path: root/gnqa/paper1_eval/src/data/datasets/human/dataset_domainexpert_aging_1.json

{
  "question": [
    "What is the significance of the length of telomeres?",
    "Which mouse genes have been associated with longevity?",
    "what genetic factor are associated with aging",
    "which genes are typically associated with early aging?",
    "How do I generate a linkage or association mapping study in mice to understand aging?"
  ],
  "answer": [
    "The length of telomeres is significant as it is associated with aging, disease, and mortality. Longer telomeres are generally associated with better health outcomes, including protection from age-related diseases, better cognitive function, and healthier lipid profiles. Shorter telomeres, on the other hand, have been linked to higher risks of heart disease, infection-related death, and other diseases. Telomere length can also be influenced by factors such as stress, with high-stress situations potentially leading to faster telomere shortening and premature aging.",
    "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.",
    "Several genetic factors are associated with aging. These include allele variants, polymorphisms (SNPs), and specific genes such as the microsomal transfer protein (MTP), PKA-anchoring protein (AKAP2) gene, FOXO3A, APOE, and genes in the HLA-DQA1/DRB1 and LPA regions. Other genes associated with aging are those highly expressed in the brain like HECW2, HIP1, BIN2, GRIA1, and genes involved in neural development and function like KCNQ4, LMO4, GRIA1, NETO1. Genes involved in autophagy like ATG4C are also associated with aging.",
    "The genes typically associated with early aging are APOE and FOXO3A.",
    "To generate a linkage or association mapping study in mice to understand aging, you would first need to select appropriate mouse strains. You could use inbred strains like C57BL/6J (B6) and DBA/2J (D2), or a recombinant inbred strain like BXD. You would then breed these mice, possibly creating an F2 generation cross or a backcross. After breeding, you would genotype and phenotype the offspring. For aging studies, you would monitor the mice over their lifespan, noting any changes in health, behavior, or physical characteristics. You could also perform genome-wide association mapping and correlation analyses against existing phenotypic and expression data sets to identify candidate genes involved in age-related decline. Additionally, you could use bioinformatics tools to analyze data and find patterns hinting at a common molecular mechanism. Finally, you would validate your findings using statistical analysis."
  ],
  "contexts": [
    [
      "In birds, where erythrocyte telomere length (ETL) is measured, the majority of species sampled have shown no sex difference (36).Nonetheless, bird telomere dynamics are complex and, as with humans, may be affected by environment and stress.For example, a longitudinal study of black-tailed gulls (Larus crassitostris) over 2-5 years found no correlation between ETL and age or sex.Rather, ETL attrition was correlated with reduced food availability and environmental stressors (55).In a captive zebra finch (Taeniopygia guttata) population, male and female mean telomere length decreased with increasing age of the animals, but did differ between sexes (56).As these examples illustrate, the relationship between telomere length, lifespan, and sex is likely to be complex in other vertebrates.Comparative studies of age-related telomere attrition in other species also reveal a variety of patterns.Barrett and Richardson (36) recently summarized the comparative data available on sex differences in telomere length.They found a strong correlation between male-biased mortality and either shorter telomeres or greater telomere attrition in males across bird and mammal taxa.However, telomere length did not differ between males and females in species where females are shorter-lived than males (36), suggesting that telomere shortening is not associated with species-specific longevity in a simple linear fashion.These studies generally suffer from relatively small sample sizes and are largely cross-sectional.Further, the use of diverse assays, different tissues (eg, leukocytes in mammals vs erythrocytes in birds), and lack of standardized benchmarks for accuracy makes comparisons between studies difficult.In some organisms, there is no clear relationship between telomere length and lifespan.Age-related telomere attrition could not be detected in Daphnia pulex (57) or sea urchin species (Strongylocentrotus franciscanus and Lytechinus variegatus) (58).Studies in C. elegans examining natural variation in telomere length and experimentally manipulated telomere length detect no correlation with lifespan (59,60), and in Drosophila, which uses a telomerase-independent mechanism for telomere maintenance, there is a similar lack of correlation between longevity and telomere length (61).Similarly, data on sex differences in age-related telomere shortening are mixed.For example, in the ant species Lasius niger, the rate of telomere shortening is more rapid in short-lived males compared to longer-lived females.But, mean telomere length does not differ between the two types of females, queens and workers, despite the fact that queens live much longer than workers (up to 28 years vs 2-3 months) (62).These findings suggest that the question of how telomere shortening affects aging across species and how sex affects telomere attrition rates are complex.",
      "With new methodologies to assess relative telomere length by Q-PCR, studies were designed to address the impact of telomere length on aging, aging associated pathologies, and mortality.One such study has correlated shorter leukocyte telomere lengths at age 60 with a three times higher risk of heart disease and an eightfold increase in risk of infection-related death (36), thereby associating measured relative cellular aging with disease and life expectancy.In a similar way, chronic stress was shown to correlate with short leukocyte telomere length, a phenomenon attributed to higher levels of oxidative stress at the cellular level (70).More recent studies have linked telomere length in smooth muscle cells with senescence and disease severity in patients with atherosclerosis (141,150).Leukocyte telomere length was also short in a cohort of similar patients and associated with a higher risk of developing occult cardiovascular disease (71).More data are needed to understand and validate the use of leukocyte telomere length as a biomarker for cardiovascular and other diseases.",
