenic mutations." + ], + [ + "Chromatin Remodeling, DNA Damage Repair and Aging Current Genomics, 2012 , Vol. 13, No. 7 539 Ercc1 also show premature aging phenotypes, providing evi- dence of a direct correlation between impaired DDR and premature aging [137, 138]. The relationship between DNA damage accumulation and aging has gained maximum credibility through studies", + "genome is being transcribed or replicated, the threshold of damage needed to activate DDRs, and 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 damage and cannot inform as to whether lesions accumulate over time. Longitudinal studies on tissues that can be serially accessed are desperately needed. DNA Repair Capacity Decreases with Aging", + "INTRODUCTION Damage to DNA occurs with surprising frequency. DNA lesions can cause mutations, blocktranscription and replication, and trigger the DNA damage response (DDR). The DDR arrests cell cycle progression and activates signaling pathways that impact cell fate: repair, apoptosis, or cellular senescence. DNA damage is widely recognized as a cause of cancer, and strong evidencenow links DNA damage to aging and diseases associated with aging.", + "DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence andageing. Curr. Opin. Genet. Dev. 26:8995 103. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, et al. 2009. Persistent DNA damage signalling triggers senescence-associated inammatory cytokine secretion. Nat. Cell Biol. 11:97379 104. Garinis GA, Uittenboogaard LM, Stachelscheid H, Fousteri M, van Ijcken W, et al. 2009. Persistent", + "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 48, 50. The analysis of apoptosis by TUNEL assay showed that leukocytes from untrained T2D subjects were more sensitive to H", + "E) (2931) and have alleviated the dependency on invitro and invivo models by using direct human samples. AGe-ReLATeD DNA DAMAGe AND DNA DAMAGe ReSPONSe (DDR) ACTiviTY Age-related accumulation of DNA damage has been studied thoroughly, showing correlation between age and damage levels or mutation frequency (32, 33). In the presence of DNA lesions or abnormalities, the DDR, a complex multigenic pathway, is", + "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 of signaling pathways termed the DDR, which facilitates repair and arrests cell cycle progression until 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,", + "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 endonuclease system, increases the burden of senescent cells in vivo and triggers hallmarks of liver aging (82), illustrating a clear path for how DNA damage can play a causal role in aging. Markers of senescence are detected at higher levels in tissues of older mice, humans, and other", + "mechanisms. In general, it appears that DDR signaling enhances DNA repair and autophagy tocontrol the level of damage in the cell. Interestingly, evidence, albeit early evidence, has been found that DNA damage is linked to proteostasis. Expression of proteins containing polyglutamine tracts that drive protein aggrega- tion linked to neurodegeneration activates the DDR and H2AX foci (148). Interestingly, DNA breaks in cells and H2AX foci in brain of a murine model of Huntington disease are detected", + "its relevance to age -related functional decline at the molecular and cellular level. The importance of oxidative stress and key DNA damage response (DDR) pathways in cellular aging is discussed, with a special focus on poly (ADP -ribose) polymerase 1, whose persistent activation depletes cellular energy reserves, leading to mitochondrial dysfunction, loss of energy homeostasis , and altered cellular metabolism. Elucidation of the relationship between genomic instability ," + ], + [ + "immune system are one of the hallmarks of the aging body. Immunosenescence is the functional decline of the adaptive immune system brought on by natural agingwhereby protection against infection by pathogens and the effectiveness of vaccination decline [45,46]. The sec- ond aging-induced change in the immune system iscalled inflammaging which is characterized by a low- grade chronic inflammation process that contributes to", + "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", + "[39] C. Castelo-Branco, I. Soveral, The immune system and aging: a review, Gynecol. Endocrinol. 30 (2014) 1622. [40] S.A. Johnson, S.J. Rozzo, J.C. Cambier, Aging-dependent exclusion of antigen-in - experienced cells from the peripheral B cell repertoire, J. Immunol. 168 (2002) 50145023 . [41] D.P. Shanley, D. Aw, N.R. Manley, D.B. Palmer, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. 