{ "question": [ "Which mouse genes have been associated with longevity?", "Is lifespan determined by genetics?", "Is there a direct association between aging and susceptibility to having diabetes?", "Which genes are associated with aging in humans?", "What genetic factors influence aging in humans?" ], "answer": [ "The mouse genes associated with longevity include the C3H allele at D2Mit58, the BALB allele at D16Mit182, the C57BL/6 allele at D4Mit84, the C3H allele at D9Mit110, and the C57BL/6 and C3H alleles at D12Mit167. Additionally, a locus on chromosome 2 and another on chromosome 6 have been associated with longevity.", "Lifespan is partially determined by genetics, with studies estimating that genetics contribute to about 25-30% of the variation in human lifespan. However, it is also significantly influenced by non-heritable factors such as environment and lifestyle.", "Yes, there is a direct association between aging and susceptibility to having diabetes. The risk of onset of type 2 diabetes increases with age, and most diabetic patients in certain regions are 40 years old or more. Additionally, aging is associated with changes in body composition and glucose tolerance, which can contribute to the development of diabetes.", "The genes associated with aging in humans are APOE and FOXO3A.", "Several genetic factors influence aging in humans. These include the apolipoprotein E gene (APOE), the forkhead box O3A (FOXO3A) gene in the insulin-IGF1 signaling pathway, and the exonuclease 1 (EXO1) gene. Other genes associated with aging are those involved in pathways such as insulin-like growth factor (IGF)-insulin signaling, regulation of lipoprotein metabolism, the mTOR pathway, and the oxidative stress response. Additionally, genes related to immune response, energy metabolism, signal transduction pathways, and cellular senescence also play a role in aging." ], "contexts": [ [ "DOI: https://doi.org/10.7554/eLife.75244 \b 24 of 30 Chromosomes and Gene Expression | Genetics and Genomics Research article\ufeff\ufeff\ufeff\ufeff\ufeff\ufeff Continued Author(s) Year Dataset title Dataset URL Database and Identifier Longevityteam 2021 Genetics of longevity in BXD mice http://www.\u200b BDL_10006, 10006 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10006&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2021 Genetics of longevity in BXD mice http://www.\u200b BDL_10010, 10010 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10010&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2021 Genetics of longevity in BXD mice http://www.\u200b BDL_10011, 10011 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10011&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2020 Genetics of longevity in BXD mice http://www.\u200b BDL_10021, 10021 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10021&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2020 Genetics of longevity in BXD mice http://www.\u200b BDL_10022, 10022 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10022&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2020 Genetics of longevity in BXD mice http://www.\u200b BDL_10025, 10025 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10025&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2021 Genetics and epigenetics of aging and longevity in BXD mice http://www.\u200b BDL_10066, 10066 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10066&\u200bdataset=\u200bBXD-\u200b LongevityPublish References Albertsen HM, Smith SA, Mazoyer S, Fujimoto E, Stevens J, Williams B, Rodriguez P, Cropp CS, Slijepcevic P, Carlson M. 1994.", "DOI: https://doi.org/10.7554/eLife.75244 \b 24 of 30 Chromosomes and Gene Expression | Genetics and Genomics Research article\ufeff\ufeff\ufeff\ufeff\ufeff\ufeff Continued Author(s) Year Dataset title Dataset URL Database and Identifier Longevityteam 2021 Genetics of longevity in BXD mice http://www.\u200b BDL_10006, 10006 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10006&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2021 Genetics of longevity in BXD mice http://www.\u200b BDL_10010, 10010 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10010&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2021 Genetics of longevity in BXD mice http://www.\u200b BDL_10011, 10011 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10011&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2020 Genetics of longevity in BXD mice http://www.\u200b BDL_10021, 10021 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10021&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2020 Genetics of longevity in BXD mice http://www.\u200b BDL_10022, 10022 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10022&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2020 Genetics of longevity in BXD mice http://www.\u200b BDL_10025, 10025 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10025&\u200bdataset=\u200bBXD-\u200b LongevityPublish Longevityteam 2021 Genetics and epigenetics of aging and longevity in BXD mice http://www.\u200b BDL_10066, 10066 genenetwork.\u200borg/\u200b show_\u200btrait?\u200btrait_\u200bid=\u200b 10066&\u200bdataset=\u200bBXD-\u200b LongevityPublish References Albertsen HM, Smith SA, Mazoyer S, Fujimoto E, Stevens J, Williams B, Rodriguez P, Cropp CS, Slijepcevic P, Carlson M. 1994.", "Leduc MS, Hageman RS, Meng Q et al (2010) Identification of genetic determinants of IGF-1 levels and longevity among mouse inbred strains. Aging Cell 9(5):823\u2013836. doi:10.1111/j.14749726.2010.00612.x 10. Lang DH, Gerhard GS, Griffith JW et al (2010) Quantitative trait loci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD) recombinant inbred mice. Aging Clin Exp Res 22(1):8\u201319 11. Gelman R, Watson A, Bronson R et al (1988) Murine chromosomal regions correlated with longevity. Genetics 118(4):693\u2013704 12. Jackson AU, Galecki AT, Burke DT et al (2002) Mouse loci associated with life span exhibit sex-specific and epistatic effects.", "Conclusions These results suggest a novel locus influencing survival in the B6/D2 genetic background, perhaps via a metabolic disorder that emerges by 200 days of age in male animals. Keywords Pathology Longevity \\ Lifespan \\ Mouse \\ Linkage \\ Introduction Longevity, the quintessential complex trait, likely reflects all aspects of an organism\u2019s life history. In humans, the estimated heritability of age at death is estimated at 25\u201333 % [1]. Genetic contributions to mortality rates are thus of great interest and may aid in the understanding of disease etiology and the process of aging itself [2].", "Here, we have extended this analysis to search for genotypes related to survival to the age of 800 days in a population of a reciprocal F2 cross between (B6) and (D2) mice. Since QTL for longevity in mice have shown strong sex specificity [10, 12], we conducted sex-specific analyses. In addition, we also determined whether there were any change in pathology changes associated with the loci that showed frequency distortions with aging. To confirm the associations of the loci of interest with longevity and pathology, we performed replication analyses on a panel of BXD recombinant inbred strains.", "352(6291): p. aad0189. Liao, C.Y. , et al. , Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell, 2010. 9(1): p. 92-5. Johnson, M., Laboratory Mice and Rats. Mater. Methods, 2012. 2: p. 113. Fontaine, D.A. and D.B. Davis, Attention to Background Strain Is Essential for Metabolic Research: C57BL/6 and the International Knockout Mouse Consortium. Diabetes, 2016. 65(1): p. 25-33. Simon, M.M. , et al. , A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biol, 2013. 14(7): p. R82. Lilue, J., et al.", "Mamm Genome 2001;12: 930\u20132. 21 Gelman R, Watson A, Bronson R, Yunis E. Murine chromosomal regions correlated with longevity. Genetics 1988;118:693\u2013704. 22 Peirce JL, Lu L, Gu J, Silver LM, Williams RW. A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 2004;5:7. 23 Rahman ZS, Tin SK, Buenaventura PN et al. A novel susceptibility locus on chromosome 2 in the (New Zealand Black \\ New Zealand White) F1 hybrid mouse model of systemic lupus erythematosus. J Immunol 2002;168:3042\u20139. 