From 00cba4b9a1e88891f1f96a1199320092c1962343 Mon Sep 17 00:00:00 2001 From: ShelbySolomonDarnell Date: Thu, 17 Oct 2024 12:24:26 +0300 Subject: Docker image built to run code, all evals run using R2R --- .../data/dataset/gpt4o/gpt4o_cs_aging.json | 289 +++++++++++++++++++++ 1 file changed, 289 insertions(+) create mode 100644 gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_cs_aging.json (limited to 'gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_cs_aging.json') diff --git a/gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_cs_aging.json b/gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_cs_aging.json new file mode 100644 index 0000000..50bedda --- /dev/null +++ b/gnqa/paper2_eval/data/dataset/gpt4o/gpt4o_cs_aging.json @@ -0,0 +1,289 @@ +{ + "question": [ + "What are the main genetic factors that influence aging?", + "How do genes affect the aging process in humans?", + "What lifestyle choices can help slow down genetic aging?", + "How do scientists study the genetics of aging in animals?", + "Are there specific genes that have been linked to longer lifespans?", + "How do telomeres affect the aging process?", + "What role does DNA repair play in aging?", + "Can genetic research lead to treatments that slow down aging?", + "How does mitochondrial DNA influence aging?", + "Are there any known genetic mutations that cause premature aging?", + "What recent discoveries have been made about the genetics of aging?", + "How do epigenetic changes affect aging?", + "What is the role of the gene FOXO3 in longevity?", + "How does the environment interact with genes to influence aging?", + "What are senescent cells and how do they contribute to aging?", + "Are there any known lifestyle interventions that can positively impact genes related to aging?", + "What is the 'epigenetic clock,' and how is it used in aging research?", + "How do researchers use model organisms like yeast or worms to study human aging?", + "Are there any promising anti-aging therapies being developed based on genetic research?", + "How do caloric restriction and diet impact the genetics of aging?" + ], + "answer": [ + "The main genetic factors that influence aging include: 1. **Genomic Instability**: Aging is associated with the accumulation of DNA damage and the dysregulation of repair mechanisms, leading to genomic instability [9]. 2. **Telomere Attrition**: The shortening of telomeres, which are protective caps at the ends of chromosomes, is a significant factor in aging [9], [10]. 3. **Epigenetic Alterations**: Changes in epigenetic marks, which regulate gene expression without altering the DNA sequence, play a crucial role in aging [2], [4], [9], [10]. 4. **Deregulated Nutrient Sensing**: The pathways that sense and respond to nutrients become deregulated with age, affecting longevity [10]. 5. **Mitochondrial Dysfunction**: Mitochondria, the energy-producing organelles in cells, become less efficient with age, contributing to the aging process [10]. 6. **Cellular Senescence**: The process by which cells lose the ability to divide and function properly is a hallmark of aging [9], [10]. 7. **Loss of Proteostasis**: The ability of cells to maintain protein homeostasis declines with age, leading to the accumulation of damaged proteins [9], [10]. 8. **Stem Cell Exhaustion**: The decline in the regenerative capacity of stem cells contributes to aging [10]. These factors collectively shape the complex genetic landscape of aging, influencing the expression of aging phenotypes and lifespan [7].", + "Genes affect the aging process in humans through complex interactions and pathways. Research has shown that single genes can regulate aging in model organisms, indicating that aging can be genetically manipulated [2]. Hundreds of genes have been identified that modulate longevity in these organisms, and some of these genes and their associated pathways, such as the insulin/IGF1/GH pathway, have been shown to affect longevity across different species, suggesting that some mechanisms of aging are evolutionarily conserved [3]. In humans, it has been more challenging to identify specific longevity candidate genes, but studies have shown that certain genes associated with aging in model organisms are evolutionarily conserved and may be relevant to human aging [5]. Additionally, approximately 4% of genes analyzed in a study of postmortem human brain tissue showed significant age-related expression changes, indicating that these genes play central roles in processes like synaptic plasticity, vesicular transport, and mitochondrial function [8]. Overall, while aging is a complex process involving multiple genes and their interactions with the environment, genetic studies in model organisms provide insights that may be applicable to understanding human aging [9].", + "To slow down genetic aging, several lifestyle choices can be beneficial: 1. **Dietary Restriction (DR)**: Reducing food intake without causing malnutrition has been shown to extend lifespan in various organisms. This approach improves healthspan by influencing nutrient-sensing signaling networks and metabolism [1]. 2. **Healthy Diet and Physical Exercise**: Engaging in regular physical activity and maintaining a healthy diet can slow down aging and prevent or modify many chronic diseases prevalent in older adults. This contributes to successful aging, allowing individuals to achieve physical, social, and mental well-being [4]. 3. **Caloric Restriction**: This is considered a reasonable anti-aging intervention, as it has been shown to slow aging in multiple species, including yeast, nematodes, fruit flies, and rodents [6]. 4. **Exercise**: While exercise may not retard aging in all tissues, it can contribute to molecular-level aging retardation, which is beneficial for overall health and longevity [10]. These lifestyle choices, when combined, can help mitigate the effects of genetic aging and promote a longer, healthier life.", + "Scientists study the genetics of aging in animals using a variety of approaches and model organisms. Here are some key methods and models mentioned in the context: 1. **Animal Model Systems**: Rodents, such as rats and mice, are indispensable for molecular biological studies on aging due to their practical advantages and similarities in aging processes to humans [1]. 2. **Tissue-Specific Studies**: Recent genomic studies have been performed on specialized mammalian tissues, both post-mitotic (e.g., heart, nervous system) and mitotic (e.g., liver), to understand the tissue-specific effects of aging. These studies also explore how caloric restriction affects age-related transcriptional changes, which are tissue- or species-specific [2]. 3. **Laboratory Models**: Common laboratory models for studying aging include Caenorhabditis elegans (nematode worm) and Mus musculus (mice), which have shorter lifespans than humans, allowing for more rapid observation of aging processes [5]. 4. **Transgenic Mouse Strains and Interventional Studies**: These studies have identified evolutionarily conserved pathways involved in lifespan regulation and common denominators of aging across different organisms [6]. These methods and models help scientists uncover the genetic and molecular mechanisms underlying aging, providing insights that can be applied to understanding human aging and developing potential interventions.", + "Yes, specific genes have been linked to longer lifespans. Research has identified more than 700 genes that regulate lifespan in model organisms, with many of these genes and their associated pathways, such as the insulin/IGF1/GH pathway, shown to affect longevity across different model organisms [2]. Additionally, variants near genes such as CHRNA3/5 and APOE have been found to have age- and sex-related effects on human lifespan [7]. Genome-wide association studies have also identified loci associated with exceptional human longevity [10].", + "Telomeres affect the aging process in several ways: 1. **Telomere Shortening**: Telomeres are specialized structures that protect the ends of linear chromosomes. They shorten during aging due to the unidirectional activity of DNA polymerase, which leaves a section of DNA unreplicated on the lagging strand [1]. This shortening is a natural part of the aging process and is exacerbated by genotoxic stress, such as oxidative damage [1]. 2. **Cellular Senescence and Apoptosis**: The shortening of telomeres can induce processes such as apoptosis (programmed cell death) and cellular senescence (a state where cells stop dividing), which affect the health and lifespan of an individual [2]. When telomeres become critically short, they trigger a DNA damage response, leading to cellular senescence or apoptosis [4]. 3. **Genome Stability**: Telomeres ensure the stability of the genome and protect chromosomes from incorrect actions by the DNA repair machinery [3]. When telomeres are too short, they can no longer form protective structures, leading to genome instability and potentially contributing to aging [8]. 4. **Cancer Prevention**: Short telomeres limit the number of cell cycles, which is important for preventing the onset of cancer. However, this also contributes to the aging process as cells enter a state of permanent cell cycle arrest (senescence) [7]. 5. **Telomerase Activity**: The enzyme telomerase can maintain telomere length, but its activity varies over the lifespan and between cell types, tissues, and species [1]. In most human somatic cells, telomerase activity is limited, which contributes to telomere shortening and aging [4]. Overall, telomere shortening acts as a biological clock that limits cellular replication, contributing to aging and age-related diseases [6].", + "DNA repair plays a significant role in aging by maintaining the integrity and stability of the nuclear genome. Impairment of DNA repair mechanisms can result in accelerated aging and/or cancer [2]. As organisms age, endogenous sources of genotoxins increase, DNA repair capacity declines, and levels of DNA damage and mutations increase [2]. This accumulation of DNA damage is associated with aging phenotypes, as DNA damage can activate cellular responses that contribute to aging [6]. The DNA damage theory of aging suggests that genomic instability, caused by accumulated DNA damage, plays a causal role in aging [5]. Additionally, the burden of DNA lesions is greater in older mammals compared to younger ones, indicating that DNA repair is crucial for mitigating the effects of aging [5].", + "Yes, genetic research can potentially lead to treatments that slow down aging. Several pieces of evidence from the context support this possibility: 1. The discovery of genetic markers for slow aging in humans suggests that understanding these genes could pave the way for therapeutic interventions for age-related maladies, including cancers, neurodegeneration, and metabolic syndrome [4]. 2. Research indicates that manipulating aging-related genes through various means, such as diet, lifestyle, and pharmaceuticals, could dramatically improve human health and lead to the development of drugs against age-related diseases [7]. 3. Advances in molecular biology, such as CRISPR/Cas9, are expected to clarify aging processes and identify new potential therapeutic targets, which could be crucial for developing treatments that slow aging [6]. 4. The use of senolytic drugs, which target senescent cells, has shown promise in halting biological aging in mice, and trials are underway to test their effectiveness in humans [3]. 5. There is a suggestion that interventions targeting DNA methylation and other genetic modifications could prevent age-related diseases and promote longevity, highlighting the potential of genetic research in developing therapeutic strategies against aging [10]. Overall, while the research is still ongoing and some findings are speculative, there is significant potential for genetic research to contribute to treatments that slow down the aging process.", + "Mitochondrial DNA (mtDNA) influences aging through several mechanisms: 1. **Oxidative Damage**: Mitochondria are crucial for energy production and are highly susceptible to oxidative damage. The accumulation of oxidative lesions in mtDNA is a significant source of age-related damage [1]. 2. **Mutations and Lifespan**: Mutations in mtDNA can reduce lifespan. These mutations can aggravate aging and impair brain development, indicating a direct link between mtDNA mutations and the aging process [2]. 3. **Mitochondrial Dysfunction**: Aging is associated with mtDNA mutations, which contribute to mitochondrial dysfunction. This dysfunction is linked to age-related diseases and metabolic disorders, further influencing lifespan [4]. 