30 (2009) 374381.", + "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 inflammation. Along with a decline in immune function, aging is accompanied by a widespread of omics remodeling.", + "ence the development of inflamm-aging and immunosenes- cence phenotypes. Finally, although discussed studies have reported age-related changes in innate immune cell processes, there is still little known about how these changes are influenced by biologicalsex. Indeed, both the adult mammalian immune system [ 80,125] and the aging process [ 126] are sex-dimorphic, suggesting that", + "tion has also been implicated in ageing across a range of non-model organisms, including mice,nematode worms ( Caenorhabditis elegans ), and primates [ 4042]. The damage caused by the ageing adaptive and innate immune systems gives us insights into how these different arms of the immune system may in uence longevity. In general, adaptive im- mune function diminishes with age, whereas innate immune function is maintained [ 34,4346].", + "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. Lymphocyte development and ageing", + "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 undergoes a gradual remodeling in the attempt to reestablisha new balance that assures survival, however, favoring thedevelopment of chronic inammatory conditions [ 5,6,8,9]. DNA damage and inammation are inevitably linked by", + "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", + "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 with the initiation of age-associated diseases and progeroidsyndromes ( Hasty et al., 2003; Lieber and Karanjawala, 2004). Furthermore, dysregulated immune and inamma- tory responses have been already documented both inhumans and mouse with increasing age ( Badawi et al., 2004; Kovaiou et al., 2007 )." + ], + [ + "tifications of biological aging: do they measure the same thing? Am J Epidemiol. 2018;187(6):122030. 74. Putin E, etal. Deep biomarkers of human aging: application of deep neural networks to bio- marker development. Aging (Albany NY). 2016;8(5):102133. 75. Rehkopf DH, etal. Leukocyte telomere length in relation to 17 biomarkers of cardiovascular disease risk: a cross-sectional study of US adults. PLoS Med. 2016;13(11):e1002188.", + "studied (Table 13.1). Thus, due to the generation of these data and technological advances, possibly in the future, artificial intelligence programs will be able to reliably forecast the life of an individual, as well as the possible diseases that he may suffer in ageing; so these advances and discoveries will allow us to achieve a personalized medical treatment as a result of to the integration of biomarkers of ageing. Ageing Is aTreatable Condition", + "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). Among the many computational algorithms, linear regres- sion and its variants have been widely used to select aging-relatedbiomarkers and build aging clocks, namely, predictors of chro- nological age and biological age, in various omics data sets and ag-", + "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- namics (Schumacher et al. 2021; Lpez-Otn et al. 2023). Although informative, they are not always quantitatively predictive of anindividual s true biological age, nor are they easy to obtain. The ad-", + "biomarkers of the aging process.", + "supervisedmachinelearningappliedtoageingresearch. Biogerontology ,18,171188. 47. Kriete,A.,Lechner,M.,Clearfield,D.andBohmann,D.(2011) Computationalsystemsbiologyofaging. WileyInterdiscip.Rev.Syst. Biol.Med. ,3,414428.Downloaded from https://academic.oup.com/nar/article/46/D1/D1083/4599180 by guest on 14 October 2023", + "associated with age, such as mouth width, nose width, and eye corner droop. This type of bioimage analysis has rendered relatively accurate calculations of the actual age, although this accuracy tended to fall with increasing age after 40years [71]. Integration ofBiomarkers ofAgeing Biomarkers of ageing allow estimating the biological age of an organism (Table 13.1) while providing information on their health status. Different studies are looking for", + "Background There is a marked heterogeneity in human lifespan and health outcomes for people of the same chronological age. Thus, one fundamental challenge is to identify mo- lecular and cellular biomarkers of aging that could pre- dict lifespan and be useful in evaluating lifestyle changes and therapeutic strategies in the pursuit of healthy aging. Here, we developed a computational method to predict biological age from gene expression data in skin fibro-", + "Background Ageing is a major risk for diseases and mortality [ 1,2]. Chronological age has been widely used as a marker of ageing due to ease and accuracy of measurement [ 1]. However, it is not necessarily a good predictor of biological ageing since individuals with the same chronological age can vary in health, especially in later life [ 3]. Therefore, researchers have attempted to search for biomarkers of ageing that can predict functional cap- ability at a later age [ 4,5]. In 2013, Hannum et al. and", + "discriminate between adverse aging-related events, such as frailty (Mitnitski et al. 2002 ), immobility (Simonsick et al. 2001 ), and propensity to fall (Lord et al.1994 ). There are additional considerations when choosing biomarkers to characterize aging. First, biomarkers measured