24 Kono DH, Burlingame RW, Owens DG et al.", "Conversely, the BXD strain with the shortest life span (BXD14) has the lowest responsiveness to the stimulatory effect of TGF-\u24242 when old (48). The region on chromosome 2 where a suggestive QTL regulating the responsiveness to TGF-\u24242 in old mice is located also contains two QTL for longevity (32). Finally, the strongest support for this hypothesis is the correlation between longevity and the age-related increase in the serum-dependent effect of TGF-\u24242 on LSK cells, the extent of which may determine stem cell function in aged mice.", "FIGURE 8-5 Genetic regulation of longevity in mice stratified by cause of death.Female mice that inherit the C3H allele at D2Mit58 plus the BALB allele at D16Mit182 (light gray bars) have significantly higher longevity than their sisters (dark gray bars) with the C57BL/6 plus DBA/2 allele combination (\"all causes\" of death combined).Subsets of mice that died either of cancer or of a nonneoplastic (\"benign\") illness both show the association between genotype and longevity.Among the mice dying of neoplasia, subsets dying of lymphoma or of fibrosarcoma show equivalent, and significant, genotypic effects.Bars indicate means plus standard error of the mean.SOURCE:Miller et al. (unpublished results).", "The available dataset also provides examples in which genetic variants seem to influence the risk of specific late-life diseases.Figure 8-6, for example, shows longevity results for mice stratified by their inheritance at the 12th chromosome locus D12Mit167.This is a locus associated with differential longevity in both male and female mice, with the strongest effect (adjusted p < 0.01) seen in those mice living more than 657 days (Jackson et al., unpublished results).The longest-lived mice are those that inherit both the C57BL/6 allele from their mother and the C3H allele from their father; on average, they survive 93 days longer than siblings with the BALB plus C3H combination.Figure 8-6 shows that the D12Mit167, like the pair of loci illustrated in Figure 8-5, has significant and similar effects in mice dying of cancer (85 days) and in mice dying of non-neoplastic diseases (126 days).A more detailed analysis of the cancers, however, suggests that while lymphoma and hepatoma victims are equally protected by the favorable alleles (effect sizes of 93 and 167 days, respec- mice of two subgroups: those dying of the urinary syndrome MUS, and those dying of all other causes.The genetic analysis contrasts mice with both the C57BL/6 allele at D4Mit84 and the C3H allele at D9Mit110 to mice with any of the three other allele combinations.In the males dying of causes other than MUS, this allele pair is associated with a 170-day increment in longevity (post-hoc p < 0.00003).But for males that do die of MUS, the same allele combination is associated with a 187-day decline in mean life span (post-hoc p < 0.03).This effect is thus pleiotropic, in that these alleles accelerate death in mice susceptible to MUS, while postponing death for all other males in the population.Although these loci are associated with differential longevity in mice that do develop MUS, they do not have a significant effect on the chances that MUS will indeed occur (not shown).The risk of developing MUS seems to be under control of a separate locus on chromosome 6.As shown in the bottom panel of Figure 8-7, males that inherit the C3H allele at D6Mit268 are far more likely to develop MUS (28 percent risk) than are their brothers who receive the DBA/2 allele at this locus (7 percent risk; p = 0.012 by two-tailed Fisher's exact test).", "High levels of CD8M cells are associated with diminished longevity in mated females (left panel; p < 0.001), but not in virgin females (center panel).Among virgin males, those dying of diseases other than the urinary syndrome MUS show no association between CD8M and longevity (open circles, upper line), but those dying because of MUS show a nonsignificant trend (filled circles, lower line, R = -0.27,p = 0.13) similar to the relationship observed in mated females.SOURCE : Miller et al. (unpublished results).Male or female mice that inherit the C57BL/6 (maternal) and C3H (paternal) alleles at D12Mit167 (light gray bars) are longer lived than their siblings that inherit the BALB plus C3H combination.The \"effect size\" shown at the right represents that difference in mean longevity between mice in the two genetically different groups, with (**) = p < 0.01 and (*) = p < 0.05 by t-test.Similar effect sizes are seen for mice dying of cancer or of non-neoplastic illnesses (\"benign\"), and among the cancer deaths the genetic effect is similar for deaths due to lymphoma and hepatoma.The genetic effect on longevity seems to be minimal, however, for mice dying of fibrosarcoma.Bars show means plus standard errors.SOURCE : Miller et al. (unpublished results).", "Our own work has taken a different tack: we have attempted to determine whether mutations with differential effects on aging may be present within the many available populations of laboratory-adopted inbred mice.The goal is not so much to clone these genes-if indeed they existbecause positional cloning strategies of this kind require many thousands of animals and would be extremely expensive using an assay, age at death, that is itself so costly.Instead, the goal has been to use gene mapping methods to test hypotheses about aging and to develop new animal models that will be useful for testing well-specified hypotheses about the molecular basis for age-dependent changes.In the absence of a validated battery of biomarkers of aging, we (like most others) have reluctantly decided to use mouse life span as a crude surrogate for aging itself, reasoning that genetic alleles that extend life span well beyond the median for the tested population may be operating via an influence on aging itself.Work conducted using recombinant inbred mouse stocks (Gelman et al., 1988;de Haan and Van Zant, 1999) has suggested that life-span differences between pairs of inbred mouse lines might reflect the influence of as few as 4-7 polymorphic loci, providing some basis for hope that some of these would have an effect large enough to be detected by a genome scan experiment involving 300-1,200 mice.", ", Vogler, G.P. , Vandenbergh, D.J. , Blizard, D.A. , Stout, J.T. & McClearn, G.E. Quantitative Trait Locus (QTL) Analysis of Longevity in C57BL/6J byDBA/2J (BXD) Recombinant Inbred Mice. Aging Clin Exp Res (in press). Lionikas, A., Blizard, D.A. , Vandenbergh, D.J. , Glover, M.G. , Stout, J.T. , Vogler, G.P. , McClearn, G.E. & Larsson, L. (2003) Genetic architecture of fast- and slow-twitch skeletal muscle weight in 200-day-old mice of the C57BL/6J and DBA/2J lineage. Physiol Genomics 16, 141\u2013152. Lionikas A., Blizard D.A. , Gerhard G.S. , Vandenbergh D.J. , Stout J.T. , Vogler G.P. , McClearn G.E.", "Deficiency mapping of quantitative trait loci affecting longevity in Drosophila melanogaster. Genetics 2000;156:1129\u20131146. [PubMed: 11063689] 33. Ma RZ, et al. Identification of Bphs, an autoimmune disease locus, as histamine receptor H1. Science 2002;297:620\u2013623. [PubMed: 12142541] Nat Rev Genet. Author manuscript; available in PMC 2007 November 5. Page 12 NIH-PA Author Manuscript 34. Vivian JL, Chen Y, Yee D, Schneider E, Magnuson T. An allelic series of mutations in Smad2 and Smad4 identified in a genotype-based screen of N-ethyl-N-nitrosourea-mutagenized mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 2002;99:15542\u201315547. [PubMed: 12432092] 35. Vogel G. Scientists dream of 1001 complex mice.", "34. Gelman R, Watson A, Bronson R & Yunis E Murine chromosomal regions correlated with longevity. Genetics 118, 693\u2013704 (1988). [PubMed: 3163317] 35. Houtkooper RHet al.The metabolic footprint of aging in mice. Sci. Rep1, (2011). 36. Houtkooper RHet al.Mitonuclear protein imbalance as a conserved longevity mechanism. Nature497, 451\u2013457 (2013). [PubMed: 23698443] 37. Williams EGet al.An Evolutionarily conserved role for the aryl hydrocarbon receptor in the regulation of movement. PLOS Genet. 