      "Shortening of the telomeres at the ends of chromosomes has been associated with age-related disease and mortality [16][17][18].A recent study identified a common haplotype of four SNPs in the human telomerase reverse transcriptase gene (hTERT) that is enriched in centenarians and associated with longer telomere length [19].It was also shown that centenarians and their offspring maintain longer telomeres compared with controls and that longer telomeres are associated with protection from age-related diseases, better cognitive function and lipid profiles of healthy ageing [19].",
      "New research has indicated how social factors, such as subordination, may translate into biological effects (epel et al. 2004;Chae et al. 2014).In a now classic study, epel et al. ( 2004) examined the telomere lengths of fifty-eight healthy premenopausal women who either had a healthy child (n = 19) or were giving care to a chronically ill child (n = 39. )They measured perceived stress, years of caregiving, telomere length, and oxidative stress.They found highly statistically significant differences in telomere length between women taking care of chronically ill children and those who had healthy children.They found highly statistically significant negative correlations between telomere length and perceived stress and years of caregiving.Telomerase activity had highly statistically significant negative correlations with perceived stress and years of caregiving.Oxidative stress was highly positively correlated with perceived stress and years of caregiving.They concluded that the telomere length shortening was equivalent to 9 to 17 years of aging in the high stress group.Telomere length is considered a biomarker of aging (Finch and Kirkwood 2000).Thus, this study showed that caregiver stress had essentially aged these women 9 to 17 years compared to women who had healthy children.",
      "The single, consistent predictor of the rate of telomere attrition shown in multiple adult and the few child longitudinal studies is the baseline measurement of telomere length at the start of each study.This suggests the importance of understanding predictors of telomere length prior to adulthood, as it determines in part the rate of change (Revesz et al. 2014a, b;Nordfjall et al. 2009).Moreover, longitudinal studies in adults have had found that telomere attrition rate is dependent on baseline telomere length independent of any phenotypic predictors of shortening, such as disease or demographic variables (Nordfjall et al. 2009), attesting to the importance of studies to evaluate risk factors for shortening prior to adulthood.Rates of decline in childhood may be particularly relevant for later chronic disease risk as shorter telomere length has been implicated in disease progression through exposure to cellular senescence, inflammatory cytokines and adipocyte hypertrophy (Raschenberger et al. 2015;Willeit et al. 2014;Monickaraj et al. 2012;Fyhrquist et al. 2013).Adult studies have also found a negative correlation with baseline telomere length, suggesting a negative feedback regulation of leukocyte telomere length (Farzaneh-Far et al. 2010;Aviv et al. 2009;Epel et al. 2008;Nordfjall et al. 2009).It is possible that while our follow-up period was shorter than Shalev et al. 2013 and adult studies, which had a minimum of 5 year intervals with the exception of Puterman et al. (2015) who followed for a one-year time period, there may be biological regulation of telomere length at 4 and 5 years of age such that shorter telomeres are more robustly maintained, whereas longer telomeres have greater rates of decline, over a short period of one year.It is unlikely that this relationship is due to assay error or regression to the mean given the consistency of our findings across studies.We have had similar findings of longer telomeres having greater rates of decline and shorter telomeres being maintained in our different studies (Farzaneh-Far et al. 2010;Epel et al. 2008;Puterman et al. 2015).We found primarily maintenance and lengthening from 4 to 5 years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4 years, plateauing by age 4. Lastly, we found close to 10 % of the variance in rate of change in children shared by mothers.While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change.Abstract Telomeres are the protective complexes at the end of chromosomes, required for genomic stability.Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change.Telomere length was assessed twice over one year, at 4 and at 5 years of age, in Latino preschool children (n = 77) and their mothers (n = 70) in whole blood leukocytes.Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs.More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6 %).Approximately 31 % of children and 16 % of mothers displayed lengthening over one year while 66 % of children showed maintenance in contrast with 74 % of mothers.The strongest predictor for child telomere length change was child's baseline telomere length (r = 0.61,p < 0.01).Maternal rate of change was associated with child rate of change (r = 0.33, p < 0.01).After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff = 0.20, 95 % CI 0.03 to 0.43; p = 0.08).",
      "Blackburn and Epel, a health psychologist who did original research on how specific lifestyle and psychological habits can protect telomeres, published The Telomere Effect (Blackburn & Epel, 2017), in which they suggested that individuals with shorter telomeres developed diseases earlier in life (a shorter \"disease span\").What follows is the evidence from these authors, their colleagues, and other researchers describing how length of telomeres contributes to mind-body connection and healthy longevity.",