at a given age are merely snapshots of important regulatory systems (Seeman et al. 2004 ); there is no information on system dynamics if each biomarker is measured only once. Having longitudinal" + ], + [ + "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", + "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. The last review in this special issue by Hou et al. brings things together nicely with a systems biology perspective of aging. In order to model the immense complexity of aging, we require systems-level approaches. This review describes how several", + "autoregulation of blood flow,218 vascular structural remodel- ing, atherogenesis,219 and angiogenic processes.220 The impact of circulating factors on aging phenotypes was also demonstrated by studies using mice with heter - ochronic parabiosis, which involves surgically connecting the circulatory system of a young and an aged mouse. 221 Cerebromicrovascular density typically declines with ad-vanced age, 222 and there is initial evidence that circulating an-", + "components, particularly chemokines and cytokines, in theblood and tissues ( Villeda et al., 2011 ). In addition to illuminating the inuence of the systemic environment on cellular function,such heterochronic studies emphasize the potential role of envi-ronmental factors in rejuvenating aged cells. Molecular signatures of aging have been directly tested as", + "related diseases. Ageing Res Rev. 2018;47:21477. 115. Kumar S, Vijayan M, Bhatti JS, Reddy PH.MicroRNAs as peripheral biomarkers in aging and age-related diseases. Prog Mol Biol Transl Sci. 2017;146:4794. 116. Smith-Vikos T, Liu Z, Parsons C, Gorospe M, Ferrucci L, Gill TM, etal. A serum miRNA profile of human longevity: findings from the Baltimore Longitudinal Study of Aging (BLSA). Aging (Albany NY). 2016;8(11):297187.", + "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 alter the function of neighboring cells, and the role of this mechanism in vascular aging should be further evaluated. The possibility of paracrine transmission of senescence from microvascular endothelial cells to parenchymal cells also requires further investigations. It should be noted that many", + "protein VSIG4 as a biomarker of aging in murine adiposetissue. Aging Cell 2020; 19:e13219. 128. Angelidis I, Simon LM, Fernandez IE, et al. An atlas of the aging lung mapped by single cell transcriptomics and deeptissue proteomics. Nat Commun 2019; 10:963. 129. Clark D, Brazina S, Yang F, et al. Age-related changes to macrophages are detrimental to fracture healing in mice. Aging Cell 2020; 19:e13112. 130. Tabula Muris Consortium. A single-cell transcriptomic", + "Ungvari et al Mechanisms of Vascular Aging 861 mechanisms of vascular aging and identify translationally relevant treatments for the promotion of vascular health in older adults. The same cellular and molecular aging processes that af- fect arterial vessels and capillaries also affect veins and the lymphatic/glymphatic system, likely contributing to various disease pathologies. Examples include the potential role of cerebral venules in neuroinflammation, Alzheimer disease, and cerebral microhemorrhages", + "et al., Plasma proteomic signature of age in healthy humans, Aging Cell 17 (2018). [17] D. Mari, P.M. Mannucci, R. Coppola, B. Bottasso, K.A. Bauer, R.D. Rosenberg, Hypercoagulability in centenarians - the paradox of successful aging, Blood 85 (1995) 31443149. [18] S.A. Phillips, The vasculature in cardiovascular diseases: will the vasculature tell us what the future holds? Prog. Cardiovasc. Dis. 57 (2015) 407408. [19] R.A. Gibbs, J. Rogers, M.G. Katze, R. Bumgarner, G.M. Weinstock, E.R. Mardis,", + "16Lidzbarsky et al. Genomic Instabilities, Cellular Senescence, and Aging Frontiers in Medicine | www.frontiersin.org April 2018 | Volume 5 | Article 104 177. Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci (2012) 125:717. doi:10.1242/jcs.099200 178. Lanceta J, Prough RA, Liang R, Wang E. MicroRNA group disorganiza- tion in aging. Exp Gerontol (2010) 45:26978. doi:10.1016/j.exger.2009. 12.009" + ], + [ + "the adaptation of the microbiota to the physiological changes of the long aging process. It has been demonstrated that the microbiota on this population maintains the health and promotes the survival. Additionally, a relationship between a healthy microbiota and longevity had been proposed [44]. A possible pathway is an immu- nological and metabolic regulation linked to the increase of bacterial compounds like Christensenellaceae, Akkermansia, and Bifidobacterium [44, 45].", + "Marchesi JR, Falush D, Dinan T, Fitzgerald G, et al:Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA 2011, 108(Suppl 1):4586 4591. 21. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S, Donehower LA, Issa JP: Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 2010, 20(3):332 340. 22. Englander EW: Gene expression changes reveal patterns of aging in the", + "microbiota present in infants, adults, and the elderly. Appl. Environ. Microbiol. 