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{
"created_at": "2024-04-02T12:04:11.979513Z",
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"answer": "The most fundamental human life expectancy extending geroscience studies include genetic and genomic research into longevity. These studies use both hypothesis-driven candidate gene approaches and explorative genome-wide analyses. They also involve the study of biomarkers related to aging, deep phenotyping, and the use of novel technologies like next-generation sequencing. Additionally, they examine the role of environmental factors, lifestyle, and heritability in human lifespan variation.",
"context": {
"04c5378f-40dc-4690-af03-e5205779b881": [
{
"document_id": "04c5378f-40dc-4690-af03-e5205779b881",
"text": "Introduction\n\nWith the development of human genomics research, a large number of studies of the genetics of longevity have been conducted.Scientists from various countries have proposed many different theories concerning the mechanisms of aging from different perspectives, involving oxidative stress, energy metabolism, signal transduction pathways, immune response, etc. [1,2].These mechanisms interact with each other and are influenced by heredity to some degree [2,3].The identification of longevity-related biological markers is critical to an indepth understanding of the mechanisms of carrier protection against common disease and/or of the retardation of the process of aging."
}
],
"1386c8ad-297d-48b1-aa34-41659a9f6544": [
{
"document_id": "1386c8ad-297d-48b1-aa34-41659a9f6544",
"text": "INTRODUCTION\n\nHuman aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining ∼20-25% of the variability of human survival to the mid-eighties (Herskind et al., 1996;Fraser and Shavlik, 2001).By contrast, genetic factors may have greater impact on survival to the ninth through eleventh decades (Tan et al., 2008).Notably, exceptional longevity is rare and may involve biological mechanisms that differ from those implicated in usual human aging."
}
],
"3043efd1-4b13-4300-b2a7-d1992c8d4e47": [
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"document_id": "3043efd1-4b13-4300-b2a7-d1992c8d4e47",
"text": "Introduction\n\nGeroscience refers to research aimed at understanding the mechanisms of biological aging (Kennedy et al. 2014).A major goal of geroscience is to define the genetic, epigenetic, and environmental features that determine individual rates of aging.From a translational perspective, a further goal is to use this knowledge to develop interventions that can slow or delay aging in order to promote healthy longevity and increase healthspan, the period of life spent in good health free from chronic disease and disability (Burch et al. 2014;Pitt and Kaeberlein 2015)."
}
],
"3bf70612-23e6-41b8-9b88-ce9ba23c1edf": [
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"document_id": "3bf70612-23e6-41b8-9b88-ce9ba23c1edf",
"text": "\nthe maximum human life span.Several avenues to studying aging have placed us on Department of Biology Massachusetts Institute of Technology the threshold of understanding basic underlying mechanisms.These approaches include the identification of Cambridge, Massachusetts 02139 key genes and pathways important in aging; genetic studies of heritable diseases that cause the appearance of premature aging in affected people; physiological ex-Introduction periments that relate the pace of aging to caloric intake; Is aging the final act in the script of developmental bioland advances in human genetics, as well as cell and ogy?The characteristic changes that are part and parcel molecular biology leading to an understanding of the of aging appear similar to developmentally regulated basis of many diseases of aging.Strikingly, single gene programs.But why would aging mechanisms have been mutations have been found to significantly extend the evolutionarily selected as advantageous?Indeed, evolife span in C. elegans, yeast, and, most recently, Drolutionary biologists might argue that aging occurs by sophila, suggesting that aging may be relatively simple, default due to the absence of selection in the postreproat least in these organisms.Further, the limited replicaductive phase of life.By this view, the aging process is tion potential of human cells in culture has been attribnot programmed, but, rather, the detritus of the absence uted to a specific mechanism (i.e., the shortening of of selection for maintenance (Medawar, 1952; Kirkwood, telomeric ends of chromosomes).An important chal- 1977).However, it is quite reasonable that any mechalenge is now to relate these recent findings to the more nisms that sprang up to slow or regulate the pace of complex case of human aging.aging would be selected, because