The relationship between normal genetic variations and consequence differences in life expectancy is enormously complex. Countless genetic variations have tiny, contingent, interacting effects on health and late life resilience to the damage of aging. Correlations found in epidemiological studies are rarely replicated between study populations. FOXO3 is one of the very small number of genes for which effects on longevity are found in multiple species and human populations. These effects are not large: a modestly increased chance of living longer. It is also worth noting recent research that downgraded the expected size of effect for FOXO3 based on more rigorous assessment of data. Here, researchers discuss some of the low-level mechanisms that might explain this association.
Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs.
FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes.
Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.