      "As early as at the time of birth, each of the 92 telomeres of the human genome has its own characteristic length.Additionally, each telomere shortens by its individual attrition rate.In general, longer telomeres at birth are associated with higher age-dependent attrition rates and vice versa.Overall, telomere shortening appears more dynamic in males.In conclusion, a combination of overall and chromosomespecifi c shorter telomeres and more pronounced age-dependent telomere erosion could be observed in males.There is a prospective clinical study strongly suggesting that longer telomeres decrease the risk of dying (Cawthon et al., 2003).With this in mind, the telomere length discrepancies between the sexes may indeed be a factor infl uencing the differences in their life expectancy.In every chromosome a linear decline of telomere length with age was observed, being more pronounced in men independent of the examined chromosome arm.This might suggest that telomere length on single chromosome arms may be infl uenced by the same factors which determine overall telomere length.S. Mayer a S. Brderlein a S. Perner a I. Waibel a A. Holdenried a N. Ciloglu a C. Hasel a T. Mattfeldt a K.V. Nielsen b P. Mller a a Institute of Pathology, University of Ulm, Ulm (Germany); b DakoCytomation A/S, Glostrup (Denmark) follow uniformity.In previous studies, sex-specifi c differences in telomere length and attrition rate of men and women were found (Benetos et al., 2001;Cawthon et al., 2003;Nawrot et al., 2004), suggesting gender differences in behavior of telomeres.In individual chromosome arms, telomere length was also shown not to be homogeneous (Lansdorp et al., 1996;Benn, 1997;Martens et al., 1998;Surralles et al., 1999;Hao and Tan, 2001;Londono-Vallejo et al., 2001;Graakjaer et al., 2003), some telomeres being signifi cantly shorter, others longer than the average length.To date, these characteristics in telomere lengths could not be set in a biological context, as only a few groups have provided detailed information about chromosome-specifi c patterns of telomere distribution (Lansdorp et al., 1996;Graakjaer et al., 2003).Whether accumulation of short telomeres (Martens et al., 2000;Londono-Vallejo et al., 2001) or rather the shortest telomere of one specifi c chromosome arm (Hemann et al., 2001) elicits senescence, remains an open question so far.In recent literature, there are hints that the average telomere length may be higher in women and that their annual shortening rate may be somewhat lower (Vaziri et al., 1993;Rufer et al., 1998;Jeanclos et al., 2000), but these reported differences failed to reach statistical signifi cance except for one study (Jeanclos et al., 2000).Here, we provide compelling evidence that this is indeed the case.It is generally accepted that telomeres shorten during DNA replication both in vitro and in vivo.In individuals, short telomeres are considered to be a sign of advanced age.Cawthon and coworkers (2003) showed that telomere shortening in humans likely contributes to mortality, supporting the hypothesis that they might act as a mitotic clock (Allsopp et al., 1992).Telomere length dynamics, however, does not seem to Abstract.During aging, telomeres are gradually shortened, eventually leading to cellular senescence.By T/C-FISH (telomere/centromere-FISH), we investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes.For all chromosome arms, we found a linear correlation between telomere length and donor age.Generally, males had shorter telomeres and higher attrition rates.Every chromosome arm had its individual age-specifi c telomere length and erosion pattern, resulting in an unexpected heterogeneity in chromosomespecifi c regression lines.This differential erosion pattern, however, does not seem to be accidental, since we found a correlation between average telomere length of single chromosome arms in newborns and their annual attrition rate.Apart from the above-mentioned sex-specifi c discrepancies, chromosome arm-specifi c telomere lengths were strikingly similar in men and women.This implies a mechanism that arm specifi cally regulates the telomere length independent of gender, thus leading to interchromosomal telomere variations.",
      "Shortening of the telomeres at the ends of chromosomes has been associated with age-related disease and mortality [16][17][18].A recent study identified a common haplotype of four SNPs in the human telomerase reverse transcriptase gene (hTERT) that is enriched in centenarians and associated with longer telomere length [19].It was also shown that centenarians and their offspring maintain longer telomeres compared with controls and that longer telomeres are associated with protection from age-related diseases, better cognitive function and lipid profiles of healthy ageing [19]."
    ],
    [
      "DOI: https://doi.org/10.7554/eLife.75244\b24 of 30Chromosomes and Gene Expression | Genetics and GenomicsResearch articleContinuedAuthor(s)YearDataset titleDataset URLDatabase and IdentifierLongevityteam2021Genetics of longevity inBXD micehttp://www.BDL_10006, 10006genenetwork.org/show_trait?trait_id=10006&dataset=BXD-LongevityPublishLongevityteam2021Genetics of longevity inBXD micehttp://www.BDL_10010, 10010genenetwork.org/show_trait?trait_id=10010&dataset=BXD-LongevityPublishLongevityteam2021Genetics of longevity inBXD micehttp://www.BDL_10011, 10011genenetwork.org/show_trait?trait_id=10011&dataset=BXD-LongevityPublishLongevityteam2020Genetics of longevity inBXD micehttp://www.BDL_10021, 10021genenetwork.org/show_trait?trait_id=10021&dataset=BXD-LongevityPublishLongevityteam2020Genetics of longevity inBXD micehttp://www.BDL_10022, 10022genenetwork.org/show_trait?trait_id=10022&dataset=BXD-LongevityPublishLongevityteam2020Genetics of longevity inBXD micehttp://www.BDL_10025, 10025genenetwork.org/show_trait?trait_id=10025&dataset=BXD-LongevityPublishLongevityteam2021Genetics and epigeneticsof aging and longevity inBXD micehttp://www.BDL_10066, 10066genenetwork.org/show_trait?trait_id=10066&dataset=BXD-LongevityPublishReferencesAlbertsen 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\b24 of 30Chromosomes and Gene Expression | Genetics and GenomicsResearch articleContinuedAuthor(s)YearDataset titleDataset URLDatabase and IdentifierLongevityteam2021Genetics of longevity inBXD micehttp://www.BDL_10006, 10006genenetwork.org/show_trait?trait_id=10006&dataset=BXD-LongevityPublishLongevityteam2021Genetics of longevity inBXD micehttp://www.BDL_10010, 10010genenetwork.org/show_trait?trait_id=10010&dataset=BXD-LongevityPublishLongevityteam2021Genetics of longevity inBXD micehttp://www.BDL_10011, 10011genenetwork.org/show_trait?trait_id=10011&dataset=BXD-LongevityPublishLongevityteam2020Genetics