How to increase FOXO3 activity? What if one has genetically defective FOXO3?

Astaxanthin as a Putative Geroprotector: Molecular Basis and Focus on Brain Aging

recent years, the scientific interest in natural compounds with geroprotective activities has grown exponentially. Among the various naturally derived molecules, astaxanthin (ASX) represents a highly promising candidate geroprotector. By virtue of the central polyene chain, ASX acts as a scavenger of free radicals in the internal membrane layer and simultaneously controls oxidation on the membrane surface. Moreover, several studies have highlighted ASX’s ability to modulate numerous biological mechanisms at the cellular level, including the modulation of transcription factors and genes directly linked to longevity-related pathways. One of the main relevant evolutionarily-conserved transcription factors modulated by astaxanthin is the forkhead box O3 gene (FOXO3), which has been recognized as a critical controller of cell fate and function. Moreover, FOXO3 is one of only two genes shown to robustly affect human longevity. Due to its tropism in the brain, ASX has recently been studied as a putative neuroprotective molecule capable of delaying or preventing brain aging in different experimental models of brain damage or neurodegenerative diseases. Astaxanthin has been observed to slow down brain aging by increasing brain-derived neurotrophic factor (BDNF) levels in the brain, attenuating oxidative damage to lipids, protein, and DNA and protecting mitochondrial functions. Emerging data now suggest that ASX can modulate Nrf2, FOXO3, Sirt1, and Klotho proteins that are linked to longevity. Together, these mechanisms provide support for a role of ASX as a potential geroneuroprotector.

4 Likes

No wonder this got so many people excited around here. I’ll have to think about astaxanthin again

5 Likes

I think astaxanthin is probably the real deal. I just wish we knew the optimal human dose.

2 Likes

This is a decent article on things that can activate FOXO3.

Briefly Rapamycin, AMPK activators (exercise/metformin), caloric restriction without malnutrition, Quercetin,berberine, NAC, NAD, PQQ, Curcumin, ECGC … and a bunch more.

5 Likes

FOXO3 – High Impact (Protective Allele Advantage)

  • Variant: FOXO3 gene SNP rs2802292. The G allele of this SNP is the longevity-associated (protective) allele, while the A allele is less favorable. FOXO3 is a gene involved in insulin signaling and stress resistance, often dubbed a “longevity gene” from prior research.
  • PGS Contribution: FOXO3 variants contribute a positive weight to longevity PGS if the protective G allele is present. If the user carries the risk allele (A), their score would be slightly lower. The effect size of FOXO3 is notable (one of the larger ones in the score, though smaller than APOE’s).
  • Longevity Association: The FOXO3 G allele has been repeatedly linked to exceptional longevity in humans:
    • Many studies (across ethnic groups) have found that carriers of the G allele at rs2802292 have higher odds of reaching very old ages. This minor G allele strongly correlates with increased human longevity​

academic.oup.com

. For example, the G variant was significantly more frequent in centenarians compared to younger controls in multiple cohorts​

academic.oup.com

.

  • The effect of FOXO3 is robust but moderate – often conferring a ~1.2 to 1.3-fold higher likelihood of extreme old age per G allele, according to various cohort studies. It influences longevity by affecting pathways of stress resistance and metabolism (as observed in model organisms and human cells).