lucky individualsIn this review, we will discuss several important mocould potentially give rise to more progeny.Therefore, lecular models of aging that come from current research.it is reasonable to suppose that life span extending pro-These are damage by reactive oxygen species (ROS) cesses have been selected and that these can be viewed generated by metabolism, genome instability, genetias an elaboration of development itself.In principle, cally programmed extension mechanisms, cell death, such extension mechanisms may act to slow or forestall and systemic aging.Questions to be posed include the deleterious changes in an organism that progressively following.What evidence exists for and against these lead to death.The life span of an organism, therefore, models?Can more than one of these models apply to is the sum of deleterious changes and counteracting aging of different tissues in humans-specifically do repair and maintenance mechanisms that respond to organs with continually dividing cells age by the same the damage (Figure 1).mechanism as organs that are postmitotic?Finally, is A priori, one imagines such longevity mechanisms to aging amenable to therapeutic intervention, and would be much less complex than those regulating embryonic such intervention be advisable?development.The spatial and temporal constraints on embryonic development are many, while requirements Oxidative Damage for longevity mechanisms might be much more specific One theory of aging proposes that ROS which are generif there were a single process (or a few processes) whose ated by metabolism cause cumulative damage over a breakdown is the limiting event in longevity (i.e., the lifetime (Harman, 1981).Roughly two to three percent Achilles heel).of oxygen taken up is chemically reduced by the addition Aging is defined when two criteria are met.First, the of single electrons, which are sequentially converted probability of death at any point in time increases with into ROS, including the superoxide anion, hydrogen perthe age of the organism.This statistical definition applies oxide, and the hydroxyl radical.ROS have been shown from yeast to mammals and reflects the progressive to cause molecular damage relatively indiscriminately nature of aging.Second, characteristic changes in pheto proteins, lipids, and nucleic acids.In addition, specific notype occur in all individuals over time due to the limdamage has been observed in the mitochondrial DNA, iting processes.which we consider below in Genome Instability.The phenotypic definition is equally general and is What is the evidence that oxidative damage causes useful in distinguishing the aging process itself from aging?One category of study that is supportive of this diseases of aging, such as cancer and heart disease.view involves animals transgenic for genes encoding Phenotypes of aging affect all of the individuals in a antioxidants.Transgenic Drosophila overexpressing both population, while diseases of aging affect only a subset.Cu/Zn SOD and catalase live 34% longer than controls Both impact on life span, but in different ways.For exam-(Orr and Sohal, 1994).A more recent study shows that ple, the many advances in medicine and public health expression of human SOD1 exclusively in Drosophila in this century have caused a large increase in the averadult motor neurons leads to a 40% extension in life age life span of humans in developed countries.Howspan (Parkes et al., 1998).Further experiments are necever, because these advances have not altered the aging essary to clarify the nature of this primary role of motor neurons in life span.Conversely, mice knocked out for either GPX1 (encoding glutathione peroxidase), SOD1,"
},
{
"document_id": "3bf70612-23e6-41b8-9b88-ce9ba23c1edf",
"text": "\n\nthe maximum human life span.Several avenues to studying aging have placed us on Department of Biology Massachusetts Institute of Technology the threshold of understanding basic underlying mechanisms.These approaches include the identification of Cambridge, Massachusetts 02139 key genes and pathways important in aging; genetic studies of heritable diseases that cause the appearance of premature aging in affected people; physiological ex-Introduction periments that relate the pace of aging to caloric intake; Is aging the final act in the script of developmental bioland advances in human genetics, as well as cell and ogy?The characteristic changes that are part and parcel molecular biology leading to an understanding of the of aging appear similar to developmentally regulated basis of many diseases of aging.Strikingly, single gene programs.But why would aging mechanisms have been mutations have been found to significantly extend the evolutionarily selected as