of longevity inBXD micehttp://www.BDL_10021, 10021genenetwork.org/show_trait?trait_id=10021&dataset=BXD-LongevityPublishLongevityteam2020Genetics of longevity inBXD micehttp://www.BDL_10022, 10022genenetwork.org/show_trait?trait_id=10022&dataset=BXD-LongevityPublishLongevityteam2020Genetics of longevity inBXD micehttp://www.BDL_10025, 10025genenetwork.org/show_trait?trait_id=10025&dataset=BXD-LongevityPublishLongevityteam2021Genetics and epigeneticsof aging and longevity inBXD micehttp://www.BDL_10066, 10066genenetwork.org/show_trait?trait_id=10066&dataset=BXD-LongevityPublishReferencesAlbertsen 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 ofgenetic determinants of IGF-1 levels and longevity among mouseinbred strains. Aging Cell 9(5):823836. doi:10.1111/j.14749726.2010.00612.x10. Lang DH, Gerhard GS, Griffith JW et al (2010) Quantitative traitloci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD)recombinant inbred mice. Aging Clin Exp Res 22(1):81911. Gelman R, Watson A, Bronson R et al (1988) Murine chromosomalregionscorrelatedwithlongevity. Genetics118(4):69370412. Jackson AU, Galecki AT, Burke DT et al (2002) Mouse lociassociated with life span exhibit sex-specific and epistatic effects.Conclusions These results suggest a novel locus influencing survival in the B6/D2 genetic background, perhapsvia a metabolic disorder that emerges by 200 days of age inmale animals. KeywordsPathologyLongevity \u0001 Lifespan \u0001 Mouse \u0001 Linkage \u0001IntroductionLongevity, the quintessential complex trait, likely reflectsall aspects of an organisms life history. In humans, theestimated heritability of age at death is estimated at2533 % [1]. Genetic contributions to mortality rates arethus of great interest and may aid in the understanding ofdisease etiology and the process of aging itself [2].Here, we have extended this analysis to search forgenotypes related to survival to the age of 800 days in apopulation of a reciprocal F2 cross between (B6) and (D2)mice. Since QTL for longevity in mice have shown strongsex specificity [10, 12], we conducted sex-specific analyses. In addition, we also determined whether there wereany change in pathology changes associated with the locithat showed frequency distortions with aging. To confirmthe associations of the loci of interest with longevity andpathology, we performed replication analyses on a panel ofBXD 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 lifeshortening. 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 andthe 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: 9302. 21 Gelman R, Watson A, Bronson R, Yunis E. Murine chromosomalregions correlated with longevity. Genetics 1988;118:693704. 22 Peirce JL, Lu L, Gu J, Silver LM, Williams RW. A new set of BXDrecombinant inbred lines from advanced intercross populations inmice. BMC Genet 2004;5:7. 23 Rahman ZS, Tin SK, Buenaventura PN et al. A novel susceptibilitylocus on chromosome 2 in the (New Zealand Black \u0004 New ZealandWhite) F1 hybrid mouse model of systemic lupus erythematosus. J Immunol 2002;168:30429. 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 ofTGF-2 when old (48). The region on chromosome 2 where asuggestive QTL regulating the responsiveness to TGF-2 in oldmice is located also contains two QTL for longevity (32). Finally,the strongest support for this hypothesis is the correlation betweenlongevity and the age-related increase in the serum-dependent effect of TGF-2 on LSK cells, the extent of which may determinestem 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 TraitLocus (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 muscleweight in 200-day-old mice of the C57BL/6J and DBA/2J lineage. Physiol Genomics 16, 141152. 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 longevityin Drosophila melanogaster. Genetics 2000;156:11291146. [PubMed: 11063689]33. Ma RZ, et al. Identification of Bphs, an autoimmune disease locus, as histamine receptor H1. Science2002;297:620623. [PubMed: 12142541]Nat Rev Genet. Author manuscript; available in PMC 2007 November 5. Page 12NIH-PA Author Manuscript34. Vivian JL, Chen Y, Yee D, Schneider E, Magnuson T. An allelic series of mutations in Smad2 andSmad4 identified in a genotype-based screen of N-ethyl-N-nitrosourea-mutagenized mouseembryonic stem cells. Proc. Natl Acad. Sci. USA 2002;99:1554215547. [PubMed: 12432092]35. Vogel G. Scientists dream of 1001 complex mice.",
      "34. Gelman R, Watson A, Bronson R & Yunis E Murine chromosomal regions correlated withlongevity. Genetics 118, 693704 (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, 451457 (2013). [PubMed: 23698443]37. Williams EGet al.An Evolutionarily conserved role for the aryl hydrocarbon receptor in theregulation 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, 819 (2010).",
      "In addition,the B6 mouse strain is one of the longest-lived mouse strains with a mean lifespan of 3years versus other mouse strains with mean lifespan from 1.5-2 years. Therefore, it isevident that the genetic background of a particular mouse strain can have a profoundeffect on the biology of the HSC population as well as organismal longevity. Indeed, it isfor this reason that it is difficult to compare findings from various laboratories wheredifferent mouse strains are used.",
      "NIH-PA Author ManuscriptThis study indicated a large amount of genetic variation for mouse longevity; heritabilitywas 34% for AL and 36% for DR (60% of AL food intake). There was no significantcorrelation between mean longevity under these two conditions, although maximumlifespans of the AL and DR mice were significantly correlated. Similar observations weremade 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% DRmales, 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 regionaffecting FE. DiscussionWe 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 usedboth 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 thisstudy (the AL efficiency model will be tested in future studies). Exp Gerontol. Author manuscript; available in PMC 2011 September 1. Rikke et al. Page 8NIH-PA Author ManuscriptOther studies have also reported that individual mice that maintained the highest BW werelikely 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 strainsLife 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)."
