Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases.
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ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC8733402 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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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.
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Project description:Abstract The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression and inflammatory cytokine levels in men and women. In agreement with earlier work, the FOXO3 longevity variant conferred protection against telomere shortening of peripheral blood mononuclear cells from adults aged 55 and older. This was accompanied by higher levels of telomerase activity in carriers of the longevity-associated FOXO3 G-allele (P=0.015). FOXO3 mRNA expression increased slightly with age in both young (P=0.02) and old (P=0.08) G-allele carriers. Older female G-allele carriers displayed a modest decline in levels of pro-inflammatory cytokine IL-6 with age (P=0.07). In contrast, older male G-allele carriers displayed an age-dependent increase in levels of anti-inflammatory cytokine IL-10 with age (P=0.04). Thus, FOXO3 may act through several different pro-longevity mechanisms, which may differ by age and sex.
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Project description:The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression, and inflammatory cytokine levels in men and women. In agreement with earlier work, the FOXO3 longevity variant conferred protection against telomere shortening of peripheral blood mononuclear cells from adults aged 55 years and older. This was accompanied by higher levels of telomerase activity in mononuclear cells for carriers of the longevity-associated FOXO3 G-allele of SNP rs2802292 (P = 0.015). FOXO3 mRNA expression increased slightly with age in both young (P = 0.02) and old (P = 0.08) G-allele carriers. Older female G-allele carriers displayed a modest decline in levels of pro-inflammatory cytokine IL-6 with age (P = 0.07). In contrast, older male G-allele carriers displayed an age-dependent increase in levels of anti-inflammatory cytokine IL-10 with age (P = 0.04). Thus, FOXO3 may act through several different pro-longevity mechanisms, which may differ by age and sex.
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Project description:Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1? as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1? in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotype.
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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.
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Project description:Aging and aging-related diseases represent an increasing burden on modern society. Thus, drugs that retard the aging process are highly desirable. Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity and blocks somatic growth. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting AMP kinase or mTOR signaling or NAD metabolism. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used as a hormone therapy to extend lifespan. Liver, epididymal fat and gastrocnemius muscle RNA expression profiles were compared between C57Bl/6J ad libitum, fasted, and calorically restricted mice, as well as between FGF-21 transgenic and their wild-type C57Bl/6J controls.
2012-10-18 | E-GEOD-39313 | biostudies-arrayexpress
Project description:FOXO3 is generally recognized as a "master" gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.
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