advantageous?Indeed, evolife span in C. elegans, yeast, and, most recently, Drolutionary biologists might argue that aging occurs by sophila, suggesting that aging may be relatively simple, default due to the absence of selection in the postreproat least in these organisms.Further, the limited replicaductive phase of life.By this view, the aging process is tion potential of human cells in culture has been attribnot programmed, but, rather, the detritus of the absence uted to a specific mechanism (i.e., the shortening of of selection for maintenance (Medawar, 1952; Kirkwood, telomeric ends of chromosomes).An important chal- 1977).However, it is quite reasonable that any mechalenge is now to relate these recent findings to the more nisms that sprang up to slow or regulate the pace of complex case of human aging.aging would be selected, because lucky individuals"
}
],
"555a1533-2905-4d91-a3b6-2fca3679ab02": [
{
"document_id": "555a1533-2905-4d91-a3b6-2fca3679ab02",
"text": "\n\nCurrently prevailing studies of genetic and biological origin of human health and longevity follow largely two approaches which focus on the aging-related diseases and on individuals with exceptionally long lives (Martin et al. 2007).This study provides de facto the rationale for a new approach.Specifically, Fig. 2 suggests that a promising strategy could be to focus on individuals who died prematurely.Studies of genetic profiles of short-lived subjects compared to those who aged more successfully (i.e., those who lived longer and perhaps healthier lives) can be a core of this strategy.Importantly, this strategy can be naturally implemented in longitudinal studies of aging and longevity by focusing on individuals who died first."
}
],
"57e2d0f5-c5eb-4ba6-8101-5bacaed53cb4": [
{
"document_id": "57e2d0f5-c5eb-4ba6-8101-5bacaed53cb4",
"text": "\n\nT he average human life expectancy has been increasing for centuries 1 .Based on twin studies, the heritability of human lifespan has been estimated to be ~25%, although this estimate differs among studies 2 .On the other hand, the heritability of lifespan based on the correlation of the mid-parent (i.e., the average of the father and mother) and offspring difference between age at death and expected lifespan was estimated to be 12% 3 .A recent study has indicated that the different heritability estimates may be inflated due to assortative mating, leaving a true heritability that is below 10% 4 .The heritability of lifespan, estimated using the sibling relative risk, increases with age 5 and is assumed to be enriched in long-lived families, particularly when belonging to the 10% longest-lived of their generation 6 .To identify genetic associations with human lifespan, several genome-wide association (GWA) studies have been performed [7][8][9][10][11][12][13][14][15][16][17][18][19][20] .These studies have used a discrete (i.e., older cases versus younger controls) or a continuous phenotype (such as age at death of individuals or their parents).The selection of cases for the studies using a discrete longevity phenotype has been based on the survival to ages above 90 or 100 years or belonging to the top 10% or 1% of survivors in a population.Studies defining cases using a discrete longevity phenotype often need to rely on controls from more contemporary birth cohorts, because all others from the case birth cohorts have died before sample collection.Previous GWA studies have identified several genetic variants, but the only locus that has shown genome-wide significance (P ≤ 5 × 10 −8 ) in multiple independent meta-analyses of GWA studies is apolipoprotein E (APOE) 21 , where the ApoE ε4 variant is associated with lower odds of being a long-lived case."
}
],
"5fefb0e4-e7f9-4df3-a984-ad4f61756cf7": [
{
"document_id": "5fefb0e4-e7f9-4df3-a984-ad4f61756cf7",
"text": "Introduction\n\nWorldwide human populations have shown an increase in mean life expectancy in the past two centuries (Oeppen & Vaupel, 2002).This is mainly because of environmental factors such as improved hygiene, nutrition, and health care.The large variation in healthy lifespan among the elderly has prompted research into the determinants of aging and lifespan regulation.The genetic contribution to human lifespan variation was estimated at 25-30% in twin studies (Gudmundsson et al., 2000;Skytthe et al., 2003;Hjelmborg et al., 2006).The most prominent genetic influence is observed in families in which the capacity to attain a long lifespan clusters (Perls et al., 2000;Schoenmaker et al., 2006).Exceptional longevity can be reached with a low degree of age-related disability (Christensen et al., 2008;Terry et al., 2008), raising the question whether protective mechanisms against disease exist in long-lived subjects."