    ],
    [
      "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.",
      "Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality.Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively.We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function.Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs.A polygenic score for GrimAge acceleration showed strong associations with adiposityrelated traits, educational attainment, parental longevity, and C-reactive protein levels.Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.",
      "INTRODUCTIONHuman aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining 20-25% of the variability of human survival to the mid-eighties (Herskind et al., 1996;Fraser and Shavlik, 2001).By contrast, genetic factors may have greater impact on survival to the ninth through eleventh decades (Tan et al., 2008).Notably, exceptional longevity is rare and may involve biological mechanisms that differ from those implicated in usual human aging.",
      "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].",
      "Even more disappointing result is that some genes predisposing to geriatric diseases discovered by GWAS appear to be not correlated with human longevity (Beekman et al. 2010;Deelen et al. 2011).This result questions whether findings obtained from GWAS may provide insights into the bio-genetic mechanisms underlying a healthy lifespan.In fact, this finding is very surprising because (1) genetic studies of non-human species have discovered numerous genes predisposing to aging-related processes (Cutler and Mattson 2006;Vijg and Suh 2005;Kenyon 2005;Johnson 2006;Greer and Brunet 2008), (2) nongenetic association studies show that the long-living individuals are typically in better health compared to the short-living individuals (Barzilai et al. 2003;Willcox et al. 2008b;Willcox et al. 2008a;Evert et al. 2003), and (3) candidate-gene studies (but not GWAS) document that the same genes can affect diseases and lifespan (Koropatnick et al. 2008;Kulminski et al. 2011).This is an apparent paradox which has to be carefully examined.A prominent geneticist and evolutionary biologist T. G. Dobzhansky asserts that \"nothing in biology makes sense except in the light of evolution. \"Evolution primarily maximizes fitness of individuals of reproductive age.The classical evolutionary biological theory of aging claims that aging occurs because of decline in the force of natural selection with age (Kirkwood and Austad 2000).Then, according to that theory, aging-related (senescent) phenotypes with post-reproductive manifestation are non-adaptive and subject to stochastic variation.Therefore, at a first glance evolution should not be relevant to senescent phenotypes (apart so-called grandmother hypothesis; Hawkes et al. 1998).Such phenotypes, however, can be caused by reproductive-age-related risk factors making, thus, evolution to be relevant to them (Vijg and Suh 2005;Di Rienzo and Hudson 2005;Drenos and Kirkwood 2010).",
      "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.",
      "This population geneticmechanism also can maintain genetic variability for aging, like antagonistic pleiotropy. LARGE-EFFECT MUTANTS AND THE GENETICS OF AGINGOne approach that has become increasingly common in the characterization of the genetics of aging is to isolate aging mutants, usually from mutagenesis experiments, andthen to determine the mechanistic basis for the unusual life span in the mutants. Thisapproach has led to the discovery of genes that can enhance (e.g. , Maynard Smith 1958;Lin et al. 1988; reviewed in Guarente and Kenyon 2000, Kim 2007) or reduce life span(e.g. , Pearl and Parker 1922).",
      "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).",
      "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  5  10 8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p  10 5 ).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.IntroductionThe 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  5  10 8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p  10 5 ).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.",
      "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 chter 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.",
      "IntroductionApproximately 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 gele 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 chter 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 resourcesIt 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 Magalhes, 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."