10, e1004673 (2014). [PubMed: 25255223] 38. Lang DHet al.Quantitative trait loci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD) recombinant inbred mice. Aging Clin. Exp. Res. 22, 8\u201319 (2010).", "In addition, the B6 mouse strain is one of the longest-lived mouse strains with a mean lifespan of 3 years versus other mouse strains with mean lifespan from 1.5-2 years. Therefore, it is evident that the genetic background of a particular mouse strain can have a profound effect on the biology of the HSC population as well as organismal longevity. Indeed, it is for this reason that it is difficult to compare findings from various laboratories where different mouse strains are used.", "NIH-PA Author Manuscript This study indicated a large amount of genetic variation for mouse longevity; heritability was 34% for AL and 36% for DR (60% of AL food intake). There was no significant correlation between mean longevity under these two conditions, although maximum lifespans of the AL and DR mice were significantly correlated. Similar observations were made at the UTHSCSA on the ILSXISS RI mice (Liao et al. , 2010a, b; Mattson 2010), where they also observed similar heritability (28% AL males, 36% AL females, 55% DR males, 53% DR females).", "For females, hairs of the congenic mice grew 31% faster, also highly significant (P = 0.0006, 1-tailed). These results validated the presence of a gene in the differential region affecting FE. Discussion We report the outcomes of a quantitative genetic study on aging and longevity in the mouse. We studied an extant series of recombinant inbred strains (ILSXISS) that have been used both in DR aging studies as well as to study alcohol sensitivity (Williams et al. , 2004).", "(2007) is a separate issue from the analyses conducted in this study (the AL efficiency model will be tested in future studies). Exp Gerontol. Author manuscript; available in PMC 2011 September 1. Rikke et al. Page 8 NIH-PA Author Manuscript Other studies have also reported that individual mice that maintained the highest BW were likely to be the longest-lived individuals among cohorts of genetically identical mice (Weindruch et al. , 1986; Harper et al. , 2006).", "Age-associated changes are conserved between mouse strains Life span and aging vary between mouse strains.For example, C57BL/6 mice are long-lived compared to the short-lived DBA/2 mice (Turturro et al. 1999).To test the generality of our observations, we also examined LT-HSCs, ST-HSC and MPPs in young and old mice from the DBA/2 strain, which originates from a distinct breeding lineage (Fox 1997)." ], [ "Our results show that longevity is partly determined by the predisposition to common diseases and, to an even greater extent, by modifiable risk factors.The genetic architecture of lifespan appears complex and diverse and there appears to be no single genetic elixir of long life.", "L ongevity is of interest to us all, and philosophers have long speculated on the extent to which it is pre-determined by fate.Here we focus on a narrower question-the extent and nature of its genetic basis and how this inter-relates with that of health and disease traits.In what follows, we shall use longevity as an umbrella term.We shall also more specifically refer to lifespan (the duration of life) and long-livedness (living to extreme old age, usually defined by a threshold, such as 90 years).Up to 25% of the variability in human lifespan has been estimated to be genetic 1 , but genetic variation at only three loci (near APOE, FOXO3A and CHRNA3/5) [2][3][4][5] have so far been demonstrated to be robustly associated with lifespan.", "GENETICS OF LIFE SPAN IN HUMANS Most studies of human twins agree that the heritability of life span is less than 50% (45,68).Of particular interest is an ongoing study of aging in Swedish twins that includes a large group of adopted twins who were reared separately.Ljungquist et al. (68) concluded that \"a maximum of one-third the variance in integrated mortality risk is attributable to genetic factors and that almost all of the remaining variance is due to nonshared, individually unique environmental factors. \"Moreover, this heritability declined with age and was negligible after the age of 85 in men and 90 in women.", "How can lifespan be controlled by a single gene?Two possibilities are, first, that the mutations that extend lifespan are in genes whose products regulate the activity of many other genes and, second, that these genes do not in fact control the rate of ageing.", "Since that time, observations across species have shown that life span can be extended by genetic factors.One of the first demonstrations of this entailed the study of recombinant inbred populations of the nematode worm Caenorhabditis elegans by Thomas E. Johnson.Then a postdoc in William (Bill) Wood's lab at the University of Colorado Boulder, Tom and Bill demonstrated that crosses of C. elegans strains did not display the heterosis effect that interfered with many other studies, \"As predicted, we found significant genetic effects on life span as well as other life history traits. \"This finding established a method for evaluating genetic factors that influenced life-span variation.In fact, their measurements of life span of the recombinant inbred strains demonstrated the heritability of life span to be 19%-51% (1).Consistent with theories of the 1970s and 1980s, it was concluded that these genetic factors were a collection of small influences across many genes.This finding was one of the first steps in demonstrating that genetic factors influence aging.As genetic analysis was making great progress in understanding other biological processes, such as developmental programming, the realization that aging could be investigated using the same tools was highly significant.", "Although it is known that health and lifespan are heavily influenced by genetics [14], variations in the lifespan of different individuals within the same species seem to be more the result of the accumulation over time of molecular damage that compromises the function of the cells [15].These molecular alterations can occur both at the genetic and epigenetic levels and depend on genetic, environmental, and stochastic factors [16].This complex multifactorial mix determined characteristics, such as longevity and a healthy lifespan, which are central concerns of human existence (Fig. 13.1).This chapter describes different types of tools in genomics used in ageing research and their different applications in clinical scenarios.", "Age at death in adulthood has a moderate genetic component overall, with a heritability of approximately 25% (Murabito et al., 2012).Heritability of longevity increases with age, with a negligible genetic contribution to survival up to approximately 60 years of age, after which an increasing genetic component to survival is observed (Brooks-Wilson, 2013;Christensen et al., 2006).Most genetic studies of aging have focused on long-lived individuals, typically defined as centenarians 100 years or older, who may have had exceptional survival due to medical interventions (Murabito et al., 2012).A number of genetic associations with exceptional longevity have been made (Atzmon et al., 2006;Bojesen and Nordestgaard, 2008;Hurme et al., 2005;Kuningas et al., 2007;Melzer et al., 2007;Pawlikowska et al., 2009;Sanders et al., 2010;Suh et al., 2008;Willcox et al., 2008), with only markers at APOE and FOXO3A being well replicated (Murabito et al., 2012).Overall, the results of genetic and epidemiological longevity studies suggest aging is a complex trait and that achievement of exceptional longevity may not best capture the genetics of resistance to or delay of age-associated disease (Christensen et al., 2006).", "Introduction Worldwide 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.", "Introduction Human lifespan is a highly complex trait, the product of myriad factors involving health, lifestyle, genetics, environment, and chance.The extent of the role of genetic variation in human lifespan has been widely debated (van den Berg et al., 2017), with estimates of broad sense heritability ranging from around 25% based on twin studies (Ljungquist et al., 1998;Herskind et al., 1996;McGue et al., 1993) (perhaps over-estimated [Young et al., 2018]) to around 16.1%, (narrow sense 12.2%) based on large-scale population data (Kaplanis et al., 2018).One very recent study suggests it is much lower still (<7%) (Ruby et al., 2018), pointing to assortative mating as the source of resemblance amongst kin.", "Many factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone.Nevertheless, Timmers et al. had hoped to narrow down their search and 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.", "Life Span During the last decade a variety of twin studies have shown that approximately 25 percent of the variation in life span is caused by genetic differences.This