73, 77677770 (2007). 40. Kong, F. et al. Gut microbiota signatures of longevity. Curr. Biol. 26, R832R833 (2016). 41. Tremaroli, V. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 22, 228238 (2015). 42. Everard, A. et al. Microbiome of prebiotic-treated mice reveals novel targets involved", + "Therefore, research in the field has demonstrated that aging is a potential modi- fier of the composition and function of the human microbiome. Figure 9.3 shows the local composition of the microbiome in an average older adult. It can be seen that Bacteroidetes and Firmicutes species are the most prevalent in this age. Recent data has shown that older people hide a microbiota that differs in the type and number of microorganisms from that of younger adults [38]. Young people", + "related malnutrition. Furthermore, it has been shownthat aging can cause bacterial overgrowth in the smallintestine [16,17] and promote changes in microbial com- position in the colon [18-20]. In addition, reported age- related changes in DNA methylation of the mouseintestine [21] might play a role in the altered gene expression levels observed in the duodenum and colon of aging mice [22]. Together these observations demon-strate that although certain aspects of the aging intestine", + "detectable. Changes in the gut microbiota in terms of compos- ition and functionality during the process of aging have previously been reported [19,20,51] and it hasbeen postulated that these changes might contribute to the development of immunosenescence and inflam- maging [18,52]. To establish whether the enhanced expression of genes playing a role in the immune sys- tem are due to modifications in the microbiota wemeasured the total number of all bacteria and of the", + "37. Li H, Qi Y , Jasper H.Preventing age-related decline of gut compartmentalization limits micro- biota Dysbiosis and extends lifespan. Cell Host Microbe. 2016;19(2):24053. 38. Mihajlovski A, Dor J, Levenez F, Alric M, Brugre J.Molecular evaluation of the human gut methanogenic archaeal microbiota reveals an age-associated increase of the diversity. Environ Microbiol Rep. 2010;2(2):27280. 39. Quercia S, Candela M, Giuliani C, Turroni S, Luiselli D, Rampelli S, etal. From lifetime to", + "[26], but at advanced ages, dramatic changes in its composition are associated with various diseases and frailty [27, 28]. Regarding pathological processes, it is known that cancer, obesity, diabetes, and inflammatory bowel disease (IBD) are associated with specific microbial alterations [29, 30]. In older ages, a burden of intrinsic and extrinsic factors affects the compo- sition of the microbiome and plays a determining role in every tract and tissue. Such mentioned factors can be seen in Fig.9.2.", + "Osawa R. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90. 14. Dugue PA, Bassett JK, Joo JE, Jung CH, Ming Wong E, Moreno-Betancur M, Schmidt D, Makalic E, Li S, Severi G, et al. DNA methylation-based biological aging and cancer risk and survival: pooled analysis of seven prospective studies. Int J Cancer. 2018;142(8):1611 9. 15. Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S. DNA", + "survival advantage that is age- and site-specific: Results from a large multi-site study. Aging Cell 18, e12905 (2019). [PubMed: 30801953] 51. Houtkooper RHet al.The metabolic footprint of aging in mice. Sci. Rep. 1, 134 (2011). [PubMed: 22355651] 52. Morrison KE, Jaarevi E, Howard CD & Bale TL Its the fiber, not the fat: significant effects of dietary challenge on the gut microbiome. Microbiome 8, 15 (2020). [PubMed: 32046785]" + ], + [ + "Metabolism Studies show that calorie restriction is the most consistent means to prolong life expectancy and health across several experimental models [55], ranging from yeasts to primates. It not only increases life expectancy, but it also delays the onset of many features and hallmarks of ageing, including age-related diseases. Transcriptional profiles are currently being applied and investigated. One of them is a caloric restric-", + "Keywords: caloric restriction; hepatic expression profiling; lifespan prolongation; metabolic signaling;microarray analysis; nutrition response. Introduction", + "(154, 155). Caloric restriction has been shown to sig- nicantly 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", + "Calorie restriction, a dietary regimen that extends the lifespan of numerous organisms, also delays the majority of age-related gene-expression changes in mice and, to a certain extent, in flies45,50. It is currently unclear whether the effect of calorie restriction on gene expression underlies its beneficial effect on lifespan or is merely a consequence thereof. Findings in yeast suggest that there may be a causal link: Sir2 not only facilitates heterochromatin and promotes DNA stability, but is", + "life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:21262128. Mair W, Goymer P, Pletcher SD, and Partridge L (2003) Demography of dietary restriction and death in Drosophila. Science 301:17311733. Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913922. Mathers JC (2006) Nutritional modulation of ageing: genomic and epigenetic ap- proaches. Mech Ageing Dev 127:584589. Meric-Bernstam F and Gonzalez-Angulo AM (2009) Targeting the mTOR signaling", + "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", + "extension by dietary restriction. Annu Rev Biochem 2008, 77:727-54. 8. Harper JM, Leathers CW, Austad SN: Does caloric restriction extend life iin wild mice? Aging Cell 2006, 5:441-9. 9. Forster MJ, Morris P, Sohal RS: Genotype and age influence the effect of caloric intake on mortality in mice. FASEB J 2003, 17:690-2. 10. Spindler SR, Mote PL: Screening candidate longevity therapeu- tics using gene-e xpression arrays. Gerontology 2007, 53:306-21.", + "Corton JC, Apte U, Anderson SP, Limaye P, Yoon L. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. J Biol Chem 2004;279:4620446212. [PubMed: 15302862] Ferguson M, Sohal BH, Forster MJ, Sohal RS. Effect of long-term caloric restriction on oxygen consumption and body temperature in two different strains of mice. Mech Ageing Dev 2007;128:539545. [PubMed: 17822741] Forster MJ, Morris P, Sohal RS. Genotype and age influence the effect of caloric intake on mortality in", + "A key question still unresolved is to what extent the mechanisms of aging are conserved between species with vastly different lifespans. Some studies suggest that similar mechanisms 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", + "10.1111/acel.12103 241. Edwards AG, Donato AJ, Lesniewski LA, Gioscia RA, Seals DR, Moore RL. Life-long caloric restriction elicits pronounced protection of the aged myocardium: a role for AMPK. Mech Ageing Dev. 2010;131:739 742. doi: 10.1016/j.mad.2010.09.007 242. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all- cause mortality in rhesus monkeys. Nat Commun. 2014;5:3557. doi: 10.1038/ncomms4557" + ], + [ + "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, resulting 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", + "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 Figure 2. Proposed scheme for mechanisms and pathological consequences of age-related oxidative stress in vascular endothelial cells. The", + "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 of literature indicates that oxidative damage to all cellular macromolecules increases with age. Furthermore, overexpression of antioxidant enzymes that detoxify ROS, such as copper- andzinc-containing superoxide dismutase (SOD), manganese-containing SOD, or catalase, increase", + "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", + "during\tthe\taging\tprocess\t(Yi,\tChang,\t&\tShong,\t2018).\tOxidative\tdam - age to cellular macromolecules, or stress arising from mitochondrial DNA\t(mtDNA)\tmutation\tand\tincreased\treactive\toxygen\tspecies\t (ROS),\tis\ta\tkey\thallmark\tof\taging\tphysiology\t(Yi\tet\tal.,\t2018).\tAlthough", + "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 damage to mtDNA could exacerbate this leakage of reactive oxygen species (ROS) (4). It is not known how mtDNA deletions accumulate during", + "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 - sis in a significant enough way to influ - ence aging. The most obvious target for this damage is mtDNA. The generation of ROS specifically by complex I corre - lates with levels of oxidative damage in mtDNA.", + "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", + "Molecular Biomarkers forOxidative Stress There are many theories that try to explain the nature of aging; however, none of them can explain every aspect of the biology of aging. One of the most accepted and studied is the one proposed by Denham Harman in 1956. This theory proposed that during lifespan organisms accumulate oxidative damage in their biomolecules. Oxidative damage is generated by reactive oxygen species (ROS), which are the", + "production by mitochondria and increased 8-oxo-dG con-tent in the mtDNA are frequently detected in aged tissues [40,4750], suggesting that progressive accumulation of oxidative DNA damage is a contributory factor to the agingprocess. Consistently, many studies have found that increasedoxidative damage in cells is associated with aging [ 5153]. Furthermore, genetic studies in worm, y, and mouse havelinked enhanced stress resistance or reduced free radical" + ], + [ + "208 Additional features that contribute to increased ar - terial 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). 208,210,211 The pathophysiological consequences of age-related ECM remodeling and arterial stiffening have been the sub-ject of a recent comprehensive review by AlGhatrif and Lakatta.", + "collagen. AGE-mediated cross-links can confer resis-tance to enzymatic degradation, and thus interferewith collagenolysis (56). In addition, increased ac- tivity of TGF- bwith aging stimulates the synthesis of interstitial collagen by vascular smooth muscle cells(VSMCs), and thereby augments arterial stiffness (57). Likewise, increased activity of the RAAS may augment collagen synthesis and heighten elastolysis (58). Endothelial dysfunction and arterial stiffness are", + "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. 