    ],
    [
      "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.",
      "Studies revealed from 300 to 750 genes related to longevity that are critically involved in a variety of life activities, such as growth and development, energy metabolism, oxidative stress, genomic stability maintenance, and neurocognition [4].These candidate genes include mainly APOE, a gene involved in lipoprotein metabolism [5,6].Others are those involved in cell cycle regulation, cell growth and signal transduction, the maintenance of genome stability, and the endocrine-related pathway [7][8][9].In addition, the candidates for longevity encompass genes related to drug metabolism, the ones involved in protein folding, stabilization, and degradation, as well those related to coagulation and regulation of circulation [10], etc.In most cases, these genes or their polymorphic sites were examined in multiple population replication studies, which discovered certain longevity-associated genes or pathways [4][5][6][7][8][9][10].",
      "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.",
      "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].",
      "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.Gene associations with age-related traits found using longitudinal study data.",
      "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  5  10 8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p  10 5 ).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.",
      "Thus, substantially more work is needed in this area to establish whether longevity is driven by nuclear genomic stability.Diverse and unexpected bits of evidence support a relationship.For example, a disproportionate number of genes identified in unbiased and targeted genome-wide association studies (GWASs) as associated with longevity are involved in genome maintenance (75).One study involved age of natural menopause in 70,000 women and led to the identification of 44 genetic variants associated with early or late menopause, a strong biomarker of healthy TIFs (telomere dysfunction-induced foci): co-localization of multiple DNA damage response factors and repair proteins on uncapped telomeric DNA aging (76).Approximately two-thirds of these are associated with genome maintenance genes.Seven of ten significantly associated pathways are involved in DNA repair.The highly significant overrepresentation of DNA repair pathways indicates an intimate connection between genome maintenance and aging phenotypes.From unrelated studies, we know that reduced expression of the repair endonuclease ERCC1-XPF causes accelerated aging (3), whereas ERCC1 is one of the top genes under positive selective pressure in the longest-lived mammalian species, the bowhead whale (77).Intriguingly, hepatocytes from old rats have impaired NER, whereas caloric restriction, which extends longevity, restored the NER capacity of old rats to that of youthful levels (42).In a human interventional study, brief caloric restriction increased NER capacity in PBMCs of individuals who had low NER prior to dietary intervention (78).Therefore, increased DNA repair capacity could promote longevity and may even prove amenable to improvement.",
      "The antagonistic pleiotropy and hyperfunction theories of ageing predict the presence of genetic variants important for growth and development in early life with deleterious effects towards the end of the reproductive window 19,20 .While we are unable to directly capture the genetic effects on individuals before age 40 due to the study design of our datasets, we found that the life-extending variant near FOXO3 is associated with a delay in the age at menarche and a decrease in intracranial volume and cognitive abilities.It thus appears that there are loci exhibiting antagonistic effects, although we are unable to discern whether this is due to true pleiotropy or due to linkage of causal variants within a region  Genes which showed a significant effect (FDR < 5%) of gene expression on ageing traits are displayed here.Gene names are annotated with the direction of effect, where + andindicate whether the life-extending association of the locus is linked with higher or lower gene expression, respectively.Locus: nearest gene to lead variant in the multivariate analysis, Chr: chromosome, Position: base-pair position of lead variant (GRCh37), Cis-genes: genes in physical proximity (<500 kb) to the lead variant of the locus which colocalise with the multivariate signal, Trans-genes: genes located more than 500 kb from the lead variant of the locus.",
      "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 es et al., 2009a), although only a handful of genes have been shown to have consistent effects across populations.",
      "Genes/loci identified by genome-wide association studies of longevity and lifespan traits.",
      "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 chter 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.",
      "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.Gene associations with age-related traits found using longitudinal study data.",
      "Candidate gene studies identified APOE and FOXO3A as human longevity genesThe first genetic longevity studies mainly focused on lifespan regulating loci that emerged from animal models [22].Lifespan Prospects & Overviews .... extension in animal models was obtained by applying caloric restriction or by modifying gene functions (mutagenesis) using RNA interference, knock-out or overexpression of single genes (GenAge; http://genomics.senescence.info/genes/)[23].The most interesting pathways identified using these models are the growth hormone (GH)/insulin/insulin-like growth factor 1 (IGF-1) signaling and mammalian target of rapamycin (mTOR) signaling pathways [24].Thus far, lifespan has been the main phenotype investigated in animal models.In order to make these models more translatable to human studies research should focus on defining the parameters that reflect the physiology and pathology of aging in both animals and humans [25,26].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]."
