FOXO3: The Longevity Gene That Helps Humans Live to 100 and Beyond

Recent research has solidified the role of the FOXO3 gene as a key player in human longevity. This gene, which has been dubbed the “longevity gene,” appears to have a significant impact on life expectancy across diverse populations worldwide.

A team of researchers at the Christian-Albrechts-University in Kiel, Germany, conducted a study comparing DNA samples from 388 German centenarians with those from 731 younger individuals. Their findings, published in the Proceedings of the National Academy of Sciences (PNAS), confirmed previous observations that certain variations in the FOXO3 gene are more prevalent in people who live to 100 years and beyond.

This German study built upon earlier research led by Bradley J. Willcox, which found a higher frequency of FOXO3 genetic variations in long-lived Americans of Japanese origin. The replication of these results in a European population strengthens the evidence for FOXO3’s global importance in longevity.

Key findings from recent studies include:

1. Five FOXO3 single nucleotide polymorphisms (SNPs) show significant correlation with longevity across multiple independent studies.
2. The longevity-associated FOXO3 variant confers protection against telomere shortening in older adults, potentially contributing to extended lifespan.
3. FOXO3 genetic variations are associated with higher FOXO3 mRNA expression in various human tissues, mirroring observations in long-lived model organisms.
4. The longevity effect of FOXO3 variants appears to be stronger in centenarians compared to nonagenarians, suggesting its impact increases with extreme age.
5. FOXO3 plays a crucial role in regulating various cellular processes, including stress resistance, metabolism, and stem cell maintenance, which may contribute to its longevity-promoting effects.

Dr. Friederike Flachsbart, the lead author of the German study, noted the challenge of recruiting centenarians for such research. However, access to large biobanks like Schleswig Holstein’s Popgen, which contains over 660 DNA samples from centenarians, has facilitated these groundbreaking studies.

As research continues, scientists are exploring the potential mechanisms by which FOXO3 influences longevity. Current evidence suggests that the gene may act through multiple pathways, including protection against oxidative stress, regulation of cellular homeostasis, and modulation of inflammatory responses.

The consistent association of FOXO3 with longevity across diverse populations makes it a promising target for future interventions aimed at promoting healthy aging and extending human lifespan. As our understanding of this remarkable gene grows, it may pave the way for new strategies to enhance longevity and improve quality of life in our later years.

Why is the Gene/Protein called FOXO3?

FOXO3 got its name from being part of a group of proteins called the Forkhead box (FOX) family, which are important for controlling how genes work. The “O” in FOXO3 stands for a specific subgroup of these proteins, while the “3” means it’s the third one identified in that subgroup. The name “Forkhead” comes from a special part of the protein’s structure that looks like a little bird’s head with wings, which was first discovered in fruit flies.

The forkhead box family is characterized by a distinct DNA-binding domain called the forkhead domain, which was first identified in the Drosophila gene fork head. This domain’s structure resembles a butterfly or “winged helix,” giving rise to the “forkhead” nomenclature. FOXO3 was previously known by other names, including FKHRL1 (Forkhead in Rhabdomyosarcoma Like 1) and FOXO3A, before the current standardized naming convention for forkhead box proteins was established

FOXO3 refers to both a gene and the protein it encodes:

1. As a gene:
   FOXO3 (Forkhead Box O3) is the gene that contains the DNA sequence coding for the FOXO3 protein. It is located on chromosome 6 in humans.
2. As a protein:
   FOXO3 (also sometimes called FOXO3a) is the protein product of the FOXO3 gene. It functions as a transcription factor, meaning it can bind to DNA and regulate the expression of other genes.

Do Foxes Have this Gene? Why no 100 Year Old Foxes?

• FOXO genes, including FOXO3, are highly conserved across many animal species, including mammals like foxes, as well as insects and simpler organisms.
• The term “variants” refers to different versions or alleles of the FOXO3 gene that can exist within a species. In humans, certain variants (specific genetic sequences) of FOXO3 have been associated with longevity.
• We don’t see 100-year-old foxes primarily due to their shorter natural lifespan, which is influenced by many factors beyond just genetics, including body size, metabolism, environmental pressures, and evolutionary adaptations.
• The specific FOXO3 variants associated with human longevity are unique to humans. Other species, including foxes, have their own FOXO3 genes, but not necessarily the same variants that contribute to extreme longevity in humans.
• Studies have shown that FOXO genes play a role in longevity across various species, from worms (C. elegans) to fruit flies (Drosophila) to mammals, but the specific mechanisms and genetic variants differ between species.
• In humans, several single nucleotide polymorphisms (SNPs) in the FOXO3 gene, such as rs2802292, rs2764264, and rs13217795, have been associated with increased lifespan and healthy aging across different populations.
• The role of FOXO3 in longevity is complex and involves interactions with various cellular processes, including stress resistance, metabolism, and DNA repair.

Checking Your Variants of FOXO3

You can learn what SNPs you have by getting your genes fully or partially sequenced using a company like 23andMe.com. Once they have processed your sample, you can lookup numbers like “rs2802292”, “rs2764264”, and “rs13217795”, on part of their web page for your data (after logging in) to see if you have the variant. While there are potential trade-offs for privacy, you can learn much about yourself by paying for this service. Once you do it, you can look up new SNPs that become relevant years later as well. So far I have not regretted having spent the money to do this years ago.

Implications for Human Species Survival

The study of longevity genes like FOXO3 has profound implications for the long-term survival of the human species. As we face global challenges such as climate change, resource depletion, and potential pandemics, extending human healthspan and lifespan could provide crucial advantages. A deeper understanding of the genetic factors contributing to longevity could lead to interventions that enhance our resilience to age-related diseases and environmental stressors. This increased resilience could buy humanity valuable time to develop solutions to existential threats and adapt to changing planetary conditions. Moreover, individuals with extended healthspans could contribute their knowledge and experience to society for longer periods, potentially accelerating scientific and technological progress. By unlocking the secrets of genes like FOXO3, we may not only improve individual quality of life but also enhance our collective ability to navigate future challenges, ultimately contributing to the long-term survival and thriving of our species.

Read More
^{[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403515/
[2] https://www.nature.com/articles/s41514-024-00142-8
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295567/
[4] https://www.nature.com/articles/s41467-017-02183-y
[5] https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.778674/full
[6] https://academic.oup.com/biomedgerontology/article/77/8/1542/6320034
[7] https://www.sciencedirect.com/science/article/pii/S1568163722000630
[8] https://www.sci.news/paleontology/article00229.html}