FOXO Genes and Human Longevity

FOXO3A is one of the very few genes shown to have an association with human longevity in more than one study population, though this is neither a sizable nor reliable effect. We all age for the same underlying reasons, and on a schedule that should by rights be held as remarkable for its comparative lack of variation, rather than for the degree of variation we do observe. The scope of that natural variation in the processes of aging is a matter of thousands of individually tiny contributions from single genes, and most of that in the late stages of life, at the point where damaged systems are failing and flailing.

Those contributions are heavily dependent on one another, and vary enormously from individual to individual, from region to region, from lifestyle to lifestyle. That is why investigation of the genetics of long-lived individuals is not a field that will produce sizable gains in human longevity. It just isn't the right place to find large improvements in human health, or ways to turn back aging rather than slightly reduce the pace at which it progresses. Nonetheless, considerably more effort has been put into this sort of genetic investigation than is put into approaches that are actually relevant to the development of actual, working rejuvenation therapies, as is illustrated by the overly enthusiastic paper on FOXO genes linked here.

Specific mechanisms involved in cellular processes that cause aging are a different story, however. FOXO4 has a role in maintaining the harmful state of cellular senescence, for example, and sabotaging that specific mechanism has been shown to selectively push senescent cells into self-destruction with little in the way of side-effects. All such senolytic therapies have the potential to produce sizable and reliable benefit. The point is that we shouldn't be looking to natural variations between individuals as the place to find potential paths to treat aging. We should be looking to the causes of aging, and where they can be turned back most effectively.

Several pathologies such as neurodegeneration and cancer are associated with aging, which is affected by many genetic and environmental factors. Healthy aging conceives human longevity, possibly due to carrying the defensive genes. For instance, FOXO (forkhead box O) genes determine human longevity. FOXO transcription factors are involved in the regulation of longevity phenomenon via insulin and insulin-like growth factor signaling. Only one FOXO gene (FOXO DAF-16) exists in invertebrates, while four FOXO genes, that is, FOXO1, FOXO3, FOXO4, and FOXO6 are found in mammals. These four transcription factors are involved in multiple cellular pathways, which regulate growth, stress resistance, metabolism, cellular differentiation, and apoptosis in mammals.

FOXOs are mainly involved in the regulation of metabolism, regulation of reactive species, and regulation of cell cycle arrest and apoptosis. FOXO1 regulates adipogenesis, gluconeogenesis, and glycogenolysis. Mechanistically, the unphosphorylated FOXO1 binds to the insulin response sequence present in the promoter region of G6P (glucose-6 phosphatase) in the nucleus. It leads to the accelerated transcription resulting in the enhanced production of glucose in the liver. Adipogenesis is negatively regulated by FOXO1 through its binding to the promoter region of PPARG (peroxisome proliferator-activated receptor gamma) and inhibiting its transcription. Moreover, FOXO1 functions as an association between transcription and insulin-mediated metabolic control; thus, FOXO1 is a promising genetic target to manage type 2 diabetes.

FOXO3 probably induces apoptosis either upregulating the genes needed for cell death or downregulating the anti-apoptotic factors. In addition, FOXO3 has been found to regulate the Notch signaling pathway during the regeneration of muscle stem cells. Moreover, antioxidants are thought to be upregulated by FOXO3 to protect human health from oxidative stress. Additionally, FOXO3 is documented to suppress tumour growth. Thus, tumour development may occur if FOXO3 is deregulated. Most importantly, FOXO3 are described to play a role in long-term living.

FOXO4 is involved in the regulation of various pathways associated to apoptosis, longevity, cell cycle, oxidative stress, and insulin signaling. FOXO4 is associated with longevity through the insulin and insulin-like growth factor signaling pathway. Finally, mutation-triggered Akt phosphorylation results in the inactivated FOXO4. It deregulates the cell cycle and activates kinase inhibitors involved in the cell cycle. It leads to the prevention of tumour progress into the G1 phase of cell division.