    ],
    [
      "Mutation Rate in the Liver of Mice with AgeThe mouse is a good biological tool that allows the analyses of different tissues with little limitation on the amount of biological materials available.Mice are economical compared to larger mammals, and there is a huge volume of literature on the physiology, behavior, and biochemistry of such rodents.Importantly, it is possible to modify the diet of mice or treat them with drugs to mimic specific diseases and/or to improve their health status.Finally, their genomics and genetics have been extensively studied to such a point that now there is a battery of transgenic and knockout mice which, to some extent, phenocopy important age-related diseases.Many mice with mutations in different DNA repair proteins are available.Importantly, at least four transgenic lines with the lacI and/or LacZ reporter genes have been intensively used to estimate the mutation frequency or rate in the genome of different tissues with age.One such transgenic line bears a lambda shuttle vector that carries a lacI target and an alpha lacZ reporter gene [9,10].Genomic DNA is isolated from the tissue under study, and the shuttle vector is recovered by exposing the DNA to lambda phage packaging extracts in vitro.Mutations in the lacI target gene that inactivate the repressor gene allow expression of the alpha lacZ reporter gene, resulting in blue mutant plaques.Sequencing of the DNA from these plaques not only allows the estimation of the mutation frequency, but it also points to the type of mutation providing insights into potential mechanisms [9,10].The lacI gene is highly sensitive to base substitution and frame shift mutations, as well as small deletions and insertions, making the transgene an ideal choice for recovery of spontaneous and induced mutations [11,12].The Big Blue mouse contains approximately 40 copies of the lambda shuttle vector stably integrated as a tandem array at a single position in chromosome 4 [12].The MutaMouse contains the sequence of a phage carrying the lacZ gene integrated in a head-to-tail arrangement of approximately 40 copies located at a single insertion site in chromosome 3 [13,14].The technical difference in identifying mutations in these two mouse systems is that the Big Blue mouse model is based on forward mutations in the lacI reporter sequence derepressing the lacZ gene thereby yielding blue plaques as mutants.Thousands of plaques need to be examined.The Muta mouse is based on forward mutations in the lacZ reporter gene that can be easily selected because only mutants will generate plaques.Finally, the lacZ transgenic mice lines 30 and 60 bear a plasmid carrying the lacZ gene.Line 60 was found to have two integration sites, which were mapped to chromosomes 3 and 4. The plasmid integration site of line 30 is on chromosome 11.Each integration site in both transgenic lines has about ten to twenty plasmids per haploid genome [15].Plasmids are rescued by excision with the restriction enzyme HindIII, followed by separation from mouse genomic DNA by the use of magnetic beads coated with the lacI repressor protein, which will bind the lacI sequence.The recuperated DNA is then self-ligated to obtain circular plasmids that are finally transferred into Escherichia coli C bacteria (harboring a deletion of its own lacZ gene) for sequence analyses [15,16].Mice of line 60 are appropriate transgenic animals for the study genome rearrangements in the aging liver [15,17], and chromosomal translocations and deletions up to 66 megabases have been observed in the tissues of such mice [17].Such chromosomal rearrangements cannot be detected using the phage-based reporter models (the MutaMouse and the Big Blue models).",
      "The availability of deep genome sequence data, and unrivaledmulti-omic and phenomic data make the BXDs a powerful tool with which to evaluate the causallinkage between genome, epigenome, and aging rates. In our previous work, we used an enrichment-based sequencing to assay the methylome in a modestnumber of BXD mice and reported rapid age-dependent methylation changes in mice on high-fat diet(HFD) and mice with higher body weight (Sandoval-Sierra et al. , 2020).",
      "Byusing bioinformatics tools, data from various studies will be clustered and analyzed to find therelationship between myelin and myelin-related genes and see if any patterns can be found thathint at a common molecular mechanism. METHODSData will be pooled from various studies of alcohol on different strains of mice. Included in thisstudy will be DBA/2J (D2) and C57BL/6J (B6), two inbred mouse strains that exhibit contrastingdrinking behaviors. Other data will come from studies on ISS (inbred short sleep) and ILS(inbred long sleep) mice.",
      "The availability of deep genome sequence data, and unrivaledmulti-omic and phenomic data make the BXDs a powerful tool with which to evaluate the causallinkage between genome, epigenome, and aging rates. In our previous work, we used an enrichment-based sequencing to assay the methylome in a modestnumber of BXD mice and reported rapid age-dependent methylation changes in mice on high-fat diet(HFD) and mice with higher body weight (Sandoval-Sierra et al. , 2020).",
      "Here, we have extended this analysis to search forgenotypes related to survival to the age of 800 days in apopulation of a reciprocal F2 cross between (B6) and (D2)mice. Since QTL for longevity in mice have shown strongsex specificity [10, 12], we conducted sex-specific analyses. In addition, we also determined whether there wereany change in pathology changes associated with the locithat showed frequency distortions with aging. To confirmthe associations of the loci of interest with longevity andpathology, we performed replication analyses on a panel ofBXD recombinant inbred strains.J Gerontol A Biol Sci Med Sci 57(1):B9B1513. Foreman JE, Lionikas A, Lang DH et al (2009) Genetic architecture for hole-board behaviors across substantial time intervalsin young, middle-aged and old mice. Genes Brain Behav8(7):714727. doi:10.1111/j.1601-183X.2009.00516.x14. Lang DH, Conroy DE, Lionikas A et al (2009) Bone, muscle, andphysical activity: structural equation modeling of relationshipsand genetic influence with age. J Bone Miner Res24(9):16081617. doi:10.1359/jbmr.09041815. Blizard DA, Lionikas A, Vandenbergh DJ et al (2009) Bloodpressure and heart rate QTL in mice of the B6/D2 lineage: sexdifferences and environmental influences. Physiol Genomics36(3):158166.",