209 Collagen synthesis is also dysregulated with age in the vascular wall likely because of the effects of increased para-crine action of TGF- (transforming growth factor- ), 123 which contributes to vascular fibrosis and arterial stiffen-ing.", + "Ungvari et al Mechanisms of Vascular Aging 859 Role of Extracellular Matrix Remodeling in Vascular Aging The extracellular matrix (ECM) is an important contribu- tor 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 biomechanical and biochemical signals required for tissue homeostasis, morphogenesis, and cell differentiation. Studies", + "1996;25(3):20915. 79. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786801. 80. Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PCDP , Pinter J, et al. Nuclear Lamin-A scales with tissue stiffness and enhances matrix- directed differentiation. Science. 2013;341(6149):1240104. 81. Vogel C, Marcotte EM. Insights into the regulation of protein abun- dance from proteomic and transcriptomic analyses. Nat Rev Genet.", + "result in extracellular matrix stiffness in aging larynx and other organs [59, 79]. Finally, Lamin A was upregulated by dehydration, by a smaller magnitude, especially when observing the mean difference within the young groups. Previous data has identified that Lamin proteins A and C are important for imparting the nucleus with its stiff - ness, and their expression has been reported to scale with", + "aging. Annu Rev Biomed Eng. 2015;17:113141. doi: 10.1146/ annurev-bioeng-071114-040829 208. Jacob MP. Extracellular matrix remodeling and matrix metalloprotein- ases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother. 2003;57:195202. 209. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, Ungvari Z. Insulin-like growth factor 1 deficiency exacerbates hyperten-", + "able human diseases such as osteoporosis and musculo- skeletal diseases [53]. Collagens are long-lived proteins known to accumulate damage during aging, leading to a decline in tissue health [54]. Also, type I collagens be- come resistant to proteolysis upon age [55, 56], affecting their turnover. Interestingly, mice expressing cleavage- resistant type I collagen go through an accelerated aging process [57]. Thus, cellular aging can be affected by the state of the extracellular matrix in mammals.", + "the characteristics of endothelial dysfunction and pheno- typic transition of smooth muscle cells, resulting in in- creased vascular stiffness and increased thickness of vascular walls. It has been reported that the age- associated phenotypic transition of VSMCs is a crucial contributor to vascular remodeling [ 17,25]. However, the mechanism that drives phenotypic transition ofVSMCs with aging remains unclarified. In this study, using RNAs extracted from the in vitro cultured VSMCs,", + "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" + ], + [ + "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 lifespan. Cell Metab. 19, 431 444 (2014). 225. S. Gelino, M. Hansen, Autophagy An emerging anti-aging mechanism. J. Clin. Exp. Pathol. (Suppl. 4), pii: 006 (2012).", + "[73] Vellai, T. Autophagy genes and ageing . Cell Death Differ. , 2009 , 16(1), 94-102. [74] Kaeberlein, M.; Kapahi, P. Cell signaling. Aging is RSKy business . Science , 2009 , 326(5949), 55-6. [75] Hansen, M.; Chandra, A.; Mitic, L.L.; Onken, B.; Driscoll, M.; Kenyon, C. A role for autophagy genes in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. , 2008 . [76] Hansen, M.; Taubert, S.; Crawford, D.; Libina, N.; Lee, S.J.;", + "chinery and upstream regulators provide evidence for a transcriptional decline in autophagy gene expression with age in human monocytes. The identification of key genes contributing to a decline in autophagy are of great interest, as pharmacologic activation of au- tophagy has been linked with increasing lifespan in animal models, including mice [45]. Further, dysfunc- tional autophagy is now widely implicated in patho- physiological processes of many age-related diseases", + "invasive pathogens, and to transport these cargos to the lysosomes for degradation [25]. In the aging field, im- paired autophagy is considered one of the principal de- terminants of cellular aging, which is supported by in vitro and animal study findings that autophagy de- clines with age [26]. However, studies of autophagy and age in humans are sparse. One of the most significant age-gene expression asso- ciations we observed in monocytes from 1,264 individ-", + "226. F. Madeo, N. Tavernarakis, G. Kroemer, Can autophagy promote longevity? Nat. Cell Biol. 12, 842 846 (2010). 227. J. Fllgrabe, M. A. Lynch-Day, N. Heldring, W. Li, R. B. Struijk, Q. Ma, O. Hermanson, M. G. Rosenfeld, D. J. Klionsky, B. Joseph, The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature 500, 468 471 (2013). 