Longevity & Aging

Intronic variant in complement factor I associated with age-related macular degeneration risk through complement dysregulation

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

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 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

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

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

Ultra-rare APOE3 missense variant that dramatically reduces HSPG binding and tau propagation, conferring near-complete resistance to Alzheimer's disease in the homozygous state and a modest protective delay in heterozygotes

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

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

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

Rare missense variant in fibronectin 1 that reduces Alzheimer's disease risk in APOE ε4 carriers by limiting pathological fibronectin accumulation at the blood-brain barrier

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

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

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

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

Intronic GPNMB variant that acts as a brain eQTL; the A allele increases GPNMB expression in cortex and putamen, conferring genome-wide significant Parkinson's disease risk and implicating lysosomal integrity and senescent cell biology in neurological aging

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 FOXO3 tag SNP whose A allele associates with higher circulating IGF-1 at genome-wide significance; the G allele may favor lower IGF-1 and stronger FOXO3 pathway activation

Synonymous IGF1R variant associated with lower circulating IGF-1 levels and enrichment in long-lived populations

Synonymous CFH variant in complete LD with rs1410996 that tags the complement-dysregulation haplotype driving age-related macular degeneration; G allele (risk) impairs complement regulation on retinal surfaces

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

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)

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

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

Promoter variant at -487 in HTRA1 that elevates HTRA1 serine protease expression, disrupting TGF-β signaling and extracellular matrix remodeling in the retina and increasing risk of neovascular (wet) age-related macular degeneration

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

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

Functional promoter variant that increases iNOS transcriptional activity up to 5-fold, raising nitric oxide output and nitrosative stress; forms a risk haplotype with the gain-of-function coding variant rs2297518

Longevity-associated intronic enhancer variant

Regulatory variant in the ANRIL long non-coding RNA at the 9p21.3 locus that influences CDKN2B expression and functional aging; the G allele is protective against physical impairment with age

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

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

Promoter-region variant in SIRT1 affecting deacetylase expression; T allele elevates SIRT1 levels and is associated with better cognition but increased metabolic and cancer risk; C allele is the common protective form

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

Intronic TERT variant influencing telomere maintenance, associated with testicular and ovarian cancer risk, reduced platinum chemotherapy benefit in lung cancer, and a protective effect against paranoid schizophrenia

Intronic CFH variant that tags the AMD-risk haplotype; the C allele tracks complement dysregulation and elevated AMD susceptibility, while the T allele is protective

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

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

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

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

Intronic ATXN2 variant associated with primary open-angle glaucoma risk; T allele elevates odds of glaucoma by ~17% per copy

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

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

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

Intronic FKBP5 variant in the stress-aging haplotype block — T allele carriers show impaired HPA axis negative feedback