seems to be a rather consistent finding in various Nordic countries in different time periods and even so among other species not living in the wild (Herskind et al., 1996;Iachine et al., 1999;Finch and Tanzi, 1997).their relative magnitude and pattern depend on sex and on the socioeconomic environment experienced by successive birth cohorts.Genetic effects were most pronounced in periods with consciously controlled fertility, suggesting that the genetic disposition primarily affects fertility behavior and motivation for having children.Analyses of fertility motivation in some of the more recent twin cohorts, measured by age at first attempt to have children, supported this interpretation.", "The Height-Life Span Nexus Several observations and lines of experimentation have raised the issue of whether interindividual differences in aging rate are influenced by genes that modulate body size and early-life growth patterns.These include (a) the association between small stature and exceptional longevity in calorically restricted rodents (Yu et al., 1985), methionine-restricted rats (Orentreich et al., 1993), and mutant dwarf mice (Brown-Borg et al., 1996;Miller, 1999); and (b) the association between small body size and longer life span in natural populations of mice (Falconer et al., 1978), flies (Hillesheim and Stearns, 1992), dogs (Li et al., 1996), and, possibly, people (Samaras andStorms, 1992).The correlation in dogs is particularly striking: selective breeding for dogs of different body size has produced breeds varying in size from Chihuahua to Irish wolfhound.These breeds also vary greatly in mean longevity, from approximately 7 to 10.5 years, and the correlation between breed longevity and breed body weight (Miller, 1999) is a remarkable R 2 = 0.56.These differences are genetic and affect stature rather than obesity: no amount of overeating will convert a West Highland white terrier to a St. Bernard.The selective pressures applied were designed to create dogs of specific sizes and temperaments and were not intended to influence aging rate or life span.The clear implication is that the effects on longevity are pleiotropic, i.e., that genes selected for their effect on body size and conformation influenced life span as a side effect.It is of interest to note that the few analyses (Eigenmann et al., 1984(Eigenmann et al., , 1988) ) of the hormonal basis for interbreed differences in body size have shown that the genes in question influence levels of IGF-1, the most likely mediator of the life-span effects in the long-lived df/df and dw/dw mouse mutants.Could it be mere coincidence that long-lived mutant nematode worms (Kimura et al., 1997) also show mutations in genes related to insulin and IGF-1 receptors?", "Altogether, the twin and genealogical studies have shown that human lifespan is heritable, but is significantly influenced by non-heritable factors, which may explain why genetic studies of lifespan have proven to be challenging.", "Twin studies have shown that the heritability of lifespan ranges between 0.01 and 0.27 in various European populations (Ljungquist et al., 1998;van den Berg et al., 2017).Large genealogical studies are more powered to address questions FIGURE 1 | Relationship between aging and lifespan variation versus species defining lifespan. (A) Lifespan comparisons within species, measured as mean (50%) or portion of a population living till extended limits of lifespan (90-95%).Differences between populations (orange and green) can identify specific genetic or environmental changes associating with long life.These factors promote viability and often associate with increasing healthspan.Mutant analysis within a particular model organism often encompasses these types of changes as it relates to lifespan. (B) Maximum lifespans recorded for different species (A-E).While lifespan variation within a species is capped to a certain extent, variation between species can range dramatically.Changes to maximum lifespan often are associated with protective mechanisms for genomic and genetic fidelity as well as life history changes as they relate to maturation and reproduction.", "The genetic component of human lifespan based on twin studies has been estimated to be around 20-30 percent in the normal population [7], but higher in long-lived families [8][9][10].Furthermore, siblings, parents, and offspring of centenarians also live well beyond average [11,12].Lifestyle choices in terms of smoking, alcohol consumption, exercise, or diet does not appear to differ between centenarians and controls [13].Taken together, these findings provide ample evidence that extreme longevity has a genetic component .", "Introduction Human 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).", "Unraveling the heritability of human longevity was one of the first problems faced by geneticists.Just over a century ago, Mary Beeton and Karl Pearson [1] described a resemblance among relatives for the duration of life.A short time later, Yule [2] and Fisher [3] proved that the correlation is to be expected if lifespan is influenced by what had recently been termed 'genes' [4].Indeed, a century of correlation studies have established that something on the order of 30-50% of the total variation in human life span is attributable to genetic variation [5].Despite the wealth of diversity, specific genes contributing to this variation have proven notoriously difficult to identify.Sample size and issues of shared environment limit family-based methods such as linkage analysis, where rough genomic positions of important genetic variants are identified by comparing a small number of exceptionally long-lived people in defined pedigrees.", "Human 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.", "Human 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.", "Studies of mono-and dizygous twins have revealed that the genetic contribution to the variation in human lifespan is about 25-30% [12,13], and is most prominent in families clustered for longevity [14,15].This genetic contribution is mainly apparent after the age of 60 years and seems to increase with age [13,16].Furthermore, human lifespan is a complex trait which is assumed to be determined by many genes with small individual effects [17], although the polygenic architecture still needs to be characterized [18,19].The diverse health features of long-lived families illustrate that different age-related diseases have common determinants and implicate that pathways can be identified that attenuate aging and delay age-related disease.From a genomic perspective, individuals from long-lived families are assumed to be characterized by a decreased prevalence of disease-promoting variants (referred to as disease-susceptibility alleles) and an increased prevalence of variants conferring maintenance of health and protection from disease, when compared to population controls.In the last 5 years, many diseasesusceptibility alleles have been identified (National Human Genome Research Institute (NHGRI) genome-wide association study (GWAS) Catalog; http://www.genome.gov/gwastudies/)[20].A first comparison between long-lived individuals, selected from both long-lived families (LLS) and the general population (Leiden 85-plus study), and young controls showed no difference in the distribution or frequency of disease-susceptibility alleles identified in cancer, coronary artery disease and type 2 diabetes [21].The search for lifespan regulating loci -contributing to longevity and population mortality -must therefore extend beyond a focus on disease-susceptibility alleles.We will first discuss the efforts to identify longevity loci by genetics approaches." ], [ "Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.", "There are two major factors that underlie these alarming projections.The first is T2D is associated with age, and Western populations are aging rapidly.The second major explanation is our lifestyles have changed dramatically in recent years.Epidemiological studies have identified strong T2D risk relationships for obesity, sedentary behavior [2][3][4], and diets rich in energy [5], processed carbohydrates [6], and animal fats [7].Collectively, these lifestyle factors impede the actions of insulin and raise hepatic glucose production, which can result in the diminution of endogenous insulin production and T2D.The strongest evidence for a causal relationship between adverse