}
],
"6005d141-8758-44b5-9baa-d553da68d167": [
{
"document_id": "6005d141-8758-44b5-9baa-d553da68d167",
"text": "Introduction\n\nHuman life expectancies are increasing almost everywhere in the world where socio-economic circumstances are permissive (Tuljapurkar et al., 2000) and there is no evidence that a limit to life is anywhere near (Oeppen and Vaupel, 2002).While this increase in life span would prevent a proposed compression of morbidity (Fries, 1980), there is no evidence that higher average life spans are associated with an extension of the period of increased morbidity (Manton and Gu, 2001).On the contrary, older individuals have never been so healthy and further improvements in life style, environmental conditions and medical care are likely to help this trend to continue.Especially the medical sciences now seem poised to push the biological limits of longevity further by a number of innovations that seem to affect basic mechanisms of ageing and disease rather than merely alleviating its symptoms.While in the past medicine contributed mainly to public health advances by redu-cing infectious diseases, thereby helping infant mortality to decline, more recent developments hold promise for a more basic intervention in the processes that underlie age-related decline.An example is atherosclerosis, a common problem in ageing and, along with hypertension, the cause of most cardiovascular disease.Basic medical research has likely contributed significantly to the current dramatic decline in cardiovascular disease by actively intervening in some of its main risk factors, i.e., lipid levels and hypertension (Levi et al., 2002).However, one could question whether age-related diseases should be seen as separate from ageing.In this respect, ageing has been considered as a process of cellular degeneration and death universal to all or most species, increasing the risk of fatal disease in humans and other mammals.Would it be possible to define such a process and ultimately understand it in terms of the timedependent, coordinated action of the products of multiple genes interacting with the environment?If so, then ageing per se rather than the diseases associated with it, may offer a more logical starting point for further increasing healthy life expectancies through prevention and therapy.This is especially true now that we have a working draft of the human genome and are in a position to determine the functional significance of each gene as part of the dynamic network of all genes that ultimately determine the physiology of an organism.Termed 'Functional Genomics', this new discipline is now often called upon to solve the complex problems in biology, such as to understand functional control mechanisms and investigate the role that genotype and environment play in determining disease phenotypes.The question is then if this same approach would apply to ageing as a complex phenotype.What is ageing, how does it differ from its diametrical opposite, i.e., organismal development, and what role can functional genomics play in unraveling the basic causes of ageing and exploit such knowledge for developing new, rational strategies for extending healthy life span?"
}
],
"6df20592-9856-49a6-8bf3-f6a701ff3b56": [
{
"document_id": "6df20592-9856-49a6-8bf3-f6a701ff3b56",
"text": "Introduction\n\nAs a result of improvements in health care and living conditions over the past two centuries, the average human life expectancy has dramatically increased in many regions of the world [1].This major success reflects the great malleability of the ageing process.Unfortunately, for most people, ageing is accompanied with an increased risk of developing age-related illnesses/disabilities and frailty.Therefore new approaches are required to understand the genetic, cellular, and molecular factors controlling ageing to identify strategies to extend healthy life span."
}
],
"79ae7122-3716-498b-9b9a-dd0960e33f99": [
{
"document_id": "79ae7122-3716-498b-9b9a-dd0960e33f99",
"text": "\nThe search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators.To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort.We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years).The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease.The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span."
},
{
"document_id": "79ae7122-3716-498b-9b9a-dd0960e33f99",
"text": "\n\nThe search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators.To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort.We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years).The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease.The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span."
