FOXO3, longevity, and brain health

The Forkhead/winged helix box gene group O3 (FOXO3) protein is a transcription factor (controls RNA levels of genes) that regulates many important cellular functions that associate with longevity in many diverse species, from worms to humans.

Evidence is accumulating for an important role of FOXO3 in the prevention of age-related diseases, including cancer and neurodegenerative diseases, through the promotion of neuronal health, autophagy, and the downregulation of oxidative stress, among other mechanisms.

FOXO3 and human longevity and cognition

A meta-analysis of genome-wide association studies of about 10,000 people showed that people with a genetic variant in the FOXO3A gene were about 17% more likely to live past 90 years old than people without it. FOXO3A is one of the few genes that has consistently shown to have variants that relate to lifespan in humans.

A study of older adults in China showed that carriers of the longevity-associated variants of FOXO3 SNPs scored higher on an Alzheimer’s cognitive test than people without them. They also showed less longitudinal cognitive decline over 14 years of follow up.

Curious whether you have the FOXO3A longevity gene variants? If you’ve had your NeuroAge genetic resilience analyzed, you can check for FOXO3A in the longevity gene section.

Having greater levels of FOXO3A in humans is generally positive for treating or preventing disease, although more research is needed.

FOXO3 in mice

FOXO3’s effects on mouse lifespan and disease have less clear evidence. I did not find a lifespan study of mice that were engineered to have more FOXO3, which strikes me as odd given how long we have had the human evidence for longevity. Female mice with more FOXO3 were more fertile, but some studies showed negative effects on heart and brain volumes. There are lifespan studies of mice engineered to lack FOXO3 and they do not live shorter lives.

My conclusion from these studies is that mice may not be the best animals to study FOXO3 or that we may need more sophisticated approaches.

Humans also have a slightly different version of FOXO3 than mice and the human variants associated with longevity may not be working through affecting its levels. These variants instead may be working by changing the ratio of amounts of differently sized FOXO3 proteins (isoforms) in different tissues. This mechanism would be complex to model in mice.

How can you increase your FOXO3 levels?

Epigallocatechin gallate (EGCG), a phytochemical found in green tea, has been shown to activate FOXO3 in breast cancer cell lines. EGCG was also shown to increase rat FOXO3 levels and lifespan. Research in animal models, suggests EGCG may play a role in preventing age-related cognitive decline and improving memory.

EGCG may have additional health benefits in humans, including modest reductions in body weight, BMI, and abdominal fat, along with improvements in metabolic parameters like blood pressure and triglyceride levels.

Some companies are creating therapeutics aimed at FOXO3, including Refoxy, which is creating small molecule pills to activate it.

Conclusion

In summary, there is compelling evidence for human FOXO3A genetic variants in increasing lifespan and decreasing cognitive decline.

In mice, the results are much less clear. This may be due to challenges in modeling the human genetics in mice.

Regardless of whether you have the protective FOXO3 genetic variant, you may be able to increase your FOXO3 levels with the green tea extract, EGCG, or by drinking green tea. Stay tuned for FOXO3 pharmaceuticals that are in development by companies like Refoxy.