228. F. Ng, B. L. Tang, Sirtuins modulation of autophagy. J. Cell. Physiol. 228, 2262 2270 (2013).", + "(2013) The hallmarks of aging. Cell 153(6):11941217. doi: 10. 1016/j.cell.2013.05.039 3. Vellai T, Takacs-Vellai K, Sass M, Klionsky DJ (2009) The regulation of aging: does autophagy underlie longevity? TrendsCell Biol 19(10):487494. doi: 10.1016/j.tcb.2009.07.007 4. Kirkwood TB (2008) A systematic look at an old problem. Nature 451(7179):644647. doi: 10.1038/451644a 5. Koubova J, Guarente L (2003) How does calorie restriction work? Genes Dev 17(3):313321. doi: 10.1101/gad.1052903", + "Eisenberg, T., Knauer, H., Schauer, A., Bu ttner, S., Ruckenstuhl, C., Carmona- Gutierrez, D., Ring, J., Schroeder, S., Magnes, C., Antonacci, L., et al. (2009).Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 13051314. Enns, L.C., Morton, J.F., Treuting, P.R., Emond, M.J., Wolf, N.S., Dai, D.F., McKnight, G.S., Rabinovitch, P.S., and Ladiges, W.C. (2009). Disruption of protein kinase A in mice enhances healthy aging. PLoS ONE 4, e5963.", + "its essential part in the anti-aging mechanism of caloric restriction. Ann N Y Acad Sci. 2007;1114:69 78. 41. Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A. Autophagy and aging: the importance of maintaining clean cells. Autophagy. 2005;1:131 40. 42. Terman A. The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocytes. Gerontology. 1995;41 Suppl 2:319 26. 43. Donati A, Recchia G, Cavallini G, Bergamini E. Effect of aging and anti-aging", + "103 Experimental findings showing increased oxidative stress, impaired bioavailability of NO, and upregulation of in-flammatory mediators in autophagy-deficient endothelial cells support this view. 104 Further, pharmacological interventions that stimulate autophagy (eg, trehalose or spermidine treat-ment) were reported to reverse aspects of arterial aging. 105,106 Proteasomes degrade unneeded or damaged proteins by pro-teolysis. There is evidence that proteasome activity declines in advanced aging", + "Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456 61. 38. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, et al. Structure of mammalian AMPK and its regulation by ADP. Nature. 2011;472:230 3. 39. Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190:881 92. 40. Bergamini E, Cavallini G, Donati A, Gori Z. The role of autophagy in aging:" + ], + [ + "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", + "matopoietic stem cells is regulated by the stemcell niche. Exp Gerontol. 2008;43(11):974-980. 18. Geiger H, Rudolph KL. Aging in the lympho- hematopoietic stem cell compartment. Trends Immunol. 2009;30(7):360-365. 19. Muller-Sieburg C, Sieburg HB. Stem cell aging: survival of the laziest? Cell Cycle. 2008;7(24): 3798-3804. 20. Beerman I, Maloney WJ, Weissmann IL, Rossi DJ. Stem cells and the aging hematopoieticsystem. Curr Opin Immunol. 2010;22(4):500-506. 21. Teschendorff AE, Menon U, Gentry-Maharaj A,", + "Abstract The regenerative potential diminishes with age and this has been ascribed to functional impairments of adult stem cells. Cells in culture undergo senescence after a certain number of cell divisions whereby the cells enlarge and finally stop proliferation. This observation of replicative senescence has been extrapolated to somatic stem cells in vivo and might", + "Because of their plasticity and accessibility these cells are also prime candidates for regenerative medicine. The contribution of stem cell aging to organismal aging is un der debate and one theory is that reparative processes deteriorate as a consequence of stem cell aging and/or de crease in number. Age has been linked with changes in osteogenic and adipogen ic potential of MSCs. Results: Here we report on changes in global gene expression of cultured MSCs isolated from the bone marrow of", + "suggesting that stem cells are not likely to be a factor limiting hematopoietic regeneration with age. However, their func-tional decits do show that HSCs are impacted by the forces of aging in a manner similar to that of differentiated cells [3134]. In our molecular analysis, we identied global age-related changes in gene expression in murine HSCs, with a view to identifying mechanisms that could be responsible for these age-associated declines in HSC function. Genes involved in", + "Discussion The deterioration of the regenerative potential upon aging might be due to functional changes in adult stem cells. To test this hypothesis we have investigated differential gene expression in primary, human MSC and HPC derived from different agegroups. In this study, we demonstrate for the first time age-related gene expression changes in human MSC and HPC and that there", + "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 and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated", + "tion associated with age: loss of stem cell pool division potential (loss of regenerative