No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes.
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ABSTRACT:
SUBMITTER: Soerensen M
PROVIDER: S-EPMC4841709 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Project description:FOXO3A variation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3A variation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3A tagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92-93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/spine/hip/wrist) fracture. Gene-based testing revealed significant associations of FOXO3A variation with ADL (P = 0.044) and bone fracture (P = 0.006). The single-SNP statistics behind the gene-based analysis indicated increased ADL (decreased disability) and reduced bone fracture risk for carriers of the minor alleles of 8 and 10 SNPs, respectively. These positive directions of effects are in agreement with the positive effects on longevity previously reported for these SNPs. However, when correcting for the test of 9 phenotypes by Bonferroni correction, bone fracture showed borderline significance (P = 0.054), while ADL did not (P = 0.396). Although the single-SNP associations did not formally replicate in another study population of oldest-old Danes (n = 1279, age 94-100), the estimates were of similar direction of effect as observed in the Discovery sample. A pooled analysis of both study populations displayed similar or decreased sized P-values for most associations, hereby supporting the initial findings. Nevertheless, confirmation in additional study populations is needed.
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Project description:Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old 'Super-Seniors' (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer's Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.
| S-EPMC5400530 | biostudies-literature
Project description:Aged population is increasing worldwide due to the aging process that is inevitable. Accordingly, longevity and healthy aging have been spotlighted to promote social contribution of aged population. Many studies in the past few decades have reported the process of aging and longevity, emphasizing the importance of maintaining genomic stability in exceptionally long-lived population. Underlying reason of longevity remains unclear due to its complexity involving multiple factors. With advances in sequencing technology and human genome-associated approaches, studies based on population-based genomic studies are increasing. In this review, we summarize recent longevity and healthy aging studies of human population focusing on DNA repair as a major factor in maintaining genome integrity. To keep pace with recent growth in genomic research, aging- and longevity-associated genomic databases are also briefly introduced. To suggest novel approaches to investigate longevity-associated genetic variants related to DNA repair using genomic databases, gene set analysis was conducted, focusing on DNA repair- and longevity-associated genes. Their biological networks were additionally analyzed to grasp major factors containing genetic variants of human longevity and healthy aging in DNA repair mechanisms. In summary, this review emphasizes DNA repair activity in human longevity and suggests approach to conduct DNA repair-associated genomic study on human healthy aging.
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Project description:Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.
| S-EPMC2722017 | biostudies-literature
Project description:Human longevity and personality traits are both heritable and are consistently linked at the phenotypic level. We test the hypothesis that candidate genes influencing longevity in lower organisms are associated with variance in the five major dimensions of human personality (measured by the NEO-FFI and IPIP inventories) plus related mood states of anxiety and depression. Seventy single nucleotide polymorphisms (SNPs) in six brain expressed, longevity candidate genes (AFG3L2, FRAP1, MAT1A, MAT2A, SYNJ1, and SYNJ2) were typed in over 1,000 70-year old participants from the Lothian Birth Cohort of 1936 (LBC1936). No SNPs were associated with the personality and psychological distress traits at a Bonferroni corrected level of significance (P < 0.0002), but there was an over-representation of nominally significant (P < 0.05) SNPs in the synaptojanin-2 (SYNJ2) gene associated with agreeableness and symptoms of depression. Eight SNPs which showed nominally significant association across personality measurement instruments were tested in an extremely large replication sample of 17,106 participants. SNP rs350292, in SYNJ2, was significant: the minor allele was associated with an average decrease in NEO agreeableness scale scores of 0.25 points, and 0.67 points in the restricted analysis of elderly cohorts (most aged >60 years). Because we selected a specific set of longevity genes based on functional genomics findings, further research on other longevity gene candidates is warranted to discover whether they are relevant candidates for personality and psychological distress traits.
| S-EPMC3583011 | biostudies-literature
Project description:Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
| S-EPMC8087267 | biostudies-literature
Project description:Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that among genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single-nucleotide polymorphisms (SNPs) in 47 genes differentially expressed in calorically restricted mice and 12 other genes for association with longevity. Subjects were American men of Japanese ancestry, 440 aged ≥95 years and 374 with an average life span. Based on a dominant model of inheritance, an association with longevity at the p < .05 level was seen for SNPs in 13 of the genes. Testing by all possible models increased the number of genes to 18. After correction for multiple testing, four genes retained significance, namely, MAP3K5 (p = .00004), SIRT7 (p = .00004), SIRT5 (p = .0007), and PIK3R1 (p = .01). In a dominant model, association with longevity was seen for multiple adjacent SNPs within two of these genes (MAP3K5 and PIK3R1), as well as in FLT1, consistent with linkage disequilibrium with a causative variant in the vicinity of each respective SNP set. MAP3K5 and FLT1 haplotypes were associated with longevity. In conclusion, the present study implicates variation in MAP3K5, FLT1, PIK3R1, SIRT7, and SIRT5 in human longevity.