4. **Genetic Instability**: The mutation rate for mtDNA is significantly higher than for nuclear DNA. These mutations can compromise mitochondrial functions, such as electron transport and oxidative phosphorylation, leading to declines in ATP levels and increased production of reactive oxygen species, which further damage both nuclear and mitochondrial DNA [9]. Overall, mtDNA influences aging by accumulating mutations and oxidative damage, leading to mitochondrial dysfunction and contributing to age-related physiological decline.", + "Yes, there are known genetic mutations that cause premature aging. Specifically, mutations in the LMNA gene are associated with Hutchinson-Gilford Progeria Syndrome, a disease characterized by premature aging [4]. Additionally, mutations in the RECQL4 gene are linked to Rothmund-Thomson syndrome, which also involves premature aging [4]. These genetic disorders highlight the connection between genome integrity and premature aging [7].", + "Recent discoveries in the genetics of aging include the identification of a number of genes capable of altering the aging process significantly in animal models and even in some humans [2]. Additionally, recent efforts have focused on isolating aging mutants through mutagenesis experiments to determine the mechanistic basis for unusual life spans, leading to the discovery of genes that can either enhance or reduce life span [4]. These findings contribute to a growing understanding of the genetic factors influencing aging and longevity.", + "Epigenetic changes affect aging through several mechanisms: 1. **Alterations in Chromatin Structure**: During aging, there are various epigenetic alterations such as the accumulation of histone variants, changes in chromatin accessibility, loss of histones and heterochromatin, and imbalances in activating/repressing histone modifications. These changes can affect transcription and translation processes, impacting cellular function [1]. 2. **Epigenetic Drift**: As individuals age, epigenetic changes accumulate, leading to a phenomenon known as epigenetic drift. This drift results in the cumulative loss of gene regulation over time, impairing cellular and tissue function. It is suggested that this disruption may also play a role in the development of age-related diseases, such as cancer [3]. 3. **DNA Damage and Chromatin Remodeling**: It is suggested that epigenetic alterations during aging are largely triggered by DNA damage. This damage leads to chromatin remodeling and redistribution of chromatin modifiers, which are recruited away from their normal sites to engage in DNA repair [4]. 4. **Increased Expression of Pro-aging Genes**: Epigenetic dysregulation can lead to increased expression of pro-aging genes, such as the cell-cycle inhibitor p16, which drives cell senescence. This contributes to increased transcriptional noise and decreased coordination of gene expression, further contributing to organismal aging [10]. 5. **Potential for Reversibility**: Despite these changes, there is potential reversibility in epigenetic modifications, offering opportunities to alter the trajectory of age-related diseases. This highlights the plasticity of aging and the potential for interventions that could slow down the aging process [7]. Overall, epigenetic changes play a crucial role in the aging process by affecting gene expression, cellular function, and the development of age-related diseases.", + "The gene FOXO3 plays a significant role in human longevity. Multiple studies have shown a strong association between variations in the FOXO3 gene and increased lifespan. For instance, the FOXO3A genotype has been strongly linked with human longevity, as demonstrated in studies by Willcox et al. (2008) and confirmed in various populations, including German and Southern Italian centenarians [1], [2], [3]. The FOXO3 locus is associated with extreme longevity in humans, particularly among centenarians [5]. Additionally, specific variants at the FOXO3 locus have been identified that respond to cellular stress, which may contribute to their role in promoting longevity [8].", + "The environment interacts with genes to influence aging through several mechanisms: 1. **Signaling Pathways and Gene Expression**: Environmental factors can trigger signaling pathways and modulate gene expression, impacting aging. For example, certain genes have varying effects on lifespan depending on environmental factors like diet [1]. 2. **Epigenetic Modifications**: Environmental factors can lead to changes in DNA methylation, acetylation, or deacetylation of histones, which are epigenetic modifications that influence gene expression. These changes can result in cellular damage and accelerated aging, such as the shortening of telomeres [2], [6]. 3. **Epigenetics as a Link**: Epigenetic modifications provide a potential link between the environment, disease, and aging. This suggests that specific environmental factors might directly induce specific epigenetic changes, which could be targeted for interventions aimed at improving healthspan or promoting healthy aging [3]. 4. **Physiological Capacity and Longevity**: Environmental factors, along with protective genetic alleles, contribute to an individual's physiological capacity, indirectly determining healthy lifespan and longevity. For instance, caloric restriction and smoking have opposite effects on the rate of aging [4]. 5. **Plasticity of Aging**: Aging is a plastic process that can be manipulated by both genetic and environmental factors. Understanding these interactions can help identify targets for anti-aging therapies, potentially through diet, lifestyle, and pharmacological interventions [5], [10]. Overall, the interaction between the environment and genes is complex and involves multiple pathways and mechanisms that collectively influence the aging process.", + "Senescent cells are cells that have stopped dividing and have entered a state of permanent growth arrest. They are characterized by an altered metabolism and the secretion of pro-inflammatory factors, a phenomenon known as the senescence-associated secretory phenotype (SASP) [1], [3]. These cells accumulate in tissues over time and are resistant to apoptosis, meaning they are not easily cleared from the body [9]. Senescent cells contribute to aging and age-related diseases in several ways. They impact the tissue environment by secreting inflammatory cytokines, proteases, and growth factors, which can lead to chronic inflammation and tissue dysfunction [3], [4]. This chronic inflammation is a significant factor in the development of age-related degenerative diseases [1], [4]. Additionally, senescent cells can alter the tissue microenvironment, promoting the degeneration of organs and stem cell niches, and potentially stimulating cancer cell growth [6]. The accumulation of senescent cells is associated with various age-related pathologies, such as atherosclerosis, osteoarthritis, and Alzheimer's disease [5], [9]. Recent studies have shown that clearing senescent cells can prevent or delay tissue dysfunction and extend health span, highlighting their causative role in aging [5].", + "Yes, there are known lifestyle interventions that can positively impact genes related to aging. Dietary interventions, such as dietary restriction (DR) and calorie restriction, have been shown to alter patterns of DNA methylation and induce long-lasting changes in gene expression that improve health during aging and extend lifespan [1], [8]. These interventions can modify the epigenome, which is linked to the biology of aging [5]. Additionally, glucose restriction has been shown to extend human cellular lifespan through SIRT1-mediated epigenetic and genetic mechanisms [7].", + "The 'epigenetic clock' is a molecular biomarker of aging that is based on the DNA methylation levels of specific CpG sites. These methylation patterns are highly correlated with an individual's chronological age, with a robust correlation coefficient of approximately 0.9 for individuals aged between 20 and 100 years [1]. The epigenetic clock serves as a reliable predictor of biological age, which refers to how well a person's body functions compared to their chronological age [2]. In aging research, the epigenetic clock is used to estimate the biological age of cells, tissues, or organs by analyzing the methylation levels of select CpGs, often referred to as clock CpGs [8]. This estimated age, known as the epigenetic age, can indicate different aging rates between individuals with the same chronological age, providing insights into the biological basis of aging [9]. The epigenetic clock has been applied in various studies to understand the relationship between epigenetic aging and factors such as metabolism, and it is considered one of the most promising molecular estimators of biological age [6], [8].", + "Researchers use model organisms like yeast and worms to study human aging due to their simpler genomes, short lifespans, and the ease with which they can be genetically and environmentally manipulated. These characteristics make them ideal for identifying and characterizing genes and signaling pathways involved in aging [3]. Yeast, specifically Saccharomyces cerevisiae, is a highly informative model for aging studies because of its genetic tools and the ability to measure aging through replicative or chronological lifespan assays [2], [5]. Yeast has been extensively used to identify genes and interventions responsible for lifespan extension, providing insights into the aging processes of all eukaryotic organisms [10]. Similarly, the nematode Caenorhabditis elegans is another widely used model organism in biogerontology. Researchers study these organisms to understand whether the aging process is evolutionarily conserved and to what degree mechanisms in these simpler organisms can be indicative of aging mechanisms in humans [1], [6]. These model organisms help explore both genetic and environmental determinants of lifespan, contributing to hypotheses surrounding extended lifespan and healthspan [7].", + "Yes, there are promising anti-aging therapies being developed based on genetic research. Several approaches are being explored: 1. **Senolytic Drugs**: Research has shown that abolishing senescent cells through genetic manipulation or senolytic drugs can significantly halt biological aging in mice. Trials are underway to test the ability of senolytics to postpone age-associated pathologies in humans [3]. 2. **Genetic Discoveries in Aging**: A number of genes capable of altering the aging process have been identified in animal models and even in humans. This area of research is promising as it explores the association of multiple alleles with human exceptional longevity [6]. 3. **Manipulation of Aging-Related Genes**: There is potential in manipulating aging-related genes through diet, lifestyle, and pharmaceuticals to improve human health and develop drugs against age-related diseases such as cancer, heart disease, type 2 diabetes, obesity, and neurodegenerative diseases [8]. These developments indicate that genetic research is paving the way for potential anti-aging therapies.", + "Caloric restriction and diet have significant impacts on the genetics of aging through various mechanisms: 1. **Gene Expression and Lifespan Extension**: Caloric restriction (CR) has been shown to delay age-related gene-expression changes in mice and, to some extent, in flies. This suggests that CR may influence the genetic pathways associated with aging, potentially contributing to lifespan extension [4]. 2. **Epigenetic and Post-Translational Mechanisms**: In calorie-restricted rats, transcriptome analysis indicates that CR involves epigenetic and post-translational mechanisms, which are implicated in neuroprotection and aging. These mechanisms may alter genome function to promote increased health and lifespan [3], [5]. 3. **mTOR Pathway**: Caloric restriction is associated with decelerating mTOR-driven aging, which is a significant pathway involved in cellular growth and metabolism. By modulating this pathway, CR may influence the genetic regulation of aging processes [5]. 4. **Genomic and Epigenetic Approaches**: Nutritional modulation, including caloric restriction, can impact aging through genomic and epigenetic approaches. This suggests that diet can influence the genetic and epigenetic landscape, potentially affecting the aging process [6]. Overall, caloric restriction and diet can modulate genetic pathways and mechanisms that are crucial for aging, potentially leading to increased lifespan and improved health during aging." + ], + "contexts": [ + [ + "It is undisputed that genetic factors influence aging. In a remarkable", + "males: what are the molecular and evolutionary causes? Aging Cell. 2007;6:225233. doi:10.1111/j.1474-9726.2007.00279.x 63. Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: link- ing environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593610. doi:10.1038/nrm4048 64. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell. 2016;166:822839. doi:10.1016/j.cell.2016.07.050", + "Clinical Genetics and Genomics of Aging", + "standing the cause and mechanisms of aging is imperative in assisting to suppress age-related diseases and promote healthylongevity. It is well-known that aging is influenced by a combin- ation of genetic and environmental factors. Previous twin stud- ies have shown that the genetic contribution to general human longevity is about 2030% [ 4,5], whereas environmental factors in human aging and longevity still account for the largest effect. Epigenetic factors influence the regulation of gene expres-", + "Recent developments on the genetics of aging can be seen as several streams of effort. In general, humans show a relatively modest ( <50%) heritability of", + "effect genetic variants on human longevity. Aging 2, 612620. Yu, C.E., Seltman, H., Peskind, E.R., Galloway, N., Zhou, P.X., Rosenthal, E., Wijsman, E.M., Tsuang, D.W., Devlin, B., Schellenberg, G.D., 2007. Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimers disease: patterns of linkage disequilibrium and disease/marker association. Genomics", + "factors shape a complex scenario for which clear answers of the regulation of longevity have been dicult to distill. With the discovery of genetic factors underlying aging in experimental laboratory models, forays into the genetic regulation of these properties have rapidly expanded, uncovering conserved mechanisms across diverse metazoa that inuence expression of aging phenotypes and lifespan. Yet, the story gets muddled in that these factors are often", + "In addition to aging- and CR-related genes, another source of candidate genes and pathways for drug designare human longevity-associated genes (Barzilai andShuldiner, 2001; Browner et al., 2004; Kenyon, 2010).Dozens of genes have now been associated with humanlongevity (de Magalha es et al., 2009a), although only ahandful of genes have been shown to have consistenteffects across populations. Many longevity-associated genes are related to spe-", + "tion for decades, the underlying molecular genetic causes of and responses to aging remain an area of active study. Research from model systems hascharacterized a range of physiological and molecular phenotypes associated with aging. These include genomic instability caused by accumulation of DNA damage, dysregulation of repair mechanisms, and telomere attri- tion; epigenetic alterations; dysregulation of transcription; loss of proteostasis; cellular senescence; and deregulated", + "143 The molecular bases of ageing are multi factorial, but there are nine distinctive features related to this process, which include genomic instability, telomere shorten- ing, de-regulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered cellular senescence, loss of proteostasis and a change in the patterns of epigenetic modifications [4, 5]. Epigenetics andAgeing Epigenetics is considered as a dynamic interface between the genome and the envi-" + ], + [ + "potentially associated with human ageing. For eachgene, a description compiled from the studies that linkthe gene to ageing is provided. It should be noted thatour focus is on genes that might affect the ageingprocess, rather than individual age-related pathologies; genes affecting multiple, even if not all, age-related", + "showing that single genes can regulate aging in modelorganisms demonstrate that aging can be geneticallymanipulated (Finch and Ruvkun, 2001; Kenyon, 2010).Hundreds of genes that modulate longevity have nowbeen identified in model organisms (de Magalha es et al.,2009a). In some cases (e.g., in worms), mutations insingle genes can extend lifespan by almost 10-fold (Ayy-adevara et al., 2008). Nonetheless, aging is a complexprocess that derives not from single genes but from theinteractions of multiple genes", + "genes (http://genomics.senescence.info/genes/), more than700 genes have been identified that regulate lifespan inmodel organisms (de Magalha es et al., 2009a). Many ofthese genes and their associated pathwayssuch as theinsulin/IGF1/GH pathwayhave been shown to affect lon-gevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolu-tionarily conserved and may have potential therapeuticapplications (Baur et al., 2006). For example, evidencesuggests the use of", + "key genes and pathways important in aging; geneticstudies of heritable diseases that cause the appearanceof premature aging in affected people; physiological ex-Introductionperiments that relate the pace of aging to caloric intake;Is aging the final act in the script of developmental biol-and advances in human genetics, as well as cell andogy? The characteristic changes that are part and parcelmolecular biology leading to an understanding of theof aging appear similar to developmentally regulatedbasis of", + "shown that genes associated with aging and/or longevity inmodel organisms are evolutionary conserved in terms of havingmore homologues than predicted by chance (Budovsky et al .,2007, 2008) and exhibiting slower molecular evolution rates (de Magalhes & Church, 2007). Therefore, it is now clear that atleast some genes identified in model organisms may be relevantto human aging. To allow researchers to focus specifically on human aging,", + "expression of certain genes have an effect upon longevity. Although similar aging processes are likely to operateacross multiple species [30], it has been much more diffi-cult to identify longevity candidate genes in human studies[30]. A key question in human aging is to what extent asignature of aging may be detectable across tissues. Until now there has been a lack of large transcriptional profiles from the same human individuals in multiple tissues. TheMuTHER study provides ins ight into the human aging", + "complex.108,109Studies on models such as the yeast Sac- charomyces cerevisiae110the nematode Caenorhabditis elegans,111the fly Drosophila melanogaster,112-114the mouse Mus musculus,115and humans116show that single gene mutations can contribute to the initiation of aging andinduce premature aging syndromes. There are, however, nospecial genes that can cause aging-associated damages. Themanifestation of aging is mostly due to the failure of main-tenance and repair mechanisms. 117,118", + "on model organisms [3] or have been confined to specificaging-associated disorders such as progeria syndromes [4]. A study of postmortem human brain tissue from 30 individuals aged 26 to 106 years [5] showed that approxi- mately 4% of approximately 11,000 genes analyzed show a significant age-related expression change (1.5-fold or more) in individuals aged >40 years. These genes were reported to play central roles in synaptic plasticity, vesi- cular transport, and mitoch ondrial function. Another", + "of multiple genes with each other and withthe environment. Evidence from animal systems showsa major impact of the environment on aging, yet envi-ronmental manipulations of aging act through genesand proteins, usually by triggering signaling pathwaysand modulating gene expression. In fact, some geneshave been shown in model organisms to have varyingeffects on lifespan depending on diet (Heikkinen et al.,2009). Genes that can regulate aging in model organ-isms cannot be directly applied to humans through", + "[2] L. Partridge, D. Gems, Mechanisms of ageing: public or private? Nat. Rev. Genet. 3 (2002) 165 175. [3] A.M. Leroi, et al., What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? Mech. Ageing Dev. 126 (2005)421429. [4] S.N. Austad, Is aging programmed? Aging Cells 3 (2004) 249 251. [5] V.D. Longo, J. Mitteldorf, V.P. Skulachev, Opinion: programmed and altruistic ageing, Nat. Rev. Genet. 6 (2005) 866 872." + ], + [ + "as diabetes, cancer and neurodegenerative disorders [1, 2]. Environmental and genetic interventions can ameliorate the effects of aging, with nutrition, nutrient-sensing signaling networks and metabolism playing evolutionarily conserved roles [1, 3 5]. Diet- ary restriction (DR), in which food intake is reducedwhile avoiding malnutrition, extends lifespan in di- verse model and non-model organisms [3, 6]. DR induces a remarkably broad-spectrum improvement in", + "limiting exposure to exogenous genotoxins and by suppressing metabolism thereby producing fewer reactive species. However, DNA damage, like caloric restriction, can also elicit a protective survival response that promotes longevity and healthy aging. Recently, the use of sirolimus in mice was found to extend their life span and de - lay the development of conditions associated with aging, including cancer. 1 Sirolimus is one of pre -", + "Longev. Heal. 2, 10 (2013). 7. Kreienkamp Ret al.Doubled lifespan and patient-like pathologies in progeria mice fed high-fat diet. Aging Cell18, e12852 (2019). [PubMed: 30548460] 8. Heilbronn LK & Ravussin E Calorie restriction and aging: review of the literature and implications for studies in humans. Am. J. Clin. Nutr. 78, 361369 (2003). [PubMed: 12936916] 9. Liang Yet al.Calorie restriction is the most reasonable anti-ageing intervention: a meta-analysis of", + "can be slowed down to some extent by eating a healthy diet and taking physical exercise, and many of the chronic diseases prevalent in older adults are either preventable or modi able with healthy lifestyle habits. Thus, older adults can experience successful aging that allows them to achieve physical, social and mental well - being over the life course and to participate in society. Much research has been conducted in recent years to", + "During the past century, remarkable progress has been made in unveiling the mechanisms of aging. Genetic and molecular pathways that regulate healthspan and lifespan have been identified in various model organisms, provid-ing a rich knowledge base (Longo etal. 2015; Lopez-Otin etal. 2013, 2016; Singh etal. 2019). However, the focus on", + "13,14 Prior studies have identified dozens of genetic and environ - mental modifiers of chronological or replicative longevity, some of which are now known to function similarly to modulate life span in multicellular eukaryotes. 15-17 One example of such a con - served longevity intervention is dietary restriction, which has been shown to slow aging in many different species including yeast, nematodes, fruit flies and rodents, 18,19 and most recently", + "Genetic studies have shown that aging can be slowed in mutants that are defective in a wide range of cellularprocesses (such as mitochondrial function, chromatin regu- lation, insulin signaling, tran scriptional regulation, and genome stability). This indicates that aging is a complex process driven by diverse molecular pathways and biochem- ical events. As such, a powerful approach to study aging is touse systems biology, which allows a multitude of factors", + "Dietary interventions, including starvation and protein deprivation, can also alter patterns of DNA methyla- tion, potentially in a long-lasting manner [42, 43], including transgenerationally [26, 44]. Dietary, genetic and pharmacological interventions that improve health during aging and extend lifespan induce long-lasting changes in gene expression that mediate their effects. Here we have asked if and how age-related DNA methylation, transcription and lipid", + "in yeast , Drosophila, and C. elegans is able to slow aging and increase lifespan [252-255]. Follow -up stud ies out of Richard Millers laboratory reproduced these findings in mice fed a diet with rapamycin incorporated [256, 257]. These studies suggested that inhibiting mTOR via rapamycin could delay age-associated diseases and extend lifespan in mammals. A subsequent study replicated these findings by genetically manipulating a", + "appears to retard aging at the molecular level as indi-cated by the gene expression analysis? Most likely,aging retardation at the molecular level by exercise isnot observed in all tissues, including some that maylimit lifespan. For example, if exercise does not reduceaging rates in replicative tissues, then it will not retardage-related tumor onset, which tends to limit maxi-mum lifespan. Another possibility relates to the obser-vation that wheel running decreased to an average 680m/day at 33 mo of age" + ], + [ + "for molecular biological studies on aging. Although material from humans should be employed where possible, for prac- tical reasons animal model systems like rats and mice are indispensible. There is evidence that, provided their health sta- tus and husbandry is optimal, rodents age much in the same way as humans do (Burek 1978). For studying certain funda- mental processes, such as the occurrence of various types of DNA rearrangement, lower organisms and cell lines can also", + "Until now most of the genomic studies of invertebrate models have been performed on whole animals. Several studies, however, recently performed on specialized mammalian tissues, either post-mitotic (heart or nervous system) or mitotic (liver), show that the effects of aging are tissue-specific [19-25]. In addition, effects of caloric restriction on age related transcriptional changes are also tissue- or species-specific [19]. To better understand the aging process in invertebrate", + "opportunities for assessing the efcacy of interventions onaging. When considering the advantages and disadvantages of dogs as a model for geroscience research, it is useful tonote that the vast majority of mammalian studies on thebasic biology of aging are performed in a relatively small number of inbred mouse strains. Typical average lifespan for most of these mouse strains is approximately 23 years,", + "[14] Gerstbrein, B., Stamatas, G., Kollias, N., Driscoll, M. In vivo spec- trofluorimetry reveals endogenous biomarkers that report health- span and dietary restriction in Caenorhabditis elegans . Aging Cell 2005 , 4: 127-137. [15] Kennedy, B.K. The genetics of ageing: insight from genome-wide approaches in invertebrate model organisms. J. Intern. Med. 2008 , 263: 142-152. [16] Kenyon, C., Chang, J., Gensch, E., Rudner, A., Tabtiang, R. A C.", + "the DNA level leads to changes in gross phenotype, we must now look downstream at changes in gene expression associ - ated with genetic variation, aging, and ARD. Comparison With Laboratory Models of Aging Laboratory models typically used to study aging, such as Caenorhabditis elegans (nematode worm) and Mus musculus (mice), have drastically shorter life spans than our own (~3 wk [ 51] and ~3 y [ 52], respectively, vs a 122 y maxi - mum for humans thus far; [ 53]). In some respects, these", + "ing studies on invertebrate models of aging, long-lived mam-mals, transgenic mouse strains, and interventional studies, have led to the identification of evolutionarily conserved path- ways involved in life span regulation, as well as common de- nominators of aging in different organisms. 4 In this review, the pathophysiological roles of these aging mechanisms, including oxidative stress, mitochondrial dysfunction, impaired resis-", + "chain triglyceride oil on life span of genetically heterogeneous mice. J. Gerontol. A. Biol. Sci. Med. Sci. 68, 616 (2013). [PubMed: 22451473] 24. Yuan R, Peters LL & Paigen B Mice as a mammalian model for research on the genetics of aging. ILAR J. Natl. Res. Counc. Inst. Lab. Anim. Resour. 