}
],
"932ef21b-9235-4210-a99c-6153a901bb89": [
{
"document_id": "932ef21b-9235-4210-a99c-6153a901bb89",
"text": "Introduction\n\nThe recent, remarkable extension of life expectancy is largely attributed to the postponement of mortality at old age (Vaupel, 1997(Vaupel, , 2010)).The years of life gained in the older population residing in developed nations are a success story of public health measures and improved health care.In addition to such external factors, longevity and healthy aging consistently show a modest heritability between 20% and 50% and aging-associated genetic research may provide further insights into the mechanisms of aging (Herskind et al., 1996;McGue et al., 1993;Reed and Dick, 2003).It has been postulated that genes involved in pathways associated with aging identified in animal models, such as insulin-like growth factor (IGF)-insulin signaling, regulation of lipoprotein metabolism, the mTOR pathway, and the oxidative stress response may also influence survival to old or even exceptionally old age in humans (Christensen et al., 2006;Kenyon, 2010;Vellai et al., 2003).However, in humans, common variants within genes involved in these pathways have not been consistently associated with lifespan (Chris-tensen et al., 2006;Kenyon, 2010;Kuningas et al., 2008;Vijg and Suh, 2005)."
}
],
"ae9d5a74-24c1-43f1-b514-5e3f10c91284": [
{
"document_id": "ae9d5a74-24c1-43f1-b514-5e3f10c91284",
"text": "DESIGNS TO STUDY PARAMETERS OF HEALTHY AGEING, MORBIDITY, MORTALITY AND LONGEVITY\n\nHuman cohorts may vary considerably in their morbidity, mortality and longevity characteristics and yet they have shown a common increase in mean life expectancy in the past two centuries [5].This is mainly due to improved hygiene, nutrition and healthcare.There is a large variation in healthy lifespan among the elderly and remarkably exceptional longevity (EL) can be reached with a low degree of agerelated disability [6,7].Heritability studies comparing the concordance of lifespan in monozygous and dizygous twins estimated a 25 -30% genetic contribution to human lifespan variation [8 -11], which becomes increasingly important at higher ages.The most prominent genetic influence is present in families in which survival to high ages clusters [12,13].Unlike model systems where single-gene mutations have major life extension effects, human longevity is presumed to be a complex trait [14]."
},
{
"document_id": "ae9d5a74-24c1-43f1-b514-5e3f10c91284",
"text": "INTRODUCTION\n\nGenomic studies into human longevity are inspired by the fact that, in animal models, healthy lifespan has proved to be remarkably plastic, and major pathways of lifespan regulation have been identified.Considerable lifespan extension has been induced in models as diverse as yeast, worms, fish, flies and rodents by applying genetic manipulation and dietary restriction (DR) (see [1] for review).Reduced activity of nutrient-sensing pathways such as insulin/insulin-like growth factor (IGF-1) signalling (IIS) and target of rapamycin (TOR) signalling mediated lifespan extension, and also the extension of lifespan by DR [2].An interesting observation from the perspective of human ageing is that, in rodents and monkeys, diets restricted in glucose, fat or protein uptake reduced or delayed the risk of cancer and metabolic disease, thus extending the healthspan of the animals [2].Following the discovery of genes and pathways involved in animal lifespan extension, human research has focused on the corresponding candidate human genes with genetic, genomic and epigenetic studies into ageing and longevity.The designs of these studies differ with respect to the selection of naturally occurring phenotypes and the study populations, which include population-based, patient-based, family-based and exposure-based cohorts."
},
{
"document_id": "ae9d5a74-24c1-43f1-b514-5e3f10c91284",
"text": "GENETIC STUDIES OF HUMAN LONGEVITY\n\nGenetic and genomic studies into longevity have been performed based on a hypothesis, referred to as a candidate gene approach.Alternatively, explorative genome-wide analyses have been applied in which genetic variation and gene transcription across the complete genome are being studied for associations with longevity and related traits.Genetic studies into human disease and longevity include candidate gene approaches, genome-wide association studies (GWASs) and genome-wide linkage studies."
