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Effect of Longevity Genetic Variants on the Molecular Aging Rate

ABSTRACT: Abstract We conducted a genome-wide association study of 1317 centenarians from the New England Centenarian Study and 2885 controls using >9M genetic variants. The most significantly associated variants were correlated to 4131 serum proteins in 224 study participants. The genetic and protein associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazy Jewish descent and a proteomic scan of approximately 1000 participants of the same study. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and underexpression of APOB in carriers of the APOE2 allele (p< 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2a/CDKN2B in chromosome 9). The analyses show that longevity variants correlate with proteome signatures that could be manipulated to discover healthy aging targets.

SUBMITTER: Sebastiani P

PROVIDER: S-EPMC7742392 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Effect of longevity genetic variants on the molecular aging rate.

Project description:We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

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Correction to: Effect of longevity genetic variants on the molecular aging rate.

Project description: Not available

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TOMM40 genetic variants associated with healthy aging and longevity: a systematic review.

Project description:IntroductionHealthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40, a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging.MethodsUsing the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging.ResultsTwenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity.DiscussionsOur systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.

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Joint influence of small-effect genetic variants on human longevity.

Project description:The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant. We show that this joint influence can be described by a relatively simple "genetic dose - phenotypic response" relationship.

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The Effect of Alzheimer's Disease-Associated Genetic Variants on Longevity.

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Renormalized basal metabolic rate describes the human aging process and longevity.

Project description:The question of why we age and finally die has been a central subject in the life, medical, and health sciences. Many aging theories have proposed biomarkers that are related to aging. However, they do not have sufficient power to predict the aging process and longevity. We here propose a new biomarker of human aging based on the mass-specific basal metabolic rate (msBMR). It is well known by the Harris-Benedict equation that the msBMR declines with age but varies among individual persons. We tried to renormalize the msBMR by primarily incorporating the body mass index into this equation. The renormalized msBMR (RmsBMR) which was derived in one cohort of American men (n = 25,425) was identified as one of the best biomarkers of aging, because it could well reproduce the observed respective American, Italian, and Japanese data on the mortality rate and survival curve. A recently observed plateau of the mortality rate in centenarians corresponded to the lowest value (threshold) of the RmsBMR, which stands for the final stage of human life. A universal decline of the RmsBMR with age was associated with the mitochondrial number decay, which was caused by a slight fluctuation of the dynamic fusion/fission system. This decay form was observed by the measurement in mice. Finally, the present approach explained the reason why the BMR in mammals is regulated by the empirical algometric scaling law.

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Genetic and epigenetic regulation of human aging and longevity.

Project description:Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during aging profoundly affect cellular function and stress resistance. Dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. Large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. As the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive "leak". There is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. Together, these phenomena contribute to aging.

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The role of genetic variants in human longevity.

Project description:Human longevity is a complex phenotype with a strong genetic predisposition. Increasing evidence has revealed the genetic antecedents of human longevity. This article aims to review the data of various case/control association studies that examine the difference in genetic polymorphisms between long-lived people and younger subjects across different human populations. There are more than 100 candidate genes potentially involved in human longevity; this article particularly focuses on genes of the insulin/IGF-1 pathway, FOXO3A, FOXO1A, lipoprotein metabolism (e.g., APOE and PON1), and cell-cycle regulators (e.g., TP53 and P21). Since the confirmed genetic components for human longevity are few to date, further precise assessment of the genetic contributions is required. Gaining a better understanding of the contribution of genetics to human longevity may assist in the design of improved treatment methods for age-related diseases, delay the aging process, and, ultimately, prolong the human lifespan.

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Genetic, Social, and Lifestyle Drivers of Healthy Aging and Longevity.

Project description:Purpose of review"Healthy aging" is the state of the aging process in which a person can maintain physical, social, mental, and spiritual wellness. This literature review presents an overview of recent studies that explore how biological, social, and environmental factors contribute to healthy aging.Recent findingsA number of genome-wide association studies have been conducted recently for traits related to healthy aging, such as frailty index, healthspan, muscle strength, and parental longevity, leading to the discovery of dozens of genetic variants associated with these traits. In parallel, associations between healthy aging measures and multiple non-biological environmental elements have been identified as key moderators of the aging process, indirectly influencing day-to-day homeostatic processes.SummaryIndividual variations in lifespan and healthspan are influenced by genetic factors, with a heritability of ~ 25% in developed countries. Non-genetic risk variance is explained in part by social, cultural, and lifestyle conditions. Altogether, these factors contribute to a multifaceted state of wellness over time, shaping individual risk to frailty and resilience during the aging process. Notably, "Blue Zone" populations, which are characterized by an abundance in healthy lifestyles across generations, share some commonalities regarding determinants of health.

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Project description:Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

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