Longevity & Aging

Longevity-associated intronic enhancer variant with 1.9-fold increased probability of reaching age 95

Longevity-associated variant exhibiting overdominance where heterozygotes show enhanced cognition and lifespan while homozygotes have reduced survival

Common intron 2 variant in the telomerase gene that influences telomere length, with the C allele associated with longer telomeres and increased cancer risk, while the A allele links to shorter telomeres and higher risk of degenerative diseases

Regulatory variant near the telomerase RNA gene associated with shorter telomeres and accelerated cellular aging

Intronic variant in SIRT1 affecting NAD-dependent deacetylase expression and oxidative stress protection

Promoter variant that reduces mTOR expression; the G allele lowers mTOR transcriptional activity and is associated with decreased cancer risk across multiple tumor types

Promoter variant reducing NRF2 transcriptional activity by >50%, impairing the master antioxidant response that controls glutathione synthesis, phase II detoxification, and cytoprotective gene expression

p53 codon 72 polymorphism producing two functionally distinct proteins — Arg72 with stronger apoptotic activity, Pro72 favoring cell cycle arrest and DNA repair — with population data associating Pro/Pro with ~3 years longer median lifespan

Synonymous IGF1R variant associated with lower circulating IGF-1 levels and enrichment in long-lived populations — affects mRNA splicing despite preserving the amino acid sequence

Intronic eQTL in SIRT6 where the rare A allele upregulates SIRT6 expression across 18 tissue types and is enriched in Ashkenazi Jewish centenarians, linking higher SIRT6 activity to improved genomic stability and longevity

Intronic regulatory variant near the SIRT3 VNTR enhancer — the A allele increases SIRT3 expression and is linked to longevity in women

Promoter variant that reduces APOC3 expression, associated with lower triglycerides, favorable lipoprotein profiles, and enrichment in centenarians

Promoter variant at position -866 of UCP2 that controls mitochondrial uncoupling protein expression; the T allele (A in coding-strand notation) increases UCP2 transcription, lowering ROS production and reducing insulin resistance, while C-allele homozygotes have lower UCP2 activity and carry higher oxidative-stress burden

Missense variant that reduces CETP enzyme activity, raising HDL-C and enlarging lipoprotein particles; the Val/Val (GG) genotype is enriched in Ashkenazi Jewish centenarians and associated with slower cognitive decline

Master mitochondrial biogenesis regulator — Ser482 variant reduces PGC-1alpha transcriptional activity, impairing mitochondrial production, aerobic capacity, and metabolic adaptation

Missense variant in the ATM DNA-damage kinase associated with increased radiation sensitivity and mildly altered genomic stability signaling

Missense variant in the PARP1 catalytic domain that reduces enzymatic activity by ~40%, impairing DNA single-strand break repair and altering NAD+ consumption dynamics

Missense variant in the XPD helicase that reduces nucleotide excision repair capacity, increasing susceptibility to DNA damage from UV, tobacco smoke, and environmental carcinogens

Strongest GWAS signal for coronary artery disease; risk C allele accelerates vascular senescence by dysregulating ANRIL-mediated repression of the p16/p15 cell-cycle-inhibitor cluster at 9p21.3

Second independent FOXO3 longevity signal tagging a distinct intronic haplotype block with centenarian enrichment across Caucasian populations

Intronic FOXO3 variant that disrupts an NKX3 transcription factor binding site; the longevity-associated C allele confers protection in male centenarians independent of rs2802292

3'UTR variant that increases glucocorticoid-resistant GRβ isoform expression, blunting cortisol signaling and HPA axis negative feedback

Intronic IL6 enhancer variant that regulates the anti-inflammatory gene GPNMB — the G allele lowers IL-6 signalling but is less common in long-lived individuals

Intronic AKT1 variant near a conserved exon-intron boundary; the G allele is associated with elevated AKT phosphorylation activity and reduced probability of exceptional longevity in centenarian studies

Missense IRS2 variant where Asp/Asp homozygotes are twice as likely to reach extreme old age — mediates longevity via reduced insulin/IGF-1 signaling, but its protective effect reverses sharply with obesity

Regulatory variant at the TERC locus associated with shorter telomeres and accelerated cellular aging, operating independently of — but overlapping with — the nearby rs12696304 signal

Intronic variant near the ATM gene affecting metformin's activation of AMPK; the C allele confers improved glycemic response to metformin and links the DNA damage response pathway to longevity-relevant AMPK-mTOR signaling

Intronic variant in the master mitochondrial biogenesis transcription factor — the G allele is associated with lower slow-twitch muscle fiber proportion and reduced aerobic training adaptability

Functionally validated FOXO3 intronic variant that creates an SRF binding site on the longevity allele, driving IGF-1-reversible enhancer activity and higher FOXO3 expression

Functional FOXO3 intronic variant with allele-specific CTCF binding and IGF-1-reversible enhancer activity; T allele raises longevity odds ~22% across European cohorts

Intronic NR3C1 variant with TT genotype enriched in Polish centenarians; C allele associated with elevated cholesterol in the oldest-old

Intronic NR3C1 variant associated with longevity in Polish nonagenarians and centenarians; the C minor allele correlates with better survival rates and altered cholesterol metabolism

Intronic NRF1 variant associated with baseline differences in ventilatory threshold and running economy — the T allele predicts lower aerobic efficiency independent of training, with a stronger signal (p=0.004) than the companion rs6949152 variant (p=0.047)

Original 2008 Willcox longevity discovery variant; C allele tags the protective haplotype and shifts FOXO3 expression toward full-length isoforms away from truncated non-functional forms

Intronic FOXO3 longevity variant; C allele (minor in East Asians) associated with ~20% lower mortality risk and better cognitive aging in Chinese cohorts; eQTL affecting FOXO3 brain expression

Intronic FOXO3 variant whose minor G allele creates an MZF1 transcription factor binding site that limits monocyte inflammation via a TGFβ1 pathway, dampening pro-inflammatory cytokines and conferring mortality resilience

NR3C1 promoter variant reducing glucocorticoid receptor transcription; G allele (coding-strand C) associated with blunted GR expression and 4.7-fold increased risk of metabolic syndrome when homozygous

Intronic FKBP5 variant in the stress-aging haplotype block — T allele carriers show impaired HPA axis negative feedback, accelerated epigenetic aging, and elevated NF-κB-driven inflammation

Near-TERC regulatory variant where the minor T allele associates with shorter telomeres and accelerated cellular aging, while the major C allele produces longer telomeres but paradoxically increases risk for certain cancers

Intronic variant in the CST complex component STN1/OBFC1 that influences telomere length; the C allele drives longer telomeres and elevated cancer risk while the A allele predisposes to shorter telomeres and accelerated cellular aging

Regulatory variant near the NAF1 telomerase assembly gene associated with shorter telomeres, higher cardiovascular risk, and lower cancer risk

Intronic IL6 variant tagging a low-producing haplotype — the T allele is protective against inflammaging, diabetic nephropathy, and severe acute inflammation

Near-gene upstream variant in IL6 associated with hepatocellular carcinoma risk through altered interleukin-6 regulation — an independent inflammaging signal

3'UTR variant that alters miR-150 binding affinity; the C allele increases microRNA-mediated suppression of MTOR expression and is associated with improved cancer prognosis and reduced mTOR pathway activity

Missense variant in the TFAM mitochondrial targeting sequence — the C allele (Thr12) is associated with longevity and reduced Alzheimer's disease risk via preserved mitochondrial DNA maintenance

Intronic NR3C1 variant with CC genotype enriched in Polish centenarians; GG genotype associated with elevated total and LDL cholesterol in the oldest-old