}
],
"b0e49b4c-954d-476a-ba3a-0215e63c98b6": [
{
"document_id": "b0e49b4c-954d-476a-ba3a-0215e63c98b6",
"text": "ANALYSIS OF HUMAN VARIATION IN THE GENETIC CONTROL OF LONGEVITY\n\nHeritability studies have convincingly demonstrated that at least some fraction of human lifespan is heritable.In tandem, large-scale genome-wide association studies (GWAS) have identified numerous loci associated with age-related traits (Buniello et al., 2019).While genetic studies have functionally shown an inverse effect of multiple age-related, diseaseassociated variants on lifespan regulation, the number of well-replicated longevity-conferring variants remains limited to variants in APOE (ApoE ε2), and more recently, CDKN2A/B and IL6 (see Table 1).To date, studies in humans have been hampered by the specific phenotype definitions used, sample sizes of the extreme phenotypes, and modest heritability of the longevity-related traits (Breitbach et al., 2019).This is due to the complex interplay of biological and social factors involved in human aging, as well as the limited power of GWAS, which require sampling thousands of subjects to achieve statistical significance (Breitbach et al., 2019).Genetic studies of aging have also been hindered by an inconsistent use of definitions of aging (reviewed in Baghdadi et al., 2020).The two main ways of conducting research on the genetics of longevity in human populations are by studying (i) the lifespan (continuous trait, years lived) and (ii) the longevity (dichotomous trait, i.e., being among the longest-lived individuals within a specific population).These complexities have limited the resolution and capability of broad association studies of human longevity.Importantly, these genomic analyses focus on a shift of survival in a population; these variables may be genetically distinct from the mechanisms establishing potential for longevity overall (Figure 1A).We argue that an understanding of this shift in lifespan as well as genetic mechanisms of regulating a species specific 'set points' (Figure 1B) will aid in the conceptual distinction of aging and longevity in humans."
}
],
"d174ea46-2c88-4047-a333-cb66e483a51f": [
{
"document_id": "d174ea46-2c88-4047-a333-cb66e483a51f",
"text": "Introduction\n\nHuman longevity is influenced by multiple genetic and environmental factors.Approximately 25-32% of the overall variation in adult lifespan is because of genetic variation that becomes particularly important for survival at advanced age (Hjelmborg et al., 2006).Epidemiological studies have revealed that long-lived individuals (LLI), that is, people surviving to the 95th percentile of the respective birth cohort-specific age distributions (Gudmundsson et al., 2000), frequently show a favorable ('healthy') course of the aging process, with the absence or a delayed onset of agerelated diseases (Hitt et al., 1999).Hence, the LLI offer the key to elucidate the molecular mechanisms underlying the 'healthy aging' phenotype (Perls, 2006)."
}
],
"f6bde053-64e5-42d9-966d-9d5d5d82a068": [
{
"document_id": "f6bde053-64e5-42d9-966d-9d5d5d82a068",
"text": "Conclusions and prospects\n\nOver the past two decades the human aging field has built up the necessary resources to study the biology of aging and longevity by establishing human populations with a diversity of designs.Meta-analyses integrating genetic and phenotypic datasets have successfully identified variants associated with a range of age-related traits and diseases.Despite these accomplishments, the number of novel leads contributing to human lifespan regulation is limited.Although positive regions of linkage and suggestive GWAS hits have been reported, the field has not yet identified the loci that explain the clustering of longevity in families and the variation in biological aging rate in the population.As for animal models, down-signaling of the IIS and mTOR pathway appeared to be relevant in humans.These findings are being followed up by molecular and physiological profiling using skin, fat and muscle tissue of long-lived family members and controls.Human studies now also include the response of nutrient sensing systems to the application of dietary and physical challenges."
},
{
"document_id": "f6bde053-64e5-42d9-966d-9d5d5d82a068",
"text": "\n\nHuman lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25-30% and expected to be polygenic.Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research.Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation.The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing.Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data -generated using novel technologies -in a wealth of studies in human populations.Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation."
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