Correction to: Effect of longevity genetic variants on the molecular aging rate.
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ABSTRACT:
SUBMITTER: Gurinovich A
PROVIDER: S-EPMC8492867 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
Correction to: Effect of longevity genetic variants on the molecular aging rate.
Gurinovich Anastasia A Song Zeyuan Z Zhang William W Federico Anthony A Monti Stefano S Andersen Stacy L SL Jennings Lori L LL Glass David J DJ Barzilai Nir N Millman Sofiya S Perls Thomas T TT Sebastiani Paola P
GeroScience 20210801 4
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Project description: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.
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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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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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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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Project description:Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer's disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.
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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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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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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:Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer's disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00 × 10-5 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00 × 10-5, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 × 10-11) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 × 10-10); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 × 10-7); ERBB4 signal transduction (p = 2.69 × 10-6); the immune system, including IL-3 and IL-13 (p = 3.83 × 10-6); programmed cell death (p = 4.36 × 10-6); and platelet degranulation (p = 8.16 × 10-6), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 × 10-8), plasma lipoprotein assembly, remodeling and clearance (p < 4.02 × 10-6), and the metabolism of fat-soluble vitamins (p = 1.96 × 10-5). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.
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