rs2802292 — FOXO3

The Longevity Variant — FOXO3's Intronic Enhancer

FOXO3 encodes a transcription factor that sits at the crossroads of aging biology, coordinating cellular responses to stress, nutrient availability, and oxidative damage. Among the hundreds of genetic variants studied for longevity associations, rs2802292 stands alone: carriers of its protective G-allele have a 1.9-fold increased probability of living past 95 years of age compared to TT homozygotes , and the association has been replicated in all human populations tested worldwide—collectively 5,746 subjects over 90 years and 6,554 controls .

The initial 2008 study¹¹ The initial 2008 study
Willcox BJ et al. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA. 2008 established the association in American men of Japanese ancestry, finding GG homozygotes had 2.75-fold higher odds of becoming centenarians. The finding has since been confirmed in Germans, Italians, Danes, Chinese, and multiple other populations, making FOXO3 one of only two genes with consistent longevity associations across ancestries (the other being APOE).

The Mechanism

For years, the molecular basis of rs2802292's longevity effect remained mysterious. The variant sits in intron 2 of FOXO3, a massive 101,625 base pair noncoding region, far from any protein-coding sequence. In 2018, researchers finally cracked the puzzle²² In 2018, researchers finally cracked the puzzle
Grossi V et al. The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. Nucleic Acids Res. 2018: the G-allele creates a novel HSE binding site for heat shock factor 1 (HSF1), which induces FOXO3 expression in response to diverse stress stimuli . The T-allele lacks this binding site, resulting in lower FOXO3 expression when cells face oxidative stress, nutrient deprivation, or heat shock—precisely the conditions where FOXO3's protective functions matter most.

Think of it as a volume knob for cellular stress resistance.

The intronic G-allele correlates with increased expression of FOXO3 , giving cells higher baseline capacity to activate antioxidant defenses, DNA repair, autophagy, and apoptosis of damaged cells. This enhanced stress response appears to slow accumulation of cellular damage across decades, ultimately translating into extended healthspan and lifespan.

The Evidence

The evidence for rs2802292 is exceptionally strong. A 17-year prospective cohort study³³ A 17-year prospective cohort study
Willcox BJ et al. The FoxO3 gene and cause-specific mortality. Aging Cell. 2016 tracked 3,584 Japanese American men, 1,595 white Americans, and 1,056 Black Americans, finding

G-allele carriers had a combined 10% reduction in all-cause mortality (HR 0.90, 95% CI 0.84–0.95, P = 0.001) . The benefit was even stronger for coronary heart disease—

26% protection against CHD mortality over 17 years .

The mechanisms behind this protection are becoming clearer.

G-allele carriers show higher telomerase activity in peripheral blood mononuclear cells (P = 0.015) , which confers substantial protection against telomere shortening as a function of age . They also exhibit significantly lower blood levels of the inflammatory cytokine TNF-α compared to TT genotypes , and older female G-allele carriers display a modest decline in pro-inflammatory IL-6 levels with age (P = 0.07) .

A Southern Italian cohort study⁴⁴ A Southern Italian cohort study
Forte G et al. Exploring the relationship of rs2802292 with diabetes and NAFLD. Int J Mol Sci. 2024 found

TT genotype is a risk factor for developing type 2 diabetes (OR 2.14, 95% CI 1.01–4.53, P = 0.05) , while

G-carriers appear protected against diabetes (OR 0.45, 95% CI 0.25–0.81, P = 0.008) .

Practical Implications

What does this mean for your daily choices? Unlike many genetic variants with modest effects, FOXO3 influences pathways you can actively support. FOXO3 activity increases during caloric restriction, fasting, and exercise—all established longevity interventions. The G-allele amplifies FOXO3's response to these stressors, but even TT individuals benefit from lifestyle choices that activate FOXO3.

Focus on intermittent cellular stress: resistance exercise, high-intensity interval training, periodic fasting, and cold exposure all trigger FOXO3 activation. These hormetic stressors—challenges that are acutely uncomfortable but trigger adaptive responses—may be especially valuable for those without the longevity-associated G-allele.

The diabetes protection seen in G-carriers suggests metabolic health is central to this variant's effects. Maintaining insulin sensitivity through diet, exercise, and healthy body composition supports FOXO3 function regardless of genotype, though TT individuals may need to be more vigilant about metabolic markers.

Interactions

FOXO3 rs2802292 is part of a longevity haplotype that includes rs2764264⁵⁵ rs2764264
additional FOXO3 variant and rs13217795⁶⁶ rs13217795
third FOXO3 longevity marker. These variants are in high linkage disequilibrium, particularly in Asian populations, functioning together as a coordinated regulatory unit. The variants appear to interact with the FOXO3 promoter through chromatin looping, fine-tuning gene expression in response to cellular stress.

FOXO3 also sits at the center of a 7.3 Mb chromatin domain on chromosome 6q21, with long-range physical contacts to 46 neighboring genes through CTCF binding sites. This suggests FOXO3's longevity effects may partially operate through trans-regulatory effects on nearby genes involved in stress resistance and metabolism.

The interaction with APOE is particularly intriguing: both genes independently associate with longevity, and both influence cardiovascular disease risk and inflammatory responses. Individuals with protective variants in both genes may experience synergistic benefits, though this awaits formal testing in large cohorts.