lifestyle behaviors and T2D comes from randomized controlled trials that show intensive lifestyle interventions involving structured exercise regimes which promote habitual physical activity (PA) and have a major beneficial impact on diabetes incidence in high-risk individuals [8,9].", "Epidemiological studies examining the associations between lifestyle behaviors and diabetes risk have reached similar conclusions as the clinical trials described above.For example, the 14-year follow-up University of Pennsylvania Alumni Health Study [52] (n = 5,990 men aged 39-68 years) showed PA (leisure time physical activity [LTPA] expressed in kcal expended per week through walking, stair climbing, and sports) was inversely associated with the incidence of T2D.Incidence rates declined as energy expenditure rose from 500 through 3,500 kcal/week.The age-adjusted relative risk ratio (RR) of T2D was reduced by about 6% for each 500 kcal increment increase in PA energy expenditure.", "Overall, results were similar in analyses restricted to diabetes mellitus identified at baseline only, although the confidence interval included 1.These results suggest that diabetes mellitus is related to risk of AD in old age.These findings are consistent with the results of 2 large longitudinal cohort studies. 5,6In one study, 5 diabetes mellitus doubled the risk of AD during 2 years of follow-up in a sample of more than 6000 older persons from a defined cohort.The other study, 6 using data from about 2500 Japanese American men, found a similar result: diabetes mellitus approximately doubled the risk of AD.In contrast, 2 other longitudinal studies 7,8 did not demonstrate a significant association between diabetes mellitus and incident AD, but in both, the results were in the direction of increased risk.Some, [9][10][11] but not all, 12 previous studies found that diabetes mellitus was related to change in cognitive function.One factor that may contribute to variability from study to study is that diabetes mellitus may be related to decline in some cognitive systems but not others.4][15] Although diabetes mellitus was related to level of global cognition and multiple cognitive domains at baseline, we found that diabetes mellitus was only related to decline in perceptual speed.The one study 12 that did not find a relation between diabetes mellitus and cognitive decline did not include a measure of perceptual speed.", "COMMENT In a cohort of more than 800 older persons, we found that diabetes mellitus sometime in the study was associated with an increased risk of developing AD during a mean of 5.5 years of observation.The risk of incident AD was 65% higher in those with diabetes mellitus than in those without it.", "In summary, these findings suggest that diabetes mellitus is associated with AD and decline in cognitive function in older persons.December 12, 2003.", "DIABETES MELLITUS AND RISK OF AD During the follow-up evaluations, 151 persons developed AD, of whom 31 had diabetes mellitus.In a proportional hazards model adjusted for age, sex, and educational level, there was a 65% increase in the risk of developing AD in those with diabetes mellitus compared with those without diabetes mellitus (hazard ratio, 1.65; 95% confidence interval, 1.10-2.47).The cumulative hazard of AD over time, adjusted for age, sex, and educational level, is shown graphically in Figure 1 for typical participants with and without diabetes mellitus.Similar results were found in analyses with diabetes mellitus identified at baseline only (hazard ratio, 1.53; 95% confidence interval, 0.96-2.45).", "Age. Age is another factor that has a considerable effect on outcomes in obesity and T2DM research.In humans, body weight increases with age and peaks at ~55 years in both men and women.Ageing per se is associated with a redistribution of both the fat-free mass and the fat mass, with the latter increase starting at ~30 years of age 129 .Intramuscular and intrahepatic fat are particularly increased in older persons, and this increase has been linked to insulin resistance 130 .Partially on the basis of these changes, ageing has been proposed to be an independent determinant of glucose tolerance, which progressively worsens with age 131,132 .", "Age also plays a vital role in the onset of diabetes (Cowie & Eberhardt, 1995).In south-east Asia almost 97% diabetic patients are 40 years old or more (IDF Atlas, 2017).In Bangladesh, the reported age of diabetes is \u226540 years in 71% urban and 85% rural female, while in the case of male the proportion is 85.5% urban and 86.5% in rural population (IDF Atlas, 2017).The current study also pinpointed an exponential increase in the risk of onset of T2DM with the increase of age when 40 years was chosen as the reference (Table S4).", "Whether age and stress variables are risk factors for type 2 diabetes incidence was assessed by multivariate logistic regression (Table S4).Subjects in the age groups of (40-60) and >60 years had 1.78\u00d7 (p = .005)and 3.19\u00d7 (p = .006)greater risk for type 2 diabetes respectively than group of <40 years.Overall, patients under stressful condition are more likely to develop T2DM than that of nonstressed respondent (p = .000).Moreover, when stress is divided into two groups-low stress and high stress, we found that both males (p = .000)and females (p = .000)with high stress were at high risk of diabetes mellitus, whereas the association between low stress and T2DM incidence was significant only among males (Male: p = .002;Female: p = .115).The distribution and association of the genotypes, age, and stress with T2DM have been summarized in Table 3 and Figure 3.There was no difference in T2DM incidence between CT (p = .030)and TT/CC (p = .034)genotype containing people who were in age group of 40-60 years (Table 3).In contrast, people who were more than 60 years old with CT genotype (OR = 4.636, p = .029)were more prone to T2DM than that of TT/CC genotype (OR = 3.714, p = .007)subjects (Table 3).", "Research Gaps There is a clear correlation of environmental influences to diabetes risk.Yet, the assembled experts agreed that hypothesis-driven research is needed to define direct causal relationships between specific environmental factors and pathophysiologies leading to diabetes.Research efforts need to address environmental etiologies of type 1 diabetes and determine their relative contribution to onset of autoimmunity and progression to symptomatic disease.Whether there is a direct causal role of the intestinal microbiota in pathogenesis of type 1 and type 2 diabetes and response to therapies needs to be determined.Public health interventions that successfully reduce the levels of consumption of energy-dense foods and/or reduce sedentary time and increase time spent in physical activity need to be evaluated to determine whether they can reduce type 2 diabetes incidence at a population level.", "In sum, it is clear that multiple risk factors are involved in diabetes-associated cognitive decrements as well as in dementia in relation to diabetes 38 .On the basis of our assessment of the literature, it is also clear that there are still substantial knowledge gaps on how the risk factors interconnect, how the risk factors translate to potentially modifiable mechanisms and which genetic factors are involved.", "The aim of this study was to investigate the association between age at natural menopause and risk of developing type 2 diabetes, and to assess whether this association is independent of potential intermediate risk factors for type 2 diabetes.Furthermore, we examined the role of endogenous sex hormone levels in the association between age at natural menopause and type 2 diabetes.", "Aims/hypothesis In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators.Methods We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study.Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40 years; early, 40-44 years; normal, 45-55 years; and late menopause, >55 years [reference]).Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits.HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens.", "Aims/hypothesis In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators.Methods We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study.Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40 years; early, 40-44 years; normal, 45-55 years; and late menopause, >55 years [reference]).Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits.HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens.Results During a median follow-up of 9.2 years, we identified 348 individuals with incident type 2 diabetes.After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause (ptrend <0.001).The HR for type 2 diabetes per 1 year older at menopause was 0.96 (95% CI 0.94, 0.98).Further adjustment for BMI, glycaemic traits, metabolic risk factors, C-reactive protein, endogenous sex hormone levels or shared genetic factors did not affect this association.Conclusions/interpretation Early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women.", "association and explore whether the timing of natural menopause can add value to diabetes prediction and prevention.", "Although drawing of definitive conclusions is difficult from these observational studies, their results suggest that young-onset type 2 diabetes is associated with a much more frequent occurrence of adverse macrovascular and microvascular outcomes and a more rapidly progressing severity of complications than is seen in type 1 diabetes or later-onset type 2 diabetes.", "In a study of the age-specific incidence of type 2 diabetes in the UK (a retrospective cohort study of patients with newly diagnosed type 2 diabetes between 1990 and 2010), the investigators reported a substantial increase in the proportion of people aged 40 years or younger at diagnosis", "The prevalence of type 2 diabetes in adolescents and young adults is dramatically increasing.Similar to older-onset type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle.Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications.Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease.Furthermore, evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe.In this Review, we describe the epidemiology and existing knowledge regarding pathophysiology, risk factors, complications, and management of type 2 diabetes in adolescents and young adults.", "The biological processes linking aging and disease risk are poorly understood.Still, aging is considered to date as one of the main factors responsible for several complex diseases including cancer, cardiovascular diseases, and diabetes." ], [ "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.", "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.", "Background: Genetic research on longevity has provided important insights into the mechanism of aging and aging-related diseases.Pinpointing import genetic variants associated with aging could provide insights for aging research.Methods: We performed a whole-genome sequencing in 19 centenarians to establish the genetic basis of human longevity.Results: Using SKAT analysis, we found 41 significantly correlated genes in centenarians as compared to control genomes.Pathway enrichment analysis of these genes showed that immune-related pathways were enriched, suggesting that immune pathways might be critically involved in aging.HLA typing was next performed based on the whole-genome sequencing data obtained.We discovered that several HLA subtypes were significantly overrepresented.Conclusions: Our study indicated a new mechanism of longevity, suggesting potential genetic variants for further study.", "Genetic linkage studies of long-lived human families identified a longevity locus while candidate gene approaches have been used to identify and confirm the association between specific variants in the FOXO3A gene and human longevity [3\u20137]. Genome-wide association studies have also been used to identify the association of APOE with life 123 Aging Clin Exp Res span and have yielded insights into potential biological pathways and processes related to aging. Despite these successes, several problems are inherent in human longevity studies including potentially high degrees of environmental heterogeneity, genetic diversity, and lack of birth matched controls, among others [8].", "Additional association studies with these families and replication of these results with an independent data set should facilitate the positional cloning of a gene that influences the ability to age well and achieve exceptional longevity.Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.", "In conclusion, we performed a genome-wide association study of longevity-related phenotypes in individuals of European, East Asian and African American ancestry and identified the APOE and GPR78 loci to be associated with these phenotypes in our study.Moreover, our gene-level association analyses highlight a role for tissue-specific expression of genes at chromosome 5q13.3,12q13.2,17q21.31,and 19q13.32 in longevity.Genetic correlation analyses show that our longevity-related phenotypes are genetically correlated with several disease-related phenotypes, which in turn could help to identify phenotypes that could be used as potential biomarkers for longevity in future (genetic) studies.", "The only two genes associated with human longevity that have been replicated in multiple populations are FOXO3A and APOE [11,12,15,26,28 -31].The effect sizes of these two genes for longevity are small with odds ratios of 1.26 and 1.45 for survival to age 100 in replicate studies for FOXO3A and APOE, respectively [10,29].These genes account for only a small portion of the genetic contribution to longevity measured through family heritability studies [4,5].Therefore, much of the heritability of lifespan remains to be explained.", "Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.", "Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.", "In most experimentally modified animal model systems, single-gene mutations in many different genes have major life extension effects (Fontana et al., 2010;Kenyon, 2010).However, natural human and animal longevity is presumed to be a complex trait (Finch & Tanzi, 1997).In humans, both candidate gene and genome-wide genetic association approaches have been applied in an attempt to identify longevity loci.The frequency of genetic variants has been typically compared between nonagenarian cases and young controls, revealing loci at which genetic variants may contribute to a higher or lower probability of survival into old age.The initial candidate gene studies aimed at finding human longevity genes were dominated by contradictory results (Christensen et al., 2006).The more consistent evidence obtained by repeated observation in independent cohort studies for association with longevity has so far only been observed for three loci, the apolipoprotein E (APOE) locus (Schachter et al., 1994;Christensen et al., 2006), the FOXO3A locus (Willcox et al., 2008;Flachsbart et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010), and the AKT1 locus (Pawlikowska et al., 2009).Thus, despite the expectation that longevity would be influenced by many genetic variants with small effect sizes, the effect of variants has consistently been shown in only three genes.", "The lack of success in the identification of genes related to aging in humans may be due to the complexity of the phenotype.One approach to investigate aging and longevity is to compare frequencies of genetic variants between nonagenarians or centenarians and the general population.This approach led to the discovery of an association between APOE (Deelen et al., 2011;Ewbank, 2007;Gerdes et al., 2000) and more recently FOXO3A (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009a;Pawlikowska et al., 2009;Willcox et al., 2008) and human aging and longevity.However, a recent genome-wide association study (GWAS) of individuals reaching the age of 90 or older failed to identify genome-wide significant variants (Newman et al., 2010).", "Human longevity and healthy aging show moderate heritability (20%-50%).We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death.No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p \u03fd 5 \u03eb 10 \u03ea8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p \u03fd 10 \u03ea5 ).These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease.In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings.These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.", "Human longevity and healthy aging show moderate heritability (20%-50%).We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death.No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p \u03fd 5 \u03eb 10 \u03ea8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p \u03fd 10 \u03ea5 ).These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease.In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings.These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.", "In addition to aging-and CR-related genes, another source of candidate genes and pathways for drug design are human longevity-associated genes (Barzilai and Shuldiner, 2001;Browner et al., 2004;Kenyon, 2010).Dozens of genes have now been associated with human longevity (de Magalha \u02dces et al., 2009a), although only a handful of genes have been shown to have consistent effects across populations.", "The genetic basis of human longevity has so far been primarily investigated by association studies.Most results from these experiments have been difficult to confirm in independent samples, probably owing to the modest heritability, multifactorial nature, and heterogeneity of the phenotype (Christensen et al., 2006).To date, variation in only two genes has been identified, which has an effect on longevity in various populations: (i) the apolipoprotein E gene (APOE) (Scha \u00a8chter et al., 1994;Christensen et al., 2006) and (ii) the forkhead box O3A (FOXO3A) gene in the insulin-IGF1 signaling (IIS) pathway (Willcox et al., 2008;Flachsbart et al., 2009).Given the apparent lack of susceptibility candidates, it is conceivable that other genetic factors influence the function or expression of genes relevant for human longevity.", "GenAge: the aging gene database Philosophy and overview of resources It is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalh\u00e3es, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging.", "The only two genes associated with human longevity that have been replicated in multiple populations are FOXO3A and APOE [11,12,15,26,28 -31].The effect sizes of these two genes for longevity are small with odds ratios of 1.26 and 1.45 for survival to age 100 in replicate studies for FOXO3A and APOE, respectively [10,29].These genes account for only a small portion of the genetic contribution to longevity measured through family heritability studies [4,5].Therefore, much of the heritability of lifespan remains to be explained.", "Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.", "Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.", "Most of the human candidate gene studies were performed in cross-sectional designs (Box 1 and Fig. 1), comparing allele frequencies of potential longevity loci between highly aged individuals and young controls.The candidate gene studies based on single genes have pointed a role for genes involved in, e.g., GH/insulin/IGF-1 signaling, immune regulation, and lipoprotein metabolism (Supporting Information Table S1), although most of these results have not (yet) been confirmed in sufficient independent studies.The most convincing human longevity loci today are APOE and FOXO3A which have frequently been associated with longevity in cross-sectional studies (see for a review [26]) and survival in prospective studies [27][28][29] (Fig. 3).APOE encodes the protein apolipoprotein E which seems to play a role in e.g., lipoprotein metabolism, cognitive function, and immune regulation [30].FOXO3A encodes the protein forkhead box O3 which acts as a transcription factor for many different genes involved in processes like apoptosis and oxidative stress [31]." ], [ "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.", "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.", "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 life spans (results obtained from twin studies discussed below).The apoE polymorphisms are remarkable for their influence on both cardiovascular disease and Alzheimer disease.In contrast, rare mutant genes with high penetrance cause these same diseases but with early onset and a major shortening of the life span.Shortlived laboratory models (fruit flies, nematodes, mice) are yielding rapid advances, with the discovery of mutants that increase life spans in association with altered metabolism, which leads to questions on the physiological organization of aging processes.Although these early findings do not show that a conserved genetic program actually controls aging processes across animal phylogeny, it is striking how frequently findings of metabolic rate, insulin signaling, and free radicals have emerged from very different approaches to aging in nematodes and mammals, for example.These findings hint that the genetic control of life span was already developed in the common ancestor of modern animals so that subsequent evolution of life spans was mediated by quantitative changes in the control of metabolism through insulin and the production of free radicals.", "Background: Genetic research on longevity has provided important insights into the mechanism of aging and aging-related diseases.Pinpointing import genetic variants associated with aging could provide insights for aging research.Methods: We performed a whole-genome sequencing in 19 centenarians to establish the genetic basis of human longevity.Results: Using SKAT analysis, we found 41 significantly correlated genes in centenarians as compared to control genomes.Pathway enrichment analysis of these genes showed that immune-related pathways were enriched, suggesting that immune pathways might be critically involved in aging.HLA typing was next performed based on the whole-genome sequencing data obtained.We discovered that several HLA subtypes were significantly overrepresented.Conclusions: Our study indicated a new mechanism of longevity, suggesting potential genetic variants for further study.", "Introduction With 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.", "INTRODUCTION Human aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining \u223c20-25% 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.", "Somatic mutations with the inherited gene variations of each individual cumulatively or synergistically influence the health span and life span [11].Very few genetic variants have been associated with human longevity, but those found include the transcription factor FOXO3 gene, the APOE/TOMM40 and the CDKN2B/ ANRIL loci, which are associated with Alzheimer's disease and cellular senescence [12][13][14].In fact, the heritability for human longevity has been estimated to be approximately 20-30%, according to studies of twins, suggesting that external factors such as diet, environment, physical activity and microbiomes are important factors that influence the health span [14][15][16].The increase in the rate of retrotranscription reflects genome deregulation, creating additional mutations, DNA damage, and other forms of genome instability.For instance, the expression of several families of retrotransposable elements increases with age, as observed in mouse skeletal muscle and human fibroblasts, particularly the long interspersed nuclear element-1 (L1 LINE) [17,18].", "Influence of Genetic Factors in Ageing and Lifespan Ageing is defined as the decline of physiological functions in several tissues and organs inducing an increasing probability of death [17].The understanding of genetic factors involved in ageing has been limited due to the complexity of this process and the heterogeneity among individuals and even among tissues [18][19][20].Tissue cells adopt a senescent phenotype as a consequence of multiple intrinsic, extrinsic, and stochastic factors [21].The combination of these genetic factors is related to longevity and healthy ageing [22].Although this decline is somewhat predictable, some individuals show a much slower decline and get to live past the age of 100.Studies in these individuals showed polymorphisms in some genes which are associated with long life, such as APOE and FOXO3.However, these associations have not been consistent across different populations, suggesting that ageing is rather polygenic [23].", "Before the advent of NGS technologies, several scientists were interested in the study of allele variants associated with aging, but they were limited by the lack of aging rate biomarkers.Now with NGS technologies, these biomarkers have been emerged such as the epigenetic clock that is described in the DNA methylation sequencing section of this chapter.In this post-genomic era, different strategies have been developed in order to understand the genetic factors involved in aging [17].One strategy used is the study of aging in extreme longevity groups of