52, 415 (2011). 25. Saul MC, Philip VM, Reinholdt LG & Chesler EJ High-diversity mouse populations for complex traits. Trends Genet. 35, 501514 (2019). [PubMed: 31133439]", + "lowing the discovery of genes and pathways involved inanimal lifespan extension, human research has focusedon the corresponding candidate human genes withgenetic, genomic and epigenetic studies into ageingand longevity. The designs of these studies differwith respect to the selection of naturally occurringphenotypes and the study populations, which includepopulation-based, patient-based, family-based andexposure-based cohorts. Studies into human age-related disease phenotypes", + "Animal studies as stalking horses for human biogerontology. For the most part, studies on the biology of aging are as difficult and imprac-tical in humans as are studies of health insurance in rodents. It is fairlyCopyright National Academy of Sciences. All rights reserved.Cells and Surveys: Should Biological Measures Be Included in Social Science Research? http://www.nap.edu/catalog/9995.html", + "review of the evidence for genotype-dependent eects on lifespan. Ageing Res. Rev. 11, 254270. doi: 10.1016/j.arr.2011.12.006 Turturro, A., Witt, W. W., Lewis, S., Hass, B. S., Lipman, R. D., and Hart, R. W. (1999). Growth curves and survival characteristics of the animals used in the biomarkers of aging program. J. Gerontol. Ser. Biol. Sci. Med. Sci 54, B492B501. doi: 10.1093/gerona/54.11.b492 Vertti-Quintero, N., Berger, S., Solvas, X. C. I, Statzer, C., Annis, J., Ruppen," + ], + [ + "genes analyzed for their possible association with human lon-gevity (http://genomics.senescence.info/genes/longevity.html).All longevity association studies in humans we could find by thetime of the latest update were added to this list. These includestudies reporting negative results, which we see as essentialsince many genes display population-specific associations withlongevity. Fig. 1 From the main page of the Human Ageing", + "genes (http://genomics.senescence.info/genes/), more than700 genes have been identified that regulate lifespan inmodel organisms (de Magalha es et al., 2009a). Many ofthese genes and their associated pathwayssuch as theinsulin/IGF1/GH pathwayhave been shown to affect lon-gevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolu-tionarily conserved and may have potential therapeuticapplications (Baur et al., 2006). For example, evidencesuggests the use of", + "Exceptional Longevity One approach to identifying genes associated with low mortality is to examine the genes of those who survive to the oldest ages. Several studieshave examined gene frequencies among centenarians or nonagenariansand compared them with frequencies at younger ages. Since changes ingene frequencies are more rapid when mortality rates are high, cross-sectional comparisons must be adjusted for differences in mortality amongcohorts.", + "informed by age-related disease identifies loci for exceptional human longevity. Li H, editor. PLoS Genet. 2015. https://doi.org/10.1371/journal.pgen. 15. Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, etal. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet. 2015;47:7029. 16. Cellerino A, Ori A.What have we learned on aging from omics studies? Semin Cell Dev Biol. 2017;70:17789.", + "GENOME-WIDE ASSOCIATION STUDY OF LONGEVITY 479 INCREASES in longevity of the general population world - wide are an unprecedented phenomenon with significant health and social impact. Although environmental factors have led to an increase in life span, there is ample evidence that genetic factors are involved in extreme longevity both in humans (17) and in other organisms (8). The protective genetic factors that lead to longevity are likely to involve", + "expression of certain genes have an effect upon longevity. Although similar aging processes are likely to operateacross multiple species [30], it has been much more diffi-cult to identify longevity candidate genes in human studies[30]. A key question in human aging is to what extent asignature of aging may be detectable across tissues. Until now there has been a lack of large transcriptional profiles from the same human individuals in multiple tissues. TheMuTHER study provides ins ight into the human aging", + "4. Joshi, P. K. et al. Variants near CHRNA3/5 and APOE have age- and sex- related effects on human lifespan. Nat. Commun. 7, 11174 (2016). 5. Pilling, L. C. et al. Human longevity is in uenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging 8, 547560 (2016). 6. Deelen, J. et al. Genome-wide association meta-analysis of human longevity identi es a novel locus conferring survival beyond 90 years of age. Hum. Mol. Genet. 23, 4420 4432 (2014).", + "79-91. [97] Smith, E.D.; Kennedy, B.K.; Kaeberlein, M. Genome-wide identification of conserved longevity genes in yeast and worms . Mech. Ageing Dev. , 2007 , 128(1), 106-11. [98] Chen, D.; Pan, K.Z.; Palter, J.E.; Kapahi, P. Longevity determined by developmental arrest genes in Caenorhabditis elegans. Aging Cell, 2007 , 6(4), 525-33. [99] Curran, S.P.; Ruvkun, G. Lifespan regulation by evolutionarily conserved genes essential for viability . PLoS Genet. , 2007 , 3(4), e56.", + "9. vB Hjelmborg J, Iachine I, Skytthe A, Vaupel JW, McGue M, et al. (2006) Genetic influence on human lifespan and longevity. Hum Genet 119: 312321.doi:10.1007/s00439-006-0144-y. 10. Sebastiani P, Perls TT (2012) The genetics of extreme longevity: lessons from the new England centenarian study. Front Genet 3: 277. doi:10.3389/fgene.2012.00277.11. Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, et al. (2002) Life-", + "39. Fortney K, Dobriban E, Garagnani P, etal. Genome-wide scan informed by age-related disease identifies loci for exceptional human longevity. PLoS Genet. 2015;11:e1005728. doi:10.1371/journal.pgen.1005728 40. Beekman M, Nederstigt C, Suchiman HE, et al. Genome-wide asso- ciation study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci U S A. 2010;107:1804618049. doi:10.1073/pnas.1003540107" + ], + [ + "Telomeres are specialized structures that protect the ends of linear chromosomes. They shorten during aging due to the unidirectional activity of DNA polymerase, which leaves a section of DNA unrepli-cated on the lagging strand. Telomeres also are subject to shortening by genotoxic stress, such as oxidative damage (33). Among many eukaryotes, the enzyme telomerase maintains telomere length; but telomerase activity varies over the lifespan and between cell types, tissues, and species (34). In most human", + "that shorten their length with progressing age. This shortening of telomeres is the result of the absence of the activity of an enzyme called telomerase, and in turn it induces several processes, such as apoptosis, senescence, or oncogenic transforma- tion of somatic cells, affecting the health and lifespan of an individual [42]. Human telomere shortening has been mostly studied in leukocytes and linked not only to ageing and life expectancy [43] but also to age-related diseases, including cardio-", + "nization may directly affect telomere attrition, resulting in accelerated replicative senescence and progeroid phenotypes [180]. Telomeres are regions constituted by tandem repeats of non-coding DNA sequences 5-(TTAGGG)n-3 and a protein complex called shelterin, bound to them. This structure ensures the stability of the genome and protects the chromosomes from a wrong action of the DNA repair machinery [184] by allowing the formation of a chromatin loop called T-Loop [185].", + "Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on thebasis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must cap eachchromosome end to avoid activation of DNA repair pathways. Repair of critically short or uncapped telomeres by telomeraseor recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many uncappedtelomeres accumulate.", + "ing (84). This process is believed to be the trigger for the aging process, according to the telomere theory (11, 85, 86). It is further supported by Bodnar etal. who proved that telomere elongation caused by ectopic expression of telomerase avoids the senescence phenotype (87). His work relied on one of the earliest studies linking telomere shortening to aging which was performed", + "telomeres, the repetitive sequence at the end of linear chromosomes, has garnered much attention for its relation to aging. Telomere repeats serve as an internal clock for cycling cells because each round of replication results in the loss of telomeric DNA in the absence of active telomerase (reviewed in [66]). Eventually, this loss over cellular generations culminates in telomere crisis and a permanent state of", + "and consequently lose telomeric sequences, thereby limiting the number of cell cycles, which is important for preventing the onset of cancer. Cells perceive critically short telomeres as persistentDNA damage. This activates the DNA damage responses, including cell cycle checkpoints, which ultimately leads to a permanent cell cycle arrest (cellular senescence). Senescence protects from cancer but contributes to the aging process (37).", + "When the telomeres shorten, this loop is no longer able to form and in turn, the epigenetic regulation is changed to activation of the TPE-OLD genes. This happens before the telomeres reach the critical length that causes activation of DDR, thus leading to another earlier possible effect of telomere shortening on aging (138, 139). Interestingly, a following study by Kim etal. showed that one of the TPE-OLD sensitive genes is hTERT, the core reverse transcriptase component of telomerase (140). This is", + "to maintain proliferation potential (94). Cells with mutated telomerase exhibited irregular morphology and short telomeres, but these changes did not cause deadly damage and determinate senescence (95). One hypothesis connects aging to telomere erosion through the transcription of subtelomeric genes. Genes located in subtelomeric regions are affected by transcriptional silencing which was found to change in an age-related manner. Kim et al. (96) found that silencing of genes in subtelomeric", + "evidence implicates telomere shortening in cellularsenescence. Telomeres consist of repetitive nucleotides e q u e n c e s( T T A G G G )a tt h ee n d so fm a m m a l i a nc h r o -mosomes, that preserve chromosome stability andintegrity by preventing deterioration or fusion withneighboring chromosomes (76) (Central Illustration ).JACC VOL. 69, NO. 15, 2017 Paneni et al . APRIL 18, 2017:1952 67 The Aging Cardiovascular System1957" + ], + [ + "Effect of age on DNA repair Research over the past decades suggest that many steps in DNA metabolism are altered with age in a variety of tissues and animal models (56,57). The relation of DNArepair to aging has been studied by measuring the ability of cells from organisms of various life spans to repair DNA damage and by experiments that have comparedthe ability of cells from young and old organisms to repair DNA damage. Interest was peaked by the original", + "BI87CH14_Niedernhofer ARI 18 May 2018 15:1 SUMMARY POINTS 1. Evolutionarily conserved DNA repair pathways maintain the integrity and stability of the nuclear genome. Impairment of DNA repair mechanisms results in accelerated agingand/or cancer. 2. Evidence in humans and model organisms supports the conclusions that with age (a) endogenous sources of genotoxins increase, ( b) DNA repair capacity declines, and (c) levels of DNA damage and mutations increase.", + "Several lines of evidence suggest that DNA repair capacity might decrease with age. However,it should be noted that measuring DNA repair in tissues is challenging and that the validity ofsurrogate markers of repair capacity is not well established. For example, a reduction in expression of DNA repair genes/proteins is not proven to impact DNA repair. Frequently, the reduction in", + "improved DNA repair. Finally, there should be a plausible mechanism by which DNA damage can drive aging. Here, we review the evidence currently supporting each of these predictions. EVIDENCE THAT DNA DAMAGE INCREASES WITH AGE Sources of Damage Increase with Age The free radical theory of aging posits that aging is caused primarily by oxidative damage in- curred by ROS that chemically modify critical cellular biomolecules (13). This theory has evolved", + "All rights reservedKeywords DNA damage, aging, mutations, senescence, DNA damage response, DNA repair Abstract The nuclear genome decays as organisms age. Numerous studies demon- strate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is acause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging,", + "repaired; otherwise the genome would soon become saturated with damage and life would cease. There is some evidence that DNA damage accumulates with age in some tissues ( Maslov et al., 2013 ), but the exact nature of the damage remains unclear. Indeed, even these low levels of spontaneous DNA damage may represent a steady state due to continu- ous repair and induction of new damage. However, DNA damage can cause certain aging phenotypes by activating cellular responses, such", + "36:1049-1062. 66. Hasty P, Vijg J: Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity. Aging Cell 2004, 3:55-65. 67. Bohr VA: Deficient DNA repair in the human progeroid dis- order, Werner syndrome. Mutat Res 2005, 577:252-259. 68. Nouspikel T, Hanawalt PC: DNA repair in term inally differenti- ated cells. DNA Repair 2002, 1:59-75. 