Numerous strategies for future research can be predicted. For instance, the triggering of FOXO-mediated processes in the tissues with metabolically different features can be valuable to explore the mechanism of FOXO-mediated longevity. In addition, the human FOXO sequence variations and their effect on the resulting proteins should be studied, the possible findings can also reveal the underlying mechanisms of FOXO-induced healthy aging. The delay in age-related pathologies including cancer and neurodegenerative diseases and living long life depends on the control of morbidity. It is therefore an exciting area of study to investigate potential antiaging compounds; however, their testing in clinical setup would need biomarkers to assess aging rate. Owing to the potential effect of FOXOs on health issues, the future therapies could be based on the FOXOs.



It is curious that there exist human phenotypes with greatly varying physical characteristics but not greatly varying longevities.

Posted by: JohnD at September 29th, 2017 12:46 PM

Both FOXO3A and FOXO4 have apoptotic pathways, so presumably they are active in getting rid of senescence and mutated cells in that way already, in addition to actively encouraging longevity by diverse other pathways cited above. FOXO3A has been much more studied than FOXO4 and there are more than 12 SNP's that have been shown to confer longevity benefits from researchers around the World. The second oldest man died in 2011 at the age of 114; since then one man lived to age 115, and a Japanese man lived to just over 117 and is the oldest verified man on record. A Harvard study of about 25 Gene SNP's thought by the authors to be representative longevity SNP's compared his SNP profile to a 114 year old woman to see what differences there might be. They used 5 SNP's from FOXO3A among the 25, and found that the man was homozygous for the longevity alleles of all 5 FOXO3A SNP's, while the women had none of these longevity alleles. Some other studies have found that FOXO1A may be more important for longevity in women. The man may have been homozygous for many other longevity SNP's of FOXO3A, but only 5 were used in the study. I had my DNA tested and found that I am homozygous for the longevity alleles of at
least 12 FOXO3A SNP's, and thus hope to live to 120. I have 6 centenarians in my family tree, with the oldest dying at 106, so maybe that will help me in my goal as well. With CRISPR technology, many without the longevity alleles may be able to have them transplanted to their genome, and thus live to ages well above 100. The average man only lives to 77, so even 110 would be a major advance in longevity.

Posted by: Biotechy at September 29th, 2017 1:11 PM

Please allow me to remind everyone that centenarians look old, really old. The centenarians that I've seen in photographs.

Posted by: NY2LA at September 30th, 2017 3:34 AM


You wrote: "With CRISPR technology, many without the longevity alleles may be able to have them transplanted to their genome, and thus live to ages well above 100." How sure are you about that? Can you point to papers? (Im not educated in biotech). And will it be possible to do the same if you have mosaicism T21 as 1/6 of the population have. 1/6 of population has a bit Down syndrom! It goes in the human germline because human got children with those with T21 in the past. Then you have to get rid of the cell line but in an already born individual it will be difficult to do the same for the brain?

Posted by: Norse at September 30th, 2017 5:27 AM

Norse: To learn about CRISPR research just Google: CRISPR George Church You can find a number of articles about what may be possible to prevent genetic diseases and increase longevity within 10 years possibly.

Posted by: Biotechy at September 30th, 2017 10:23 AM

I just noticed that the FOXO4 gene is found on the long arm of the X chromosome, and that men thus only receive one allele for each SNP of this very important gene. Could this be the reason that women live about 5 years longer than men? Women receive 2 alleles of each SNP, and thus receive more robust beneficial factors for longevity and other traits. It would be great if some geneticist would study this gene from the standpoint of its location on the X chromosome relating to lifespan.

Posted by: Biotechy at October 1st, 2017 9:38 AM

@Biotechy: Extremely interesting. Have read here in the comments section before that women lives longer because they have 2 X chromosomes and that it ads stability against mutations.

Posted by: Norse at October 2nd, 2017 3:58 AM

Don't forget about X-inactivation. One of the X chromosomes is permanently silenced in females.

Posted by: gabor at October 2nd, 2017 12:26 PM

Yes, one of the X chromosomes in women is often totally silenced, but about 25% of the SNP alleles on the inactive X chromosome are expressed and probably provide some genetic benefits over men who are strictly limited to one allele per SNP.

Posted by: Biotechy at October 2nd, 2017 5:38 PM

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