FOXO longevity genes

From Longevity Wiki

FOXO proteins are a family of transcription factors specially known for their role in longevity and for being a central component of the insulin signalling pathway. The insulin/IGF-1 signalling (IIS) pathway senses insulin and other insulin-like peptides (ILPs) and activates a signalling cascade which connects nutrient levels to metabolism, growth, reproduction, development and aging.

The activity of FOXO antagonises that of insulin: when insulin binds to the insulin receptor, FOXO is sequestered in the cytoplasm and is not able to activate downstream target genes. On the contrary, when insulin levels are low, FOXO translocates to the nucleus and acts on a wide range of cytoprotective and stress-response genes that eventually extend lifespan.

FOXO function

FOXO transcription factors are homeostasis regulators and are particularly important for responding to cellular stresses such as heat-shock, oxidation or metabolic stress.[1] They are also involved in a variety of other processes including glucose and lipid metabolism, autophagy, cell cycle control, DNA repair and inflammation. FOXO proteins can also act as tumour suppressors.[1][2]

In addition, FOXO is required for the striking lifespan extension (of 60%) of insulin-signalling mutants.[3]

FOXO isoforms and orthologs

In humans, the family of Forkhead box O (FOXO) proteins consists of four members (known as “isoforms”): FOXO1, FOXO3, FOXO4 and FOXO6.[4] Whilst expressed ubiquitously in all tissues, FOXO1 is more highly expressed in adipocytes, FOXO3 in the liver, FOXO4 in muscle cells and FOXO6 in the nervous system.[4] In invertebrates there is only one FOXO gene counterpart or “ortholog”, known as daf-16 in C. elegans nematodes, or dFOXO in Drosophila flies.

FOXO in aging and longevity

FOXO proteins are nowadays well established as longevity genes, especially FOXO3.[5] They are believed to protect cells from damage and to remove or repair already existing cellular damage.

Genetic association studies of single nucleotide polymorphisms (SNPs) have shown that FOXO3 consistently associates with centenarians of diverse human populations.[6] In humans, to date only two genes have shown to be consistently associated with extreme old age across human populations: FOXO3 and APOE (the latter coding for the protein apolipoprotein E, a subtype of which is well known for being a risk-factor gene to Alzheimer’s Disease).[7]

Interestingly, the Hydra, an invertebrate species considered to be biologically immortal, requires the FOXO transcription factor to maintain its capacity for cellular self-renewal and thus its immortality.[8]

Deregulation of FOXOs has also been associated with several diseases such as cancer, neurological diseases, diabetes and cardiovascular disease.[9]

  1. 1.0 1.1 Eijkelenboom, A., & Burgering, B. (2013). FOXOs: signalling integrators for homeostasis maintenance. Nature Reviews Molecular Cell Biology, 14(2), 83-97. doi: 10.1038/nrm3507
  2. Dansen, T., & Burgering, B. (2008). Unravelling the tumor-suppressive functions of FOXO proteins. Trends In Cell Biology, 18(9), 421-429. doi: 10.1016/j.tcb.2008.07.004
  3. Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature, 366(6454), 461-464. doi: 10.1038/366461a0
  4. 4.0 4.1 Burgering, B. (2008). A brief introduction to FOXOlogy. Oncogene, 27(16), 2258-2262. doi: 10.1038/onc.2008.29
  5. Morris, B., Willcox, D., Donlon, T., & Willcox, B. (2015). A Major Gene for Human Longevity - A Mini-Review. Gerontology, 61(6), 515-525. doi: 10.1159/000375235
  6. Willcox, B., Donlon, T., He, Q., Chen, R., Grove, J., & Yano, K. et al. (2008). FOXO3A genotype is strongly associated with human longevity. Proceedings Of The National Academy Of Sciences, 105(37), 13987-13992. doi: 10.1073/pnas.0801030105
  7. Broer, L., Buchman, A., Deelen, J., Evans, D., Faul, J., & Lunetta, K. et al. (2014). GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy. The Journals Of Gerontology: Series A, 70(1), 110-118. doi: 10.1093/gerona/glu166
  8. Bridge, D., Theofiles, A., Holler, R., Marcinkevicius, E., Steele, R., & Martínez, D. (2010). FoxO and Stress Responses in the Cnidarian Hydra vulgaris. Plos ONE, 5(7), e11686. doi: 10.1371/journal.pone.0011686
  9. Calissi, G., Lam, E., & Link, W. (2020). Therapeutic strategies targeting FOXO transcription factors. Nature Reviews Drug Discovery, 20(1), 21-38. doi: 10.1038/s41573-020-0088-2