capacity) and loss ofdierentiated somatic cell function, which directly leads to loss of organ function. Loss of dierentiated somatic cell function can additionally indirectly aect adult stem and progenitor cells by altering the tissue microenviron- ment that is essential for stem cell support (the stem cellniche). In general, loss of stem cell pool division potential", + "1. Introduction Stem cell aging is regarded as one of the contributors to several degenerative conditions af icting the elderly because it underlies the physiological decline in tissue maintenance and regenerative capacity of many organs ( Rossi et al., 2008 ). The brain is one such organ that contains discrete populations of stem cells and their precursors (collectively referred to as neural progenitor cells [NPCs]) that continue to generate new neurons throughout life", + "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-" + ], + [ + "vascular and kidney diseases [47]. Advanced glycation end-products (AGE) are the result of nonenzymatic glyca- tion, which produces heterogeneous bioactive molecules, such as lipids, proteins, and nucleic acids [59]. The accumulation of AGEs in aged tissues leads to several processes, such as inflammation, obesity, apoptosis, and other adverse processes related to ageing [47]. These AGEs are detected by various techniques, such as", + "and leading to vascular hypertrophy and stiffening of collagen with subsequent reduction of arterial compliance. These are processes that are associated with aging but seem to be accelerated by hyperglycemia. These cross-linked macromolecules, called advanced glycosylation end products (AGEs), are implicated in the pathogenesis of vascular complications. Once", + "proposed mechanisms are the development of advanced glycosylation end products and sorbitol accumulation. Advanced glycosylation end products (AGEs) comprise a heterogeneous group of molecules that accumulate in plasma and tissues with advancing age, diabetes and renal failure. They are characterized by browning, fluorescence, cross-linking and biological response through specific AGE receptors and were first described in 1912 by French chemist L.C. Maillard (Fig. 5).", + "the accumulation of AGEs which can further perp etuate and amplify local inflammation and 197 oxidant stress through irreversible glycation of the various protei ns and lipids to promote long 198 term vascular and end-organ damage. Thus AGEs, acting through receptors such as RAGE, 199 could also contribute to hyperglycemic memo ry (18, 96, 147). These studies have begun to 200", + "AGEs are taken up by specific AGE receptors (RAGE), cytokines, growth factors, and adhesion factors are released, leading to further cellular changes. AGEs also can impair endothelial function and vascular reactivity, such as in response to nitric oxide. Modification of LDL as a result of glycation may contribute to foam cell formation.4 Thus, AGEs appear to be main players not only in the development of diabetic complications and atherosclerosis,", + "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", + "Introduction In individuals with diabetes, nonenzymatic glycation of proteins leads to the formation of advanced glycation end products (AGE) and this process occurs at an accelerated rate in chronic hyperglycaemia1, and also the levels are found to be increased in complications of diabetes, such as diabetic retinopathy (DR).2 AGE induces a variety of pathological changes, such as increased basement membrane thickening, arterial stiffness, and glomerular sclerosis.3,4AGEs bind to a specic receptor", + "AGEs accelerate atherosclerosis through cross-linking of proteins, platelet aggregation, defective vascular relaxation, and abnormal lipoprotein metabolism. 30 AGEs have a vital role in pathogenesis of diabetic nephropathy and progression of renal failure. Renal failure, in turn, results in decreased excretion and increased generation of AGEs (Figure 6). 629", + "vessels show enhanced subintimal protein and lipoprotein deposition; increased vascular permeability, e.g. to albumin; inactivation of nitric oxide; activation of endothelial receptors, leading to vasoconstriction and thrombosis; altered proteoglycan milieu; altered basement membrane cellular structure; proliferation of matrix. Strategies directed at the prevention of formation or the disruption of AGE cross-links may be promising. REFERENCES:", + "proteins and nucleic acids, leads to modification and then decline in structure and function of these molecules, as the cross-links accumulate both extracellularly and intracellularly over time. A prime example would be the crosslinking of collagen, which is thought to lead to typical phenomena observed in aging, such as increased susceptibility to atherosclerosis, osteoporosis, decreased joint elasticity, the formation of cataracts, and" + ] + ], + "task_id": [1,2,3,4,5,6,7,8,9,10,1,2,3,4,5,6,7,8,9,10] +}
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