FOXO3

Among the best supported candidates are P53-MDM2, P16-INK4A-BMI1, SIRT1-DBC1, Telomerase-TRF1, PTN-PI3K-AK-TMTOR, and NRF2-KEAP1.

Other candidate axes involve FOXO3, AMPK, Clotho, PGC1-alpha, Feb, and additional regulators.

The evidence varies substantially across these pathways, and many proposed restoration strategies remain preclinical or conceptual.

The review also introduces a conceptual aging axis profile that would combine proteomic, transcriptomic, epigenomic, senescence, and telomere measurements to characterize individual pathways as functional, declining, or dysfunctional.

Proposed approaches include modulating endogenous negative regulators and, in some cases, AV-based gene delivery.

For chronically overactivated tumor suppressor pathways, such as p53 or p16, the theoretical objective would be to reduce persistent signaling without eliminating their cancer protective functions.

For protective pathways that decline with age, such as SIRT1, FOXO3, NRF2 or Clotho, restoring physiological activity is proposed for future investigation.

These strategies remain theoretical or preclinical and carry important safety concerns.

Researchers have found links to variants in genes involved in cholesterol handling, insulin signaling, and cell repair.

One well-known example is a variant near FOXO3, which appears more often in long-lived populations.

Other studies point to changes that keep harmful cholesterol patterns in check, which can protect blood vessels for decades.

Genetics does not guarantee a long life, and it does not excuse harmful habits.