Analysis of Cell and Molecular Phenotypes of a Highly Replicated Longevity-Associated FOXO3 Variant in Older Adults
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ABSTRACT:
SUBMITTER: Chen R
PROVIDER: S-EPMC8680384 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human longevity is a polygenic and multifactorial trait. Pathways related to lifespan are complex and involve molecular, cellular, and environmental processes. In this analytical observational study, we evaluated the relationship between environment factors, oxidative stress status, DNA integrity level, and the association of FOXO3 (rs2802292), SOD2 (rs4880), APOE (rs429358 and rs7412), and SIRT1 (rs2273773) polymorphisms with longevity in oldest-old individuals from southeastern Brazil. We found an association between the FOXO3 GG genotype and gender. While lifestyle, anthropometric, and biochemical characteristics showed significant results, DNA damage and oxidative stress were not related to lifespan. We found that long-lived individuals with FOXO3 GT genotype had low levels of triglycerides. This study is the first to demonstrate that FOXO3 could be a candidate gene for longevity in the Brazilian population. These results are important in terms of provisions of health care for age-related diseases and lifespan, and provide insight for further research on epigenetic, gene regulation, and expression in oldest-old individuals.
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Project description:Abstract Telomere attrition in proliferative tissues is a hallmark feature of human aging. To date, identification of genetic influence on the rate of telomere attrition is poorly understood. The two genes with the most robust effect on human longevity are FOXO3 and APOE. Notably, we discovered a genetic variant of the FOXO3 gene that is strongly associated with human longevity. This observation has now been reproduced in independent studies of over a dozen different populations around the world. In the present study, we sought to assess the effect of the longevity associated variant of FOXO3 (rs2802292 - G allele) as well as variants of APOE on telomerase activity and the rate of telomere attrition during aging. The preliminary results from a cohort of Okinawan Japanese (N=120) ranging in age from 25 – 90 years, indicates no substantial effect of the variants for either FOXO3 or APOE on telomerase levels in peripheral blood leukocyte (PBL) samples. Analysis of the rate of telomere attrition during aging as a function of the different variants of APOE also revealed no significant effect. In contrast, carriers of 1 or 2 copies of the rare longevity-associated G allele of FOXO3 showed markedly reduced rates of telomere loss in PBL during aging, as compared to carriers of the more common variant of FOXO3 (TT). Interestingly, no loss of telomere length was observed as a function of age for G allele carriers. These results mark the first report on genetic influence on slowing the rate of telomere attrition in humans.
| S-EPMC6242152 | biostudies-literature
Project description:Next-generation DNA sequencing has ushered in a new era of genotype-phenotype comparisons that have the potential to elucidate the genetic nature of complex traits. Since such methods rely on short sequence reads and since the human genome is composed largely of repetitive DNA elements larger than these read lengths many results cannot be mapped and are discarded, thus eliminating a large portion of the genome from analysis. Discerning associations in complex traits, such as longevity, will require either longer read lengths or methods to address these sequence complexities. Whole genome analysis, such as Genome Wide Association Studies (GWAS), also suffers from the repetitive nature of the human genome, as there exist many gaps in the availability of useable genetic markers, often in interesting regulatory regions. Methods are described here whereby some of these problems have been addressed by targeted DNA sequencing, full exploitation of available public databases, and a careful evaluation of genomic features where we use the FOXO3 gene as an example to identify functional variations and how they may relate to longevity.
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Project description:Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target.
| S-EPMC7749196 | biostudies-literature
Project description:FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis-regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of FOXO3 toward neighboring genes. FOXO3 resides at the center of this early-replicating and highly conserved syntenic region of chromosome 6. Thus, in addition to its role as a transcription factor regulating gene expression genomewide, FOXO3 may function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation via topologically associated domains. We believe that the FOXO3 'interactome' on chromosome 6 is a chromatin domain that defines an aging hub. A more thorough understanding of the functions of these neighboring genes may help elucidate the mechanisms through which FOXO3 variants promote longevity and healthy aging.