69. Nouspikel T, Hanawalt PC: When parsimony backfires: neglect- ing DNA repair may doom neurons in Alzheimer's disease.", + "DNA repair. In the latterdifficult to arrive at a strict, experimentally useful defini-context, most premature aging syndromes are causedtion of aging. Factors implicated in organismal declineby mutations in genes encoding proteins involved inin genetic models might not play a role in the normalDNA repair ( Karanjawala and Lieber, 2004 ). Accumula-aging processes. A related difficulty is that prematuretion of mutations in critical genes may be one generalaging models fail to recapitulate all aspects of", + "escape the repair process and accumulate in the genome, impacting several processes and aging [67,145147]. There is little evidence of association between DNA repair improvement and life- time expansion [ 148,149], thus, indicating that such mechanism seems to have evolved to maintain DNA stabilityand therefore healthonly until reproductive age, without any regard for the fate of the individual in old age, both in terms of quality and length of", + "with age, and DNA repairtween different tissues. These differences likely reflectdefects can cause phenotypes resembling prematurefunctional characteristics of those tissues, such as mi-aging. We discuss how cellular DNA damage re-totic rate, transcriptional activity, metabolism, and thesponses may contribute to manifestations of aging.action of specific DNA repair systems.We review Sir2, a factor linking genomic stability, me-Reactive Oxygen Species: An Important Sourcetabolism, and aging. We conclude" + ], + [ + "raises the possibility of therapies to slow aging. Therefore the discoveryof a gerontogene with even very rare mutations that increased longevitywould cause speculation about future trends in mortality. However, thediscovery of such a gene would be relevant only to long-term (and, there-fore, very speculative) projections. Prospective Epidemiologic Surveys that Include Genetic Information Some epidemiologic cohort studies of populations have collected", + "need to develop approaches and therapies targeting theaging process and age-related diseases (Butler et al.,2008). Delaying the process of aging, even slightly,would have profound social, medical and economic ben-efits (Olshansky et al., 2006; Butler et al., 2008). Forexample, slowing aging by a mere 7 years would cutmortality of age-related diseases by half at every age.Therefore, the potential benefits from research on thebasic biology and genetics of aging are unparalleled interms of improving quality", + "Interestingly, when senescent cells are abolished either through genetic manipulation or via senolytic drugs, biological aging is signicantly halted in mice [ 53,54]. Therefore, trials are now under way to test the ability of senolytics to postpone age-associated pathologies in humans [ 55]. Notably, multi- ple drugs are being pursued that either directly or indirectly impact DNA repair or the consequenceof DNA damage. Future Prospects: Developing Interventions through DNA Repair", + "and potentially important genetic markers for slow aging have been found in humans (Suh et al. 2008). Elucidating the function of such genes is believed to enable decipher- ing the core of the aging process, answer to what extentthe process is conserved, and pave the way for therapeutic interventions of age-related maladies, including cancers, neurodegeneration, and metabolic syndrome (Guarente 2011). The identity of the virtual gerontogenes so far discov-", + "discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease. DOI: https://doi.org/10.7554/eLife.39856.002", + "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", + "century. Manipulation of aging-related genes by diet,lifestyle, and pharmaceuticals could dramatically im-prove human health and could be used to develop drugsagainst age-related diseases such as cancer, heart dis-ease, type 2 diabetes, obesity, and neurodegenerativediseases. The hundreds of aging-related genes and genesrelated to CR already identified offer enormous oppor-tunities for target discovery (Fig. 2). Although aging-related genes cannot be modified in humans, under-standing how these can be", + "5. Goldman DP, etal. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff (Millwood). 2013;32(10):1698705. 6. Esplin ED, Oei L, Snyder MP.Personalized sequencing and the future of medicine: discov- ery, diagnosis and defeat of disease. Pharmacogenomics. 2014;15(14):177190. 7. Marian AJ.Clinical applications of molecular genetic discoveries. Transl Res. 2016;168:614.", + "a medical intervention), without changing the fundamental rateof organismal aging. Nevertheless, it does seem that manyso-called longevity genes, as well as dietary restriction, appear to extend not only life span, but also health span (Kauffman et al., 2010; Luo et al., 2010 ). In that regard, it does appear that it is possible to experimentally slow the rate of aging. Still, in each case, aging does continue on as if there is some", + "genetic modification. Currently, emerging evidence suggeststhat certain interventions (e.g. CR, dietary supplementation andchemical drugs) can prevent age-related diseases and promote longevity, at least in part, through reversing the aberrant age- associated changes in DNA methylation, suggesting the greatpotential of DNA methylation in therapeutic strategies againstage-related diseases ( Figure 1B ).However, to further understand the roles of DNA methyla-" + ], + [ + "In addition to nuclear DNA, mitochondrial DNA (mtDNA) also is affected by aging. Alterations in mitochondrial function and mito-chondrial-nuclear signaling occur during aging and have been linked to sex biases in aging and age-related diseases (28). Due to their role in energy production, mitochondria are at high risk of oxida-tive damage. Not surprisingly, accumulation of oxidative lesions is an important source of age-related mtDNA damage (29). In aged Wistar rats brains, DNA oxidation, as measured by", + "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.", + "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.", + "other studies, the risk for metabolic disorders is highly associated with age-related diseases that affect lifespan, and interestingly these conditions exhibit mitochon- drial dysfunction [73]. Aging is a complex process as a time-dependent progressive loss of physiologi- cal integrity, leading to impaired function and increased vulnerability to death [74], and as we described above, aging is highly associated with mtDNA mutations; in", + "mt, and overall mitonuclear genomic compatibility. Given the uncertainty of mtDNA mutation accumulation in driving the natural aging process, it is plausible that mito - chondrial communication may be a significant evolutionarily conserved force that influences lifespan and/or healthspan. Acknowledgements Funding was provided by the American Federa- tion for Aging Research (AFAR), the National Institute on Aging (T32", + "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.", + "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,", + "than ones that affect mitochondrial DNA12,57,58,71.So,this is an important reason for favouring nuclear DNA as the ultimate damage target in natural ageing. Nevertheless, it is conceivable that when mutations occur in the mitochondrial genome, mutant-protein production could increase the inefficiency of the mitochondrial respiratory chain, thereby resulting in more reactive oxygenspecies, which would then damage nuclear and mitochondrial DNA further.", + "generation animals as they grow older.Mitochondrial DNAGenetic instability outside of the nuclear genome mightalso contribute to aging (reviewed in Lee et al., 1997;Wallace et al., 1998). The mutation rate for mitochondrialDNA (mtDNA) is 10- to 20-fold greater than for nuclearDNA, and it is believed that mtDNA mutations may com-promise mitochondrial functions in different ways (Fig-ure 4). First, defects in electron transport and oxidativephosphorylation could lead to declines in ATP levelsand the NAD:NADH", + "of the human aging process(Corral-Debrinski et al., 1992; Soong et al., 1992;Wei etal., 1996b), and it has been demonstrated that certain pointmutations of mitochondrial DNA accumulate in the aginghuman brain (Zhang et al., 1993; Liu et al., 1997). However,thefunctionalimplicationsofthesendingsarecontroversial(Hayashietal.,1994).Tocomplicatethematterfurther,Takaiand co-workers discuss the possibility that the commonage-associated changes in human and mouse" + ], + [ + "logical phenomena is often facilitated by the study of genetic mutants, and, in the case of humans, genetic disorders. Accordingly, a search was made, over the years, for genetic disorders characterized by premature aging. If DNA dam- age and repair has anything to do with aging it should be evidenced in such individuals. Martin (1978) listed 162 genetic syndromes in humans with some or many signs of premature aging. About 21 feahares are considered as markers for", + "[315] Szilard, L. On the nature of the aging process. Proc. Natl. Acad. Sci. USA 45:3545; 1959. [316] Vijg, J.; Dolle, M. E. Large genome rearrangements as a primary cause of aging. Mech. Ageing Dev. 123:907915; 2002. [317] Vijg, J. Somatic mutations and aging: a re-evaluation. Mutat. Res. 447:117135; 2000. [318] Martin, G. M. Genetic syndromes in Man with potential relevance to the pathobiology of aging. Birth Defects Orig. Artic. Ser. 14:539; 1978.", + "19 6. Milholland B, Suh Y , Vijg J.Mutation and catastrophe in the aging genome. Exp Gerontol. 2017;94:3440. 7. Maslov AY , Ganapathi S, Westerhof M, Quispe-Tintaya W, White RR, Van Houten B, etal. DNA damage in normally and prematurely aged mice. Aging Cell. 2013;12:46777. 8. Blokzijl F, de Ligt J, Jager M, Sasselli V , Roerink S, Sasaki N, etal. Tissue-specific mutation accumulation in human adult stem cells during life. Nature. 2016;538:2604.", + "143 Gonzalo S, Kreienkamp R & Askjaer P (2017) Hutchinson -Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res. Rev. 33, 1829. 144 Lu L, Jin W & Wang LL (2017) Aging in Ro thmund -Thomson syndrome and related RECQL4 genetic disorders. Ageing Res. Rev. 33, 3035. 145 de Renty C & Ellis NA (2017) Blooms syndrome: Why not premature aging? Ageing Res. Rev. 33, 3651. 146 Shiloh Y & Lederman HM (2017) Ataxia -telangiectasia (A -T): An emerging", + "genetic disease model of premature aging, In: Harrison,D.E., eds, Genetic Effects on Aging II (Telford Press, Caldwell,NJ), pp. 521542. [2] Djawdan, M., Sugiyama, T., Schlaeger, L., Bradley, T.J. and Rose, M.R. (1996) Metabolic aspects of the trade-off between fecundity and longevity in Drosophila melanogaster ,Physiol. Zool. 69, 11751195. [3] Fleming, J.E., Spicer, G.S., Garrison, R.C. and Rose, M.R.", + "genes of a whole chromosome ineffective, couldbe a main causal factor in aging (Szilard, 1959).According to Maynard Smith, such types of mu-tations do not seem likely to be common enoughto be the main cause of aging. However, at thetime quantitative information on the possible age-related accumulation of different types of muta-tions in various tissues of mammals wascompletely lacking. The question, therefore,whether somatic mutations are a cause of aging,has not been resolved, more than four decadesafter", + "features of premature aging (16, 17). Subsequent experiments conrmed that mitochondrial DNA mutations and deletions were the driving force behind the observed accelerated aging phenotypes(18). THE LINK BETWEEN NUCLEAR GENOME INTEGRITY AND PREMATURE AGING The notion that the majority of currently identied progeria syndromes originate from defects in genome maintenance highlights the importance of the condition of DNA in the process of", + "Tryggvason K,ZhouZ.Genomicinstability inlaminopathy based premature aging,NatMed. 2005;11:780 785. 13.MisteliT,ScaffidiP.Genomeinstability inprogeria:when repairgetsold,NatMed. 2005;11:718 719. 14.PereiraS,Bourgeois P,NavarroC,EstevesVieiraV,CauP,De SandreGiovannoli A,LvyN.HGPSandrelatedpremature aging disorders: Fromgenomicidentification tothefirsttherapeutic approaches, MechAgeingDev.2008;129:449 459. 15.SmithED,Kudlow BA,FrockRL,KennedyBK.Atypenuclear", + "Nature Genetics | Volume 55 | February 2023 | 268279 278 Article https://doi.org/10.1038/s41588-022-01279-621. Tiwari, V. & Wilson, D. M. 3rd. DNA damage and associated DNA repair defects in disease and premature aging. Am. J. Hum. Genet. 105, 237257 (2019). 22. Tamae, D., Lim, P., Wuenschell, G. E. & Termini, J. Mutagenesis and repair induced by the DNA advanced glycation end product N2-1-(carboxyethyl)-2-deoxyguanosine in human cells. Biochemistry 50, 23212329 (2011).", + "[36] J. de Boer, J.O. Andressoo, J. de Wit, J. Huijmans, R.B. Beems, H. van Steeg, et al., Premature aging in mice decient in DNA repair and transcription, Science 296 (2002) 12761279. [37] S.M. Schuh-Huerta, N.A. Johnson, M.P. Rosen, B. Sternfeld, M.I. Cedars, R.A. Reijo Pera, Genetic markers of ovarian follicle number and menopause in women of multiple ethnicities, Hum. Genet. 