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Project description:BackgroundLittle is known about the role of specific leisure activities in affecting cognitive functions. We aim to examine the associations of specific leisure activities with the risk of cognitive impairment among oldest-old people in China.MethodsThis community-based prospective cohort study included 10,741 cognitively normal Chinese individuals aged 80 years or older (median age 88 years) from the Chinese Longitudinal Healthy Longevity Survey. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Cox proportional hazards models were utilized to estimate the effects of specific leisure activities on cognitive impairment outcome.ResultsDuring a median follow-up time of 3.4 years (41,760 person-years), 2,894 participants developed cognitive impairment. Compared to those who "never" engaged in watching TV or listening to radio, reading books or newspapers, and playing cards or mah-jong, those who engaged in such activities "almost every day" reduced their risk of cognitive impairment, the fully-adjusted hazard ratios were 0.56 (0.51-0.61), 0.64 (0.53-0.78), and 0.70 (0.56-0.86), respectively. The association between the risk of cognitive impairment and watching TV and listening to the radio, playing cards or mah-jong, and reading books or newspapers were stronger among those who had two or more years of education. Moreover, the association between risk of cognitive impairment and watching TV and listening to radio was stronger in men than in women.ConclusionsIn conclusion, a greater frequency of TV watching or radio listening, reading books or newspapers, and playing cards or mah-jong may decrease the risk of cognitive impairment among the oldest-old.
| S-EPMC6776703 | biostudies-literature
Project description:Health and longevity in humans are influenced by numerous factors, including lifestyle and nutrition. However, the direct relationship between lifetime eating habits and functional capacity of the elderly is poorly understood. This study investigated the dietary changes across nutrition transition (NT) in the early 1960s, in a population located in the Sardinia island known for its longevity, dubbed as "Longevity Blue Zone" (LBZ), as well as the relationship between the dietary patterns and a panel of health indicators. A total of 150 oldest-old participants (89 women and 61 men, age range 90-101 years) living in the LBZ were recruited. Participants were interviewed using validated questionnaires to assess the consumption frequency of common food items, as well as the correlation with self-rated health, comorbidity, affective and cognitive level, physical mobility, disability and anthropometric parameters. Differences between subgroups were evaluated using the Mann-Whitney U test for independent samples or the Wilcoxon signed-rank test for paired samples. Correlation analysis was performed by calculating the Spearman correlation coefficient, separately in males and females. Compared to the pre-NT epoch, the consumption of meat, olive oil and fresh fruit slightly increased, while the consumption of lard, legumes and vegetables decreased. A significant association was found between increased olive oil intake across NT and self-rated health (ρ = 0.519), mobility (ρ = 0.502), improved vision (ρ = -0.227) and hearing (ρ = -0.314); increased chicken meat intake and performance in activities of daily living (basic activities of daily living: ρ = 0.351; instrumental activities of daily living: ρ = 0.333). Instead, vegetable consumption showed low correlation with health indicators. A mild increase in meat intake, mostly pastured poultry, is associated with better physical performance in the Sardinian LBZ elders, suggesting that a supply of protein may have been crucial to maintaining adequate functional capacity.
| S-EPMC8146058 | biostudies-literature
Project description:Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI34 scores were computed from 34 common health variables and compared between the two groups. The FI34 was better correlated than chronological age with mortality. The mean FI34 value of the OSLP was 31 % higher than that of the OLLP (P = 0.0034). The FI34 increased exponentially, at an instantaneous rate that accelerated 2.0 % annually in the OLLP (P = 0.024) and 2.7 % in the OSLP (P < < 0.0001) consequently yielding a 63 % larger accumulation in the latter group (P = 0.0002). The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, sib pairs were significantly correlated regarding FI34 scores, and heritability of the FI34 was estimated to be 0.39. Finally, hierarchical clustering suggests that the OLLP and OSLP differ in their aging patterns. Variation in the FI34 is, in part, due to genetic variation; thus, the FI34 can be a phenotypic measure suitable for genetic analyses of healthy aging.
| S-EPMC3776103 | biostudies-literature