people, called centenarians.Centenarians are a group that can reach an age above 100 years and has an incidence of 1 every 10,000 people [18].In a pioneering study using extreme longevity people (308 individuals belonging to 137 sibships showing extreme longevity), genome-wide scan analysis identified a region on chromosome 4 associated with extreme longevity [19] that corresponds to the microsomal transfer protein (MTP) [20], which is associated with abetalipoproteinemia and hypobeta lipoproteinemia in humans [21,22].Another approach to study the genetic factors involved in longevity consists in assessing allele frequencies from people of different ages, looking for those polymorphisms (SNPs) with enhanced allele frequencies in high-longevity individuals.Those alleles with diminished frequencies in aged individuals may be associated with age-related diseases.Using this approximation, an SNP that shifts isoleucine to valine was identified in the PKA-anchoring protein (AKAP2) gene.This polymorphism is associated with reduced longevity and cardiac disease [23].Genome-wide association studies (GWAS) have confirmed only three loci that affect longevity: FOXO3A, APOE, and an intergenic locus on chromosome 5q33.3[24][25][26].", "M OST genetic studies involved with aging have focused on identifying genes contributing to particular diseases.More recently, it has been recognized that it is also valuable to examine genetic factors related to diseasefree or healthy aging (1,2).Utilizing twins from the National Academy of Sciences-National Research Council (NAS-NRC) twin panel, we have demonstrated that healthy physical aging is under a significant degree of genetic influence, with a heritability over 50% (3).Our definition of healthy aging focused principally on freedom from cardiovascular disease, and has received considerable support in the more recent literature.Brand and colleagues (4) reported that parental age at death was a significant predictor of coronary heart disease death in the Framingham offspring study and concluded that familial similarities for age at death may be mediated through shared coronary heart disease risk factors.Frederiksen and colleagues (5) reported that increased parental life was associated with a reduction in odds ratio for their children to have diabetes, ischemic heart disease, heart failure, stroke, and hypertension.We have found that better midlife lipid levels and blood pressures were associated with increased parental longevity in the National Heart, Lung, and Blood Institute twin study (6).Centenarian siblings and offspring, besides having increased longevity, have been shown to have better health and better cardiovascular risk factor profiles (7)(8)(9)(10).", "Introduction The 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).", "Human longevity and healthy aging show moderate heritability (20%-50%).We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death.No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p \u03fd 5 \u03eb 10 \u03ea8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p \u03fd 10 \u03ea5 ).These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease.In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings.These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.", "Translational A LTHOUGH there is much debate about the processes driving human aging, there is little doubt that genetic influences play a significant role (1).Humans clearly live very much longer than the currently favored laboratory models of aging, and such interspecies differences in reproductively 'fit' life span must have an inherited genetic foundation.Within human populations, environmental and behavioral exposures are important but at least a quarter of life expectancy variation in twin or family studies is attributable to inherited genetic or epigenetic factors (2).Age-related conditions such as type 2 diabetes, myocardial infarction, common cancers, and Alzheimer's disease (AD) typically have onsets after the fourth decade of life; \"successful\" agers delay these onsets until relatively late in life (3).Many aging traits and diseases show moderate heritability, including cardiovascular disease (CVD) (4) and impaired physical functioning (5), independent of known environmental risk factors.", "Many factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics.", "The genetic basis of human longevity has so far been primarily investigated by association studies.Most results from these experiments have been difficult to confirm in independent samples, probably owing to the modest heritability, multifactorial nature, and heterogeneity of the phenotype (Christensen et al., 2006).To date, variation in only two genes has been identified, which has an effect on longevity in various populations: (i) the apolipoprotein E gene (APOE) (Scha \u00a8chter et al., 1994;Christensen et al., 2006) and (ii) the forkhead box O3A (FOXO3A) gene in the insulin-IGF1 signaling (IIS) pathway (Willcox et al., 2008;Flachsbart et al., 2009).Given the apparent lack of susceptibility candidates, it is conceivable that other genetic factors influence the function or expression of genes relevant for human longevity.", "Introduction Human 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).", "Introduction Approximately 25-30% of the variation in adult lifespan is attributable to genetic factors that become more important with increasing age and exert their strongest effects in nonagenarians and centenarians (Go \u00a8gele et al., 2010;Hjelmborg et al., 2006).As yet, however, only a few genetic variants have been found consistently to influence longevity.The first to be discovered was the e4 allele of the apolipoprotein E (APOE) gene, a mortality factor that predisposes to both Alzheimer's and cardiovascular diseases (Corder et al., 1993; Panza et al., 2004).APOE e4 is the only variant with a reportedly large adverse effect upon survival at advanced age (Scha \u00a8chter et al., 1994), and this association has been replicated in several populations (Christensen et al., 2006).Variation in the human forkhead box O3A gene (FOXO3A), in contrast, has been found to be associated with the ability to live long, an effect corroborated by studies in Japanese, German, Italian, US-American, Jewish, Chinese and Danish populations (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010;Willcox et al., 2008).More recently, we have identified exonuclease 1 (EXO1) as a potential novel longevity gene (Nebel et al., 2009).All three genes were detected through candidate-gene approaches.", "GenAge: the aging gene database Philosophy and overview of resources It is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalh\u00e3es, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging.", "I NCREASES 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 (1-7) and in other organisms (8).The protective genetic factors that lead to longevity are likely to involve fundamental processes of aging that may be different from those associated with early mortality or premature onset of age-related diseases in younger individuals.The mechanisms of aging in humans are far from understood, but available evidence suggests that several pathways-inflammation, oxidative stress and stress responses, cellular senescence, DNA damage and repair, and the growth hormone or insulinlike growth factor and insulin (GH, IGF, INS) axis-may play key roles (9)(10)(11)(12).Model organisms suggest that inhibiting the GH, IGF, or INS axis, which is involved in regulating cell proliferation, cell death, wound repair, and metabolism, may promote longevity by reducing oxidative stress and slowing the rate of cell replication and the accumulation of somatic-cell DNA mutations (13).There is also evidence for other important pathways such as the heatshock proteins and heat-shock factors that are highly conserved across species and play a role in prolongevity transcription pathways.Clinical and epidemiological investigations, including candidate gene studies, have suggested that inflammation pathways may affect life span and risk of age-related conditions such as cardiovascular disease (CVD) and its risk factors (14)(15)(16)(17)(18)(19).A combination of multiple genetic variants may be required for an individual to achieve exceptional longevity, which may account in part for its rarity.", "Human 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." ] ] }