<b><i>FOXO3:</i></b> A Major Gene for Human Longevity - A Mini-Review

Abstract

Background: The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. Objective: Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. Methods: The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword. Results: We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis. Conclusions: The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported.

Blunting Autoantigen-induced FOXO3a Protein Phosphorylation and Degradation Is a Novel Pathway of Glucocorticoids for the Treatment of Systemic Lupus Erythematosus

“…In mammals, there are four FOXO proteins, FOXO1, FOXO3a, FOXO4, and FOXO6. FOXO1, FOXO3, and FOXO4 are widely distributed and are expressed in most tissues, whereas FOXO6 expression is largely restricted to neural cells (13)(14)(15)(16). In recent years, accumulating evidence has demonstrated the critical roles of several FOXO family members in immunoregulation, although their function may be diverse and in some cases even antagonistic (15)(16)(17)(18).…”

The somatotropic axis and longevity in mice

“…The FOXO transcription factors are downstream of the growth factor pathways. FOXO3 appears to be involved in a wide variety of processes that are involved in healthy aging with polymorphisms in FOXO3a, showing con-sistent associations with longevity in several populations of humans (79). The evidence to date suggests that reduced somatotropic signaling may potentially be linked to human longevity via a reduction in age-related disease.…”

Colonic PDGFRα Overexpression Accompanied Forkhead Transcription Factor FOXO3 Up-Regulation in STZ-Induced Diabetic Mice

“…It is well known that the FOXO transcription factors have a broad range of biological functions; however, the contributions of the mammalian FOXO family members (FOXO1, 3, 4 and 6) have not been fully investigated [23], especially their involvement in diabetes-induced colonic motility disorders. Therefore, the expression of FOXO1, FOXO3 and FOXO4 was measured in the proximal colon smooth muscles of STZ-induced diabetic mice.…”

“…In mammals, there are four FOXOs, FOXO1, 3, 4 and 6 [23, 38], and each FOXO can regulate different genes, depending on the cell type [39], to control cell proliferation, apoptosis and differentiation. They also regulate life span and energy metabolism [40, 41].…”