131 (2012) 17091724." + ], + [ + "During the past century, remarkable progress has been made in unveiling the mechanisms of aging. Genetic and molecular pathways that regulate healthspan and lifespan have been identified in various model organisms, provid-ing a rich knowledge base (Longo etal. 2015; Lopez-Otin etal. 2013, 2016; Singh etal. 2019). However, the focus on", + "series of recent breakthroughs, a number of genes capable ofaltering the aging process as a whole or at least to a largedegree have been identified in animal models and even a fewin humans (Finch & Ruvkun, 2001; de Magalhes, 2005; Kenyon,2005). Furthermore, multiple alleles have been examined fortheir association with human exceptional longevity (Vijg & Suh,2005). This is a fascinating and important area of research, yetthere are now so many genes being associated with aging andlongevity that keeping", + "Recent developments on the genetics of aging can be seen as several streams of effort. In general, humans show a relatively modest ( <50%) heritability of", + "One approach that has become increasingly common in the characterization of the ge-netics of aging is to isolate aging mutants, usually from mutagenesis experiments, andthen to determine the mechanistic basis for the unusual life span in the mutants. Thisapproach has led to the discovery of genes that can enhance (e.g., Maynard Smith 1958;Lin et al. 1988; reviewed in Guarente and Kenyon 2000, Kim 2007) or reduce life span(e.g., Pearl and Parker 1922). Most of the large-effect mutants affecting aging", + "One approach that has become increasingly common in the characterization of the ge-netics of aging is to isolate aging mutants, usually from mutagenesis experiments, andthen to determine the mechanistic basis for the unusual life span in the mutants. Thisapproach has led to the discovery of genes that can enhance (e.g., Maynard Smith 1958;Lin et al. 1988; reviewed in Guarente and Kenyon 2000, Kim 2007) or reduce life span(e.g., Pearl and Parker 1922). Most of the large-effect mutants affecting aging", + "genetics of aging I. What is aging? Frontiers in Genetics. doi:10.3389/fgene.2012.00134. r ose, Michael r ., Anthony D. Long, Laurence D. Mueller, Cristina L. r izza, Kennedy C. Matsagas, LeeF. Greer, and Bryant villeponteau. 2009. e volutionary nutrigenomics. In The future of aging, eds. G. M. Fahy, M. D. West, L. S. Coles, and S. B. h arris. Berlin: Springer. r ushton, J. p hillippe. 1995. Race, evolution, and behavior: A life history approach. New Brunswick, NJ: Transaction p ublishers.", + "informed by age-related disease identifies loci for exceptional human longevity. Li H, editor. PLoS Genet. 2015. https://doi.org/10.1371/journal.pgen. 15. Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, etal. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet. 2015;47:7029. 16. Cellerino A, Ori A.What have we learned on aging from omics studies? Semin Cell Dev Biol. 2017;70:17789.", + "eries that have inspired thousands of researchers across the world to study aging, and we acknowledge the wider significance of the creation of a field that has the potential to transform human health. Genetics Aging is influenced by genetic factors. It may be surprising to know that as recently as the 1970s and 1980s, the concept of modulating Downloaded from https://academic.oup.com/biomedgerontology/article/76/7/e85/6145792 by guest on 15 October 2023", + "discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease. DOI: https://doi.org/10.7554/eLife.39856.002", + "males: what are the molecular and evolutionary causes? Aging Cell. 2007;6:225233. doi:10.1111/j.1474-9726.2007.00279.x 63. Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: link- ing environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593610. doi:10.1038/nrm4048 64. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell. 2016;166:822839. doi:10.1016/j.cell.2016.07.050" + ], + [ + "Figure 1. Epigenetics of aging and aging-relate d diseases. During aging, various ep igenetic alterations occur including accumulation of histone variants, change s in chromatin accessibility mediated by chromatin remodeling complexes, loss of histones and heterochroma tin, imbalance of activating /repressing histone modifications and aberrant expres- sion/activity of miRNAs. These deregulations can affect transcrip tion and, subsequently, transl ation, as well as the stabi-", + "ment of 5 years corresponded to a 21% increased risk of mortality overall [7]. Thus, predictions of epigenetic agemay be an indication of an individual s biological state of aging. Beyond these examples of advanced epigenetic aging, a complementary but unanswered question is whether epigenetic clocks can also be slowed. Epigenetic aging studies in humans have not thus far been well suited to address questions of slowed aging, given the lack of well-documented interventions that enhance health or", + "al., 2005 ). The epigenetic changes that accumulated with age had a dramatic effect on gene expression, thus the authors propos e that a so-called epigenetic drift accompanies the aging process. Epigenetic modifications can result in the cumulative loss of gene regulation over time, ultimately impairing cellular and tissue function. Further, recent data sugge st that epigenetic disruption of tissue specific stem and progenitor cells may play a role in cancer development (Feinberg et al., 2006 ). The", + "epigenetic changes during aging are currentlyunknown (Fig. 3). It has been suggested thatthe epigenetic alterations are largely triggered by DNA damage (reviewed in Oberdoerffer and Sinclair 2007). In this scenario, randomlyoccurring DNA damage leads to chromatin remodeling and to redistribution of chromatin modiers within the genome with modiersbeing recruited away from their normal sites so that they can engage in the repair of the", + "Epigenetic Dysregulation with Age", + "Epigenetic Dysregulation with Age", + "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", + "in gene transcription and, as a consequence, translation as well as the stabilization or degradation of molecular factors. While mechanisms underlying aging-related pathologies remain to be elucidated in detail, various studies demonstrate an epigenetic component. In fact, the aforementioned epigenetic modications were shown to play essential roles in diseases including inammation, cancer, osteoporosis, neurodegenerative diseases, and diabetes.", + "PLoS Biology | www.plosbiology.org August 2007 | Volume 5 | Issue 8 | e201 1759 Epigenetic Dysregulation with Age", + "and increased expression of proaging genes such as the cell-cycle inhibitor p16, which drives cell senescence. Additional consequences of epigenetic dys-regulation include increased transcriptional noise and decreased coordination of gene expression that contributes to organismal aging. Cell148, January 20, 2012 2012 Elsevier Inc. 53" + ], + [ + "27 Willcox, B. J. et al. 2008 FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13 98713 992. ( doi:10.1073/ pnas.0801030105 ) 28 Flachsbart, F., Caliebe, A., Kleindorp, R., Blanche, H., von Eller-Eberstein, H., Nikolaus, S., Schreiber, S. & Nebela, A. 2009 Association of FOXO3A variationwith human longevity conrmed in GermanGenomics of human longevity P . E. Slagboom et al. 41", + "3. Willcox BJ, Donlon TA, He Q et al (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA 105(37):1398713992. doi: 10.1073/pnas.0801030105 4. Anselmi CV, Malovini A, Roncarati R et al (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res 12(2):95104. doi: 10.1089/ rej.2008.0827 5. Flachsbart F, Caliebe A, Kleindorp R et al (2009) Association of FOXO3A variation with human longevity conrmed in German", + "are, in fact, part of the same insulin/IGF1/GH pathway(Fig. 1) that modulates lifespan across organisms (Ke-nyon, 2010). A strong association between FOXO3 and human longevity has been reported (Willcox et al., 2008)and subsequently validated in other populations (forreview, see Kenyon, 2010). FOXO3 was also associatedAGING GENES AS TARGETS FOR DRUG DISCOVERY 95", + "Biogerontology 11:28797 117. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, et al. 2008. FOXO3A genotype is strongly associated with human longevity. Proc. Natl. Acad. Sci. USA 105:1398792 118. Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, et al. 2010. Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell 9:101017 119. Mardis ER. 2011. A decades perspective on DNA sequencing technology. Nature 470:198203", + "FOXO3 locus is associated with extreme longevity in humans (centenarians) [2, 58, 59]. NRF/SKN-1 activates the expression of genes involved in protecting the cell in response to ROS, toxins, and metabolic changes through mTOR and insulin/IGF signaling, and it is also dysregulated later in life [60, 61]. Increasing the levels of L. Garca-Velzquez and C. Arias", + "A. 2003;100:406671. https://doi.org/10.1073/pnas.2628028100. 24. van den Akker EB, Deelen J, Slagboom PE, Beekman M. Exome and whole genome sequencing in aging and longevity. Adv Exp Med Biol. 2015;847:12739. https://doi. org/10.1007/978-1-4939-2404-2_6. 25. Flachsbart F, etal. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A. 2009;106:27005. https://doi.org/10.1073/ pnas.0809594106. A. Garca-Venzor and E. A. Mandujano-Tinoco", + "X.L., 2009. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum. Mol. Genet. 18, 48974904. Lunetta, K.L., DAgostino Sr., R.B., Karasik, D., Benjamin, E.J., Guo, C.Y., Govindaraju, R., Kiel, D.P., Kelly-Hayes, M., Massaro, J.M., Pencina, M.J., Seshadri, S., Murabito, J.M., 2007. Genetic correlates of longevity and selected age-related phenotypes:", + "theFOXO3 locus is not surprising, since this locus was previously reported in the longevity GWA study from the CHARGE con- sortium 7, from which many cohorts are included in these meta- analyses. So far, three functional longevity-associated variants have been identi ed at the FOXO3 locus (rs2802292, rs12206094, and rs4946935). For all of them, an allele-speci c response to cellular stress was observed. Consistently, the longevity-associated alleles of all three variants were shown to induce FOXO3", + "exceptional longevity with no significant genetic contribution. Interestingly, the authors found that FOXO3A, a longevity allele, may not be related to healthy aging phenotype [29]. Aging is a complex process usually accompanied by the onset of different dis- eases like neurodegenerative disorders (Alzheimers disease and Parkinsons dis- ease), cardiovascular illnesses, and cancer. The study of the genetic basis of these aging-related diseases is another approach in the study of the genomic basis of", + "centenarians. Proc Natl Acad Sci USA 106(8):27002705. doi: 10. 1073/pnas.0809594106 6. Li Y, Wang WJ, Cao H et al (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18(24):48974904. doi: 10.1093/ hmg/ddp459 7. Soerensen M, Dato S, Christensen K et al (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. AgingCell 9(6):10101017. doi: 10.1111/j.1474-9726.2010.00627.x" + ], + [ + "of multiple genes with each other and withthe environment. Evidence from animal systems showsa major impact of the environment on aging, yet envi-ronmental manipulations of aging act through genesand proteins, usually by triggering signaling pathwaysand modulating gene expression. In fact, some geneshave been shown in model organisms to have varyingeffects on lifespan depending on diet (Heikkinen et al.,2009). Genes that can regulate aging in model organ-isms cannot be directly applied to humans through", + "Several studies show the influence of the environment on the ageing process [24]. Environmental factors may affect homeostasis and lead to the development of dis- eases, thus affecting the quality of life in older age [25]. They also produce cellular damage, which causes an accelerated shortening of the telomeres at the genetic level, accompanied by changes in DNA methylation, acetylation or deacetylation of histones, among others. Altogether, these changes induce an aberrant gene", + "changes are generated during the aging process. For a long time it has been believed that epigenetic modications occurring during aging may depend on environmental factors. This idea is attractive because, if true, epigenetics could provide a link between the environment, disease and aging. It also opens the possibility of targeted intervention aimed, for example, at improving healthspan or healthy aging. Thus, the rst question is whether specic environmental factors can directly induce specic epigenetic", + "In addition, environmental factors influence the organism s ability to withstand the increase in entropy with aging: for example, caloric restriction and smoking can exert opposite effects on the rate ofaging (Colman et al. 2009 ; Fraser and Shavlik 2001 ). Both protective alleles and a benevolent environment contribute to excess physiological capacity, which in turn indirectly determines an individual s healthy life span and longevity (Martin et al. 2007 ). The well-", + "to humans through ge-netic manipulations for numerous legal, ethical, andtechnical reasons. If we could understand how the envi-ronment modulates these aging-related genes, we mightbe able to create antiaging therapies applicable to hu-mans, potentially through diet, lifestyle, and even phar-macological interventions. Therefore, understanding ge-nome-environment interactions in the context of agingcan be a powerful approach to identify attractive targetsfor drug design.", + "ing human life span have been identified [2,3]. At the same time, there is a growing realization that environ- mental factors are major contributors to aging and age- associated illness. Epigenetics is the study of chemical modifications of the genome, heritable by cell progeny, and it has been an attractive target for studies of aging and environmentally influenced disease. Several groups have shown differences in DNA methylation - a covalent", + "al., 2009; Stanfel et al., 2009). Many of these genesmodulate the response to environmental signals, such asfood availability, and act in signaling pathways that ifunderstood can be targeted (Fig. 1). The genetic regula-tion of aging is therefore an emerging field with multipleapplications in the human nutrition, cosmetic, and phar-maceutical industries. AGING GENES AS TARGETS FOR DRUG DISCOVERY 91", + "standing the cause and mechanisms of aging is imperative