| S-EPMC5595686 | biostudies-literature
Project description: Not available
| S-EPMC10737034 | biostudies-literature
Project description:Abstract Telomere attrition in proliferative tissues is a hallmark feature of human aging. To date, the genetic influence on the rate of telomere attrition is poorly understood. Previously we discovered a variant of the FOXO3 gene that is strongly associated with human longevity, an observation that has been now reproduced in over a dozen independent studies. In the present study, we sought to assess the effect of the longevity associated variant of FOXO3 (rs2802292 - G allele) on the rate of telomere attrition during aging. The results from a cohort of Okinawan-Japanese (N=121), ranging in age from 25 – 94 years, demonstrates carriers of 1 or 2 copies of the longevity-associated G allele of FOXO3 showed markedly reduced rates of telomere loss in peripheral blood leucocytes as compared to carriers of the more common FOXO3 variant (TT – common genotype, m= -33bp/year, P=0.008). Interestingly, telomere shortening was not observed as a function of age for G allele carriers (m= -2bp/year, P>0.1). In an independent study of women (N=6,565) from the Nurses’ Health Study cohort, ranging in age from 40 to 70 years, a similar observation was found. Notably, carriers of the TT or GT FOXO3 genotype showed a significant decline in telomere length with age (m= -15.5 bp/year, P0.1). These results mark the first validated longevity gene variant showing an association with negligible loss of telomere length with age in humans.
| S-EPMC6845095 | biostudies-literature
Project description:BackgroundOptimism has been linked to better physical health across various outcomes, including greater longevity. However, most evidence is from Western populations, leaving it unclear whether these relationships may generalize to other cultural backgrounds. Using secondary data analysis, we evaluated the associations of optimism among older Japanese adults.MethodsData were from a nationwide cohort study of Japanese older adults aged ≥65 years (Japan Gerontological Evaluation Study; n = 10,472). In 2010, optimism and relevant covariates (i.e., sociodemographic factors, physical health conditions, depressive symptoms, and health behaviors) were self-reported. Optimism was measured using the Japanese version of the Life Orientation Test-Revised (LOT-R). Lifespan was determined using mortality information from the public long-term care insurance database through 2017 (7-year follow-up). Accelerated failure time models examined optimism (quintiles or standardized continuous scores) in relation to percent differences in lifespan. Potential effect modification by gender, income, and education was also investigated.ResultsOverall, 733 individuals (7%) died during the follow-up period. Neither continuous nor categorical levels of optimism were associated with lifespan after progressive adjustment for covariates (e.g., in fully-adjusted models: percent differences in lifespan per 1-SD increase in continuous optimism scores= -1.2%, 95%CI: -3.4, 1.1 higher versus lower optimism quintiles= -4.1%, 95%CI: -11.2, 3.6). The association between optimism and lifespan was null across all sociodemographic strata as well.ConclusionContrary to the existing evidence from Western populations, optimism was unrelated to longevity among Japanese older adults. The association between optimism, as evaluated by the LOT-R, and longevity may differ across cultural contexts.
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Project description:Background: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) has hindered diagnosis, management, and treatment development. This study clustered adult SLE patients through comprehensive molecular phenotyping to improve distinctions with prognostic and therapeutic relevance. Methods: Plasma, serum, and RNA were collected from 198 adult SLE patients. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray gene-expression data. Plasma soluble mediators (n=23) and autoantibodies (n=13) were assessed by multiplex bead-based assays and ELISAs. Phenotypic patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators. Findings: SLEDAI scores correlated strongly with interferon module scores, more modestly with plasma cell and select cell cycle modules, and with circulating IFNα, IL21, IL1α, IL17A, IP10, and MIG levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. The other clusters differed in monocyte, neutrophil, plasmablast, B cell, and T cell modules. Clusters 1 and 4 had higher SLEDAI scores, and more frequent anti-dsDNA, low complement, and renal activity. These features were also prominent in Cluster 3, which lacked the interferon and inflammation signatures. Arthritis and rashes were common in all clusters. Interpretation: Molecular profiles can distinguish SLE subsets. Prospective longitudinal studies of these profiles may help to improve prognostic evaluation, clinical trial design, and precision medicine approaches.
2020-03-16 | GSE138458 | GEO
Project description:S. cerevisiae WT vs snf2 KO mutant RNA-seq data with 7 technical and 48 biological replicates (336 total) of each condition
| PRJEB5348 | ENA