      "Assessing epigenetic age in long-lived miceThe epigenetic-aging model was applied to the methylation profiles of long-lived mice and the age-matched controls not used for training (Additional file 2: Datasets used summary).Reductions in age were calculated by subtracting the epigenetic ages of the untreated, wild-type mice from those of the treated mice of the same genetic background.To assess the significance, we used an ANOVA for all 22-month-old mice or only 22-month-old UM-HET3 mice.We also compared the epigenetic ages between treatments with their agematched controls from the same genetic background using a t-test (Additional file 4: Treatment vs wild type stats).",
      "Experimental Goals and SignificanceThe experimental goal of the work performed in this dissertation was to identifyspecific gene(s) and molecular pathways underlying HSC aging in two commonly usedstrains of inbred mice using a forward genetic approach.In order to understand the geneticbasis for the variation of HSC numbers in old B6 and D2 mice, we used theaforementioned forward genetic approach and performed genetic linkage analysis inBXD RI strains of mice. Using this approach, we identified a locus on murinechromosome 2 that is significantly linked to the variation in frequency of HSCs in agedB6 and D2 animals.Thus, in vitro and invivo results confirmed the linkage analysis, and demonstrated that the influence exertedby the D2 allele caused a significant reduction in HSC frequency and activity with age(Geiger et al. , 2005). Aging phenotypes in mice are difficult to study, partly because test subjects mustage ~2 years before they can be used in an experiment.In mice, the effect of aging onstem cells is highly strain-specific, thus suggesting genetic regulation plays a role in HSCaging. In C57BL/6 (B6) mice, the HSC population steadily increases with age, whereas inDBA/2 (D2) mice, this population declines. Our lab has previously mapped aquantitative trait locus (QTL) to murine chromosome 2 that is associated with thevariation in frequency of HSCs between aged B6 and D2 mice. In these dissertationstudies, I first aim to characterize the congenic mouse model which was generated byintrogressing D2 alleles in the QTL onto a B6 background.",
      "We further demonstrated the effectiveness of the combineduse of genome-wide association mapping with correlation analysesagainst existing phenotypic and expression data sets to identifycandidate genes that may be involved in the age-related decline inadult neurogenesis. 18-month-old mice (at least 2 males and 2 females for C57BL/6J,A/J, CBA/J, DBA/2J, 129S1/SvImJ, and 129X1/SvJ; females only for theBALB/cByJ, C3H/HeJ, and FVB/NJ) were examined and comparedamong the 9 strains.",
      "Accessing data resources in the mousephenome database for genetic analysis of murine life span and health span. J.Gerontol. A Biol. Sci. Med. Sci. 71 (2), 170177. Brown, R.E. , Stanford, L., Schellinck, H.M., 2000. Developing standardized behavioraltests for knockout and mutant mice. ILAR J. 41 (3), 163174. Bubier, J.A. , Jay, J.J., Baker, C.L. , Bergeson, S.E. , Ohno, H., Metten, P., Crabbe, J.C.,Chesler, E.J. , 2014. Identication of a QTL in Mus musculus for alcohol preference,withdrawal, and Ap3m2 expression using integrative functional genomics and precision genetics. Genetics 197 (4), 13771393. Burn, C.C. , 2008.",
      "Breeding schemes for mouse genome-wide association study populationsa | In the classic F2 generation cross, two parental strains are mated to generate F1 strains. The F1 strains are then either mated to each other (intercross) or to one of the parentalstrains (backcross; not shown) to generate F2 offspring. These offspring are then genotypedand phenotyped. b | Recombinant inbred strains are generated by sibling mating F2intercross animals until the resulting progeny, at least 20 generations later, is fully inbred. These inbred lines are maintained in breeding colonies and can be purchased fromcommercial vendors.",
      "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.",
      "Future studies may involve examination of aging mice from the CxB sRI strains todetermine whether the differences in EP and marginal cell density persist throughout thelifespan. The relationship between the cochlear lateral wall metrics (strial thickness,marginal cell density, and spiral ligament thickness) may become more obvious in oldermice with more pronounced age-related strial pathology. Additionally, due in part to therelatively small set of CxB RI strains, the suggested QTLs must be confirmed usingadditional methods.",
      "To identify genes and molecularpathways regulating memory capabilities during aging, here weperform a forward systems genetic analysis on an aged cohort ofstrains from the BXD GRP. 2. Methods2.1. AnimalsMale and female mice were group housed (2e5 per cage) andmaintained in colony housing (12-hour light/dark cycle) with adlibitum access to food and water.",
      "If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.Validation of the aging signature in mice\" subsection.A total of 110 male and virgin female C57BL/6JN mice were used.Mouse groups are summarized in ST9.In the aging cohort, 6 1 months old (mo), 10 3mo, 6 6mo, 6 9mo, 10 12mo, 6 15mo, 10 18mo, 10 21 mo, 5 24 mo, 6 27mo and 6 30mo were used.In the parabiosis cohort, 11 4mo and 18 19mo were used.",
      "The DNA methylation results at these sites can be integrated into a multivariablemodel for epigenetic age predictions in B6 mice, which clearly correlate with the chronological age.10MethodsStatistical analysisMiceLaboratory C57BL/6J (B6), DBA/2J (D2) and BXD inbred micewere obtained from Janvier Labs (France). All mice were fed acidified water and food ad libitum, and housed under pathogen-freeconditions at the University of Kentucky, Division of LaboratoryAnimal Resource, the animal facility at CCHMC.",
      "34. Gelman R, Watson A, Bronson R & Yunis E Murine chromosomal regions correlated withlongevity. Genetics 118, 693704 (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, 451457 (2013). [PubMed: 23698443]37. Williams EGet al.An Evolutionarily conserved role for the aryl hydrocarbon receptor in theregulation 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, 819 (2010)."
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