Longevity Genes

APOE

Apolipoprotein E gene with three common alleles (ε2/ε3/ε4) that dramatically alter lifetime Alzheimer's risk and lipoprotein metabolism. The most consequential single common variant in longevity genetics.

CDKN1A (p21)

Encodes the p21 CDK inhibitor — a central enforcer of cellular senescence downstream of p53 and DNA-damage responses.

CETP

Cholesteryl ester transfer protein gene. Specific variants (particularly the I405V VV genotype) are over-represented in Ashkenazi centenarians and associate with lower CV risk and better cognitive aging.

FOXO3

Forkhead box O3 — the human ortholog of the C. elegans daf-16 longevity gene. Common variants in FOXO3 are among the most replicated genetic associations with extreme longevity across populations.

IGF1R

Insulin-like growth factor 1 receptor. Loss-of-function variants are over-represented in centenarian cohorts (especially Ashkenazi) — direct human evidence for the conserved insulin/IGF-1 lifespan-extension principle.

Klotho KL-VS Variant

A common Klotho haplotype (KL-VS) carried heterozygously by ~20–25% of Europeans. Associated with higher circulating Klotho, longer life expectancy, and modestly better cognition.

LPA Gene

Encodes apolipoprotein(a), the unique component of Lp(a) particles. LPA variants explain ~90% of inter-individual Lp(a) variation and confer lifelong cardiovascular risk modification.

MTHFR

Methylenetetrahydrofolate reductase. Two common variants (C677T, A1298C) modestly affect folate metabolism and homocysteine. Heavily over-marketed in functional medicine; effects on hard outcomes are smaller than often claimed.

PCSK9

Protease that degrades hepatic LDL receptors — loss-of-function variants confer lifelong low LDL and dramatically reduced cardiovascular risk; the target of PCSK9-inhibitor drugs.

PRKAG2

Encodes the γ2 subunit of AMP-activated protein kinase (AMPK) — gain-of-function mutations cause AMPK hyperactivation with striking metabolic and cardiac phenotypes.

SIRT6

Nuclear sirtuin maintaining telomere integrity, repressing LINE-1 retrotransposons, and supporting genome stability. SIRT6 overexpression extends mouse male lifespan; loss-of-function causes progeroid phenotype.

SOD2

Mitochondrial manganese superoxide dismutase — the primary defense against superoxide produced by oxidative phosphorylation. A common variant (V16A) affects mitochondrial import efficiency and modestly modulates aging-related disease risk.

TERT

Telomerase reverse transcriptase. Loss-of-function variants cause severe telomere-biology disorders with premature aging. Hyperactive variants drive cancer. The tightest known longevity-cancer trade-off.

TP53 (p53)

Guardian of the genome — encodes the p53 tumour suppressor, a master regulator of DNA-damage response, senescence, and apoptosis with complex longevity-cancer trade-offs.