in assisting to suppress age-related diseases and promote healthylongevity. It is well-known that aging is influenced by a combin- ation of genetic and environmental factors. Previous twin stud- ies have shown that the genetic contribution to general human longevity is about 2030% [ 4,5], whereas environmental factors in human aging and longevity still account for the largest effect. Epigenetic factors influence the regulation of gene expres-", + "known to affect the function of epigenetic regulators, this may be an example of how aging interacts with our genome to inuence AD development.", + "consequently the incidence of age-related diseasessuch as heart disease, cancer, and neurodegenerativediseases, is projected to increase considerably in thecoming decades. Findings from model organisms haverevealed that aging is a surprisingly plastic processthat can be manipulated by both genetic and environ-mental factors. Here we review a broad range of find-ings in model organisms, from environmental to ge-netic manipulations of aging, with a focus on thosewith underlying gene-environment interactions" + ], + [ + "senescence, exhausting the ability for a tissue to regenerate after injury, impacting mitochondrial function,and inducing protein aggregation. Senescent cells have altered metabolism, and they can secreteproinammatory factors and alter the local tissue environment, thereby contributing to aging andage-related degenerative diseases. In addition, stem cell function can be impacted by DNA damage by bothcell autonomous and nonautonomous mechanisms. Proper function of mitochondria is dependent upongenome", + "[87] and the accumulation of senescent cells in human tissues with age has been implicated as a driver of aging- related diseases. Indeed, pharmacological approaches targeting senescent cells, like senolytics, are a major and timely area of research that could result in human clin- ical applications [ 5,88]. It is imperative that we fully understand and deconstruct cellular senescence in order to target aging-related diseases. We hope that CellAge will help researchers understand the role that CS plays", + "An important source of inflammatory signals in aged organ- isms is thought to be the accumulation of senescent cells across tissues [ 5,7]. Indeed, accumulating evidence has shown that senescent cells are characterized by a senescence-associatedsecretory phenotype [ 810], which includes a panoply of pro-inflammatory cytokines, proteases, growth factors and metabolites [ 10,11]. The impact of senescent cells on age-related inflammation, and their potential role as a target for pro-", + "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", + "atherosclerosis, osteoarthritis, sarcopenia, ulcer formation, cancer, and Alzheimer disease, which is suggestive of a causative role. However, the most convincing evidence that senescent cells causeaging comes from recent genetic (85) and pharmacologic studies (86) revealing that clearance of senescent cells can prevent or delay tissue dysfunction and extend health span. Senescent cells induce autocrine, as well as paracrine, signaling by secretion of proinamma-", + "senescence can deplete both stem (5153) and stromal (10,11) cell pools. Moreover, because senescent cellspersist, they have the ability to alter the tissue micro-environment, and can therefore also promote the degen-eration of organs and stem cell niches (14,46). Finally, senescent cells secrete factors such as matrix metallopro- teinase-3 (MMP-3), which favors extra-cellular matrixremodeling, promotes defects in epithelial cell dierentia-tion and stimulates cancer cell growth (46,54,55).", + "potential role of senescence in in vivo aging and disease has been difficult to assess and somewhat controversial [146]. However, recent studies have shown that senescent cells accumulate in normal arterial tissue over the lifespan of humans [147, 148]. Likewise, the accumulation of senescent cells has been reported in diseased tissues, such as atherosclerotic plaques [149] and abdominal aortic aneurysms [150]. Baker et al. showed that", + "51. Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. 2007. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128:3644 52. Boyle J, Kill IR, Parris CN. 2005. Heterogeneity of dimer excision in young and senescent human dermal broblasts. Aging Cell 4:24755 53. Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V. 2004. DNA end joining becomes less efcient and more error-prone during cellular senescence. PNAS 101:762429", + "in many accelerated-aging mouse models and in a plethora of human age-associated pathologies, including osteoporosis, atherosclerosis, glomerular disease, diabetic venous ulcers, chronic ob-structive pulmonary disease and emphysema, osteoarthritis, herniated intervertebral discs, and vascular calcication (112). Senescent cells are resistant to apoptosis and accumulate exponen- tially with age as a consequence of inefcient clearance. Unlike apoptotic tissues, senescent tissues 436 VermeijHoeijmakersPothof", + "wound healing [ 8], and immune clearance [ 9,10]. By contrast, the gradual accumulation and chronic persistence of senescent cells with time promotes dele- terious effects that are considered to accelerate deterior- ation and hyperplasia in aging [ 11]. Senescent cells secrete a cocktail of inflammatory and stromal regula- torsdenoted as the senescence-associated secretory phenotype, or SASP which adversely impact neighbor- ing cells, the surrounding extracellular matrix, and other" + ], + [ + "Dietary interventions, including starvation and protein deprivation, can also alter patterns of DNA methyla- tion, potentially in a long-lasting manner [42, 43], including transgenerationally [26, 44]. Dietary, genetic and pharmacological interventions that improve health during aging and extend lifespan induce long-lasting changes in gene expression that mediate their effects. Here we have asked if and how age-related DNA methylation, transcription and lipid", + "Longev. Heal. 2, 10 (2013). 7. Kreienkamp Ret al.Doubled lifespan and patient-like pathologies in progeria mice fed high-fat diet. Aging Cell18, e12852 (2019). [PubMed: 30548460] 8. Heilbronn LK & Ravussin E Calorie restriction and aging: review of the literature and implications for studies in humans. Am. J. Clin. Nutr. 78, 361369 (2003). [PubMed: 12936916] 9. Liang Yet al.Calorie restriction is the most reasonable anti-ageing intervention: a meta-analysis of", + "a medical intervention), without changing the fundamental rateof organismal aging. Nevertheless, it does seem that manyso-called longevity genes, as well as dietary restriction, appear to extend not only life span, but also health span (Kauffman et al., 2010; Luo et al., 2010 ). In that regard, it does appear that it is possible to experimentally slow the rate of aging. Still, in each case, aging does continue on as if there is some", + "As we describe above, a small but growing number ofinterventions has been shown to reproducibly increase lifespan in laboratory animals and, in a few cases, to also delay or reverse age-related declines in multiple organsystems. These healthy aging interventions could, in prin- ciple, be tested to determine whether they also increase lifespan and promote healthspan in dogs (Table 1). There are several questions that immediately present themselves when considering the design of a healthy aging interven-", + "be linked to the biology of stem cell quiescence and self-renewal. Although genetic and environmental interventions have clearly proven to be effective in prolonging life span, we postulate thatthose interventions, as well as the rejuvenating interventions described above, are, in fact, acting primarily to modify theepigenome. Consistent with this, genetic interventions directlytargeting the epigenome can extend life span ( Greer et al., 2010 ). Studying aging and rejuvenation through the lens of", + "During the past century, remarkable progress has been made in unveiling the mechanisms of aging. Genetic and molecular pathways that regulate healthspan and lifespan have been identified in various model organisms, provid-ing a rich knowledge base (Longo etal. 2015; Lopez-Otin etal. 2013, 2016; Singh etal. 2019). However, the focus on", + "205. Li, Y.; Tollefsbol, T.O. p16INK4a Suppression by Glucose Restriction Contributes to Human Cellular Lifespan Extension through SIRT1-Mediated Epigenetic and Genetic Mechanisms. PLoS ONE 2011 ,6, e17421. [CrossRef] 206. Daniel, M.; Tollefsbol, T.O. Epigenetic linkage of aging, cancer and nutrition. J. Exp. Biol. 2015 ,218, 5970. [CrossRef] 207. Kapahi, P .; Kaeberlein, M.; Hansen, M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res. Rev. 2017 , 39, 314. [CrossRef]", + "as diabetes, cancer and neurodegenerative disorders [1, 2]. Environmental and genetic interventions can ameliorate the effects of aging, with nutrition, nutrient-sensing signaling networks and metabolism playing evolutionarily conserved roles [1, 3 5]. Diet- ary restriction (DR), in which food intake is reducedwhile avoiding malnutrition, extends lifespan in di- verse model and non-model organisms [3, 6]. DR induces a remarkably broad-spectrum improvement in", + "53. Mair W & Dillin A Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727754 (2008). [PubMed: 18373439] 54. Masoro EJCaloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms. Biochim. Biophys. Acta1790, 10401048 (2009). [PubMed: 19250959] 55. Weindruch R, Walford RL, Fligiel S & Guthrie D The retardation of aging in mice by dietary", + "In addition to genes associated with aging, research has focused on identifying genes associated with the life- extending effects of CR. One method is to identify genesthat decrease or cancel out the life-extending effects of CRwhen mutated (Gems et al., 2002; Bishop and Guarente,2007). More than 100 such genes have been identified inmodel organisms (D. Wuttke, C. Vora, J. P. de Magalhes,unpublished observations). The growth hormone receptor(GHR) is the only gene so far identified in mammals that" + ], + [ + "vided one of the most reliable aging biomarkers. An epigenetic clock is a group of CpG sites with particular methylation patterns that are highly related to the chrono- logical age of an individual. This correlation is very robust (r=0.9) for individuals between 20 and 100years. The epigenetic clock is a breakthrough discovery that will allow novel experimental approaches to understand the biological basis of aging [113]. For example, by using the epigenetic clock as a measure of cellular", + "Epigenetic Clock Chronological age is the number of years a person has lived, and biological or phys- iological age refers to a measure of how well your body functions compared to your chronological age. Biological age is influenced by multiple factors (genes, lifestyle, behavior, environment, among others) and correlates with mortality and health sta- tus. The epigenetic clock is one potentially reliable predictor of biological age.", + "Background Epigenetic clocks are sets of CpG dinucleotides whose DNA methylation (DNAm) can be used to accurately predict a person s chronological age [ 1]. In recent years, various epigenetic clocks have been developed [ 25]. Well-known examples are the clocks de- veloped by Hannum et al., trained on blood samples and containing 71 CpGs [ 2], and Horvath, a multi-tissue predictor consisting of 353 CpGs [ 3]. A popular application of", + "An EpigeneticClock The aging transcriptome could be used to gauge the physiological age of worms, and in that way serve as an epigenetic clock revealing how much of life span has been spent and how much remains (23). Middle-aged worms show an aging transcriptome half-way between the aging expression profiles of young and old worms. This provides an independent way to assess the age of an animal independent of its life span. This is important as there are at least 2 explanations to", + "The epigenetic aging clock measures the sum of all the age-related pathways affecting cellular physiology in old age. The aging epigen- etic clock is heavily enriched for germline- and intestinal-expressed genes, but lack muscle- and neuronal-expressed genes (23, 25). Expression changes in the germline and intestine were expected as there are massive changes in the morphology of gonad at the end of fertility and the intestine in old age. The aging transcriptome pro-", + "etic mouse aging and may be used to inform future studies in other model organisms and humans focused on studying the relationship between epigenetic aging and metabolism. Introduction Epigenetic clocks are widely used molecular biomarkers of aging (Horvath and Raj, 2018). These DNA methylation (DNAm) age predictors are based on the methylation levels of select CpGs that are RESEARCH ARTICLE *For correspondence: kmozhui@uthsc.edu Competing interest: See page 22 Funding: See page 22", + "etic mouse aging and may be used to inform future studies in other model organisms and humans focused on studying the relationship between epigenetic aging and metabolism. Introduction Epigenetic clocks are widely used molecular biomarkers of aging (Horvath and Raj, 2018). These DNA methylation (DNAm) age predictors are based on the methylation levels of select CpGs that are RESEARCH ARTICLE *For correspondence: kmozhui@uthsc.edu Competing interest: See page 22 Funding: See page 22", + "estimators epigenetic clocks; telomere length; transcriptomic-, proteomic-, and metabolomic-based estimators; and composite biomarkers concluded that the epi- genetic clock is the most promising molecular estimator of biological age [26]. Epigenetic age estimators are sets of CpGs (also known as clock CpGs) that are coupled with a mathematical algorithm to estimate the age of a DNA source, such as cells, tissues, or organs. This estimated age, also referred to as epigenetic age or", + "proved epigenetic clock. It should be noted that building a biological age predictor is difficult since there is no clear definition of biological age. Nevertheless, one of the essential features of biological age is its ability to in- dicate the different ageing rates between individuals with the same chronological age. A previous study has re- ported a number of CpG sites that show variation in the longitudinal changing rates between individuals [ 40].", + "ranging from 0.15 to 0.19 [ 8,9]. Individuals with epigenetic clock estimates greater than their chronological age display age acceleration and have been shown to be at a greater risk of all-cause mortality and multiple adverse health outcomes [ 10]. Conse- quently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field [ 11]. The first generation of epigenetic aging clocks used penalized regression models to" + ], + [ + "the nematode Caenorhabditis elegans , and the budding yeast Saccharomyces cerevisiae , have emerged as the most widely used and, hence, best characterized, model organisms in bio- gerontology. When considering the use of simple eukaryotes to study aging and age-related disease, it is pertinent to ask whether, and to what degree, the aging process is evolutionarily con- served. Does a yeast cell age by the same mechanism(s) as a", + "Studies on the aging of mammals are rather limited by the long life span of the commonly used model organisms. Thus, both nonverte-brate and invertebrate organisms, with their shorter life span and ease of genetic and environmental manipulations, gained popularity amongresearchers in the aging field as experimental models for aging studies. Among them, budding yeast or Saccharomyces cerevisiae is a highly in- formative organismal model for aging studies with its genetic tools,", + "Abstract Cellular models such as yeasts are a driving force in biogerontology studies. Their simpler genome, short lifespans and vast genetic and genomics resources make them ideal to characterise pro-ageing and anti-ageing genes and signalling pathways.Over the last three decades, yeasts have contributed to the understanding of fundamental aspects of lifespan regulation including the roles of nutrient response, global protein translation rates and quality, DNA damage, oxidative stress,", + "usually chosen for convenience rather than for specific features applicable to human aging. Hence, choosing the suitable animal model to answer the specific question we aim to understand is of high importance in these types of studies. Among the most prevalent aging model organisms are Saccharomyces cerevisiae , Caenorhabditis elegans, Drosophila melanogaster, and Mus mus - culus . As a single-celled organism, S. cerevisiae is easily grown,", + "mammalian genes that affect aging than any other model organism. Aging in yeast is assayed primarily by measurement of replicative or chronological life span. Here, we review the genes and mechanisms implicated in these two aging model systems and key remaining issues that need to be addressed for their optimization.", + "be more exaggerated in more distantly related species (such as the worm and mouse models). There are, however, simi - larities between aged humans and aged model organisms; they all tend to have decreasing overall fitness, and there - fore, studies using model organisms continue as they may be at least indicative of some aging mechanisms in humans. Extensions to life span in model organisms are mostly associated with disruption to fundamental metabolic path -", + "eukaryote model organisms, namely yeast, worms, ies,and sh, as well as mice and rats, to explore both genetic and environmental determinants of lifespan. While these short-lived models have each yielded a number of fasci- nating ndings and insights into hypotheses surrounding extended lifespan and healthspan, they may also haveconstrained this complex, multifactorial eld to areas in which they are best suited, most notably short-term inter-", + "et al., 2010 ). These effects require an intact germline, andTable 2. Repositories and Tools for Aging Research Models Description Link/Reference Yeast Saccharomyces genome database http://www.yeastgenome.org/ published lifespan data http://lifespandb.sageweb.org/ (McCormick et al., 2015 ) Wilcoxon rank sum test to test signicance of lifespan differenceshttp://data.kaeberleinlab.org/scripts/ranksum.php yeast outgrowth data analyzer (YODA) for chronological lifespan assayshttp://yoda.sageweb.org/", + "for molecular biological studies on aging. Although material from humans should be employed where possible, for prac- tical reasons animal model systems like rats and mice are indispensible. There is evidence that, provided their health sta- tus and husbandry is optimal, rodents age much in the same way as humans do (Burek 1978). For studying certain funda- mental processes, such as the occurrence of various types of DNA rearrangement, lower organisms and cell lines can also", + "short life span, and fully sequenced genome (20 ,21). Despite being uni- cellular, yeast has been an excellent model to identify and characterize conserved basic biological processes, including aging. Yeast has beenextensively used to identify genes and interventions responsible for lifespan extension and to gain insights into the aging processes of all eu- karyotic organisms. In parallel, over the years, studies on invertebrate organisms, such as Drosophila melanogaster (flies) and Caenorhabditis" + ], + [ + "need to develop approaches and therapies targeting theaging process and age-related diseases (Butler et al.,2008). Delaying the process of aging, even slightly,would have profound social, medical and economic ben-efits (Olshansky et al., 2006; Butler et al., 2008). Forexample, slowing aging by a mere 7 years would cutmortality of age-related diseases by half at every age.Therefore, the potential benefits from research on thebasic biology and genetics of aging are unparalleled interms of improving quality", + "raises the possibility of therapies to slow aging. Therefore the discoveryof a gerontogene with even very rare mutations that increased longevitywould cause speculation about future trends in mortality. However, thediscovery of such a gene would be relevant only to long-term (and, there-fore, very speculative) projections. Prospective Epidemiologic Surveys that Include Genetic Information Some epidemiologic cohort studies of populations have collected", + "Interestingly, when senescent cells are abolished either through genetic manipulation or via senolytic drugs, biological aging is signicantly halted in mice [ 53,54]. Therefore, trials are now under way to test the ability of senolytics to postpone age-associated pathologies in humans [ 55]. Notably, multi- ple drugs are being pursued that either directly or indirectly impact DNA repair or the consequenceof DNA damage. Future Prospects: Developing Interventions through DNA Repair", + "5. Goldman DP, etal. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff (Millwood). 2013;32(10):1698705. 6. Esplin ED, Oei L, Snyder MP.Personalized sequencing and the future of medicine: discov- ery, diagnosis and defeat of disease. Pharmacogenomics. 2014;15(14):177190. 7. Marian AJ.Clinical applications of molecular genetic discoveries. Transl Res. 2016;168:614.", + "J.L. Kirkland, Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms, J. Gerontol. A Biol. Sci. Med Sci. 71 (11) (2016) 1388 1394 . [2]D.J. Baker, B.G. Childs, M. Durik, M.E. Wijers, C.J. Sieben, J. Zhong, R.A. Saltness, K.B. Jeganathan, G.C. Verzosa, A. Pezeshki, K. Khazaie, J.D. Miller, J.M. van Deursen, Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan, Nature 530 (7589) (2016) 184 189.", + "series of recent breakthroughs, a number of genes capable ofaltering the aging process as a whole or at least to a largedegree have been identified in animal models and even a fewin humans (Finch & Ruvkun, 2001; de Magalhes, 2005; Kenyon,2005). Furthermore, multiple alleles have been examined fortheir association with human exceptional longevity (Vijg & Suh,2005). This is a fascinating and important area of research, yetthere are now so many genes being associated with aging andlongevity that keeping", + "pharmaceutical and other interventions for human aging based on research that starts with the genomic information required to sustain adaptation, and thus health, in older fruit flies [36-39]. Naturally, any such genomic short-cut to reverse-engineering the evolution of slowed aging from fruit flies to humans is fraught with potential for error. Such evolutionarily deep orthologies are sure to supply", + "century. Manipulation of aging-related genes by diet,lifestyle, and pharmaceuticals could dramatically im-prove human health and could be used to develop drugsagainst age-related diseases such as cancer, heart dis-ease, type 2 diabetes, obesity, and neurodegenerativediseases. The hundreds of aging-related genes and genesrelated to CR already identified offer enormous oppor-tunities for target discovery (Fig. 2). Although aging-related genes cannot be modified in humans, under-standing how these can be", + "[7] Hughes, S.E., Evason, K., Xiong, C., Kornfeld, K. Genetic and pharmacological factors that influence reproductive aging in nema- todes. PLoS Genet. 2007 , 3: e25. [8] Vijg, J., Campisi, J. Puzzles, promises and a cure for ageing. Na- ture 2008 , 454: 1065-1071. [9] Rolland, Y., Czerwinski, S., Abellan Van Kan, G., Morley, J.E., Cesari, M., Onder, G., Woo, J., Baumgartner, R., Pillard, F., Boirie, Y., Chumlea, W.M., Vellas, B. Sarcopenia: its assessment, etiol-", + "for the aging process during the 20th Century. Thissituation poses a fundamental challenge to anti-aging medicine: how to develop effective therapies for a genomically complex pathology. We propose such astrategy. As a rst step, we recommend the use of modelsystems in which signicant genetic intervention is not proscribed or impractical. Second, we propose that work" + ], + [ + "caloric restriction. Physiol. Genom. 17, 307 315.Van Remmen, H., Ward, W.F., Sabia, R.V ., Richardson, A., 1995. Gene expression and protein degradation. In: Masoro, E.J. (Ed.), Handbook ofPhysiology. Section 11: Aging. Oxford University Press, New York, pp. 171234. Weindruch, R., Walford, R.L., 1982. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence.Science 215, 1415 1418.S.R. Spindler / Mechanisms of Ageing and Development 126 (2005) 960 966 966", + "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.", + "analysis in calorie-restricted rats implicates epigenetic and post-translational mechanisms in neuroprotection and aging. Genome Biol. 2015;16:285. 21. Gillespie ZE, Pickering J, Eskiw CH. Better living through chemistry: caloric restriction (CR) and CR mimetics alter genome function to promote increased health and lifespan. Front Genet. 2016;7:142. 22. Jiang T, Liebman SE, Lucia MS, Phillips CL, Levi M. Calorie restriction modulates renal expression of sterol regulatory element binding proteins, lipid", + "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", + "Transcriptome analysis in calorie-restricted rats implicates epigenetic and post- translational mechanisms in neuroprotection and aging. Genome Biol. 16,2 8 (2015). 204. M. V. Blagosklonny, Calorie restriction: Decelerating mTOR-driven aging from cells to or- ganisms (including humans). Cell Cycle 9, 683 688 (2010). 205. D. K. Ingram, G. S. Roth, Calorie restriction mimetics: Can you have your cake and eat it, too? Ageing Res. Rev. 20,4 662 (2015).", + "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", + "Keywords: Caloric restriction; Short-term; Longevity; Cancer; Microarray; Affymetrix Aging is widely assumed to result from the gradual age- related accumulation of essentially irreversible moleculardamage. In this context, CR is often viewed as preventing orslowing the accumulation of such damage, thereby slowingthe process of aging ( Bokov et al., 2004 ). This view is intuitively appealing, as it provides a straightforwardexplanation for the stochastic nature of aging and the onset", + "of short- and long-term caloric restriction effects in the liver of agingmice. Proc. Natl. Acad. Sci. U.S.A. 98, 10630 10635.Capstick, F., Brooks, B.A., Burns, C.M., Zilkens, R.R., Steinbeck, K.S., Yue, D.K., 1997. Very low calorie diet (VLCD): a useful alternative inthe treatment of the obese NIDDM patient. Diab. Res. Clin. Pract. 36, 105111. Chen, H., 2004. Gene expression by the anterior pituitary gland: effects of age and caloric restriction. Mol. Cell. Endocrinol. 222, 21 31.", + "genomic effects of caloric restriction. Mech. Ageing Dev. 126 : 960 966 . Sun , H. , R.J. Bennett , and N. Maizels . 1999 . The Saccharomyces cerevisiae Sgs1 helicase effi ciently unwinds G-G paired DNAs. Nucleic Acids Res. 27 : 1978 1984 . Thompson , L.H. , and D. Schild . 2002 . Recombinational DNA repair and human disease. Mutat. Res. 509 : 49 78 .", + "L. & Spindler, S. R. Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc. Natl Acad. Sci. USA 98, 1063010635 (2001). 62. Harman, D. The aging process. Proc. Natl Acad. Sci. USA 78, 71247128 (1981). 63. van der Pluijm I, G. G.et.al. Impaired genome maintenance suppresses the growth hormoneinsulin-like growth factor 1 axis in mice with cockayne syndrome. PLoS Biol. 5, 2338 (2006). 64. Yang, H., Baur, J." + ] + ], + "task_id": [1,2,3,4,5,6,7,8,9,10,1,2,3,4,5,6,7,8,9,10] +} \ No newline at end of file -- cgit v1.2.3