FOXO3: 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.

Fig. 1

Cellular processes regulated by FoxOs that serve as homeostatic regulators, particularly in response to stress, to potentially affect ageing and lifespan.

Fig. 2

Mechanisms by which FoxOs influence healthy ageing. Shown are several of the key intracellular pathways targeted by FoxO transcription factors. FoxOs are master regulators that translate environmental stimuli arising from insulin, growth factors, nutrients and oxidative stress into specific gene expression programs. The role of FoxO3 in longevity may involve upregulation of target genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis. Effective control of FoxO3 in response to environmental stimuli is likely critical to prevent ageing and age related diseases including cardiovascular disease, type 2 diabetes, cancer and neurodegenerative diseases. The diagram shows how the well-known longevity-associated intervention of caloric restriction helps to maintain the redox state of the cell by cycling calories through the mitochondria so as to restore NAD⁺. Caloric restriction results in activation of sirtuins, leading to activation of FoxOs, improved autophagy, amino acid recycling via inhibition of mTOR activity, and other mechanisms leading to a healthy ageing phenotype. On the other hand, excess calories, particularly from carbohydrates, increase the NADH/NAD⁺ ratio and leads to lipogenesis, overproduction of ROS by mitochondria, poor autophagy and activation of mTOR as a result of an excess of protein intake. Abbreviations: AKT1, a term derived from the “Ak” mouse strain that develops spontaneous thymic lymphomas (AKT1 is also known as protein kinase B); CAD, coronary artery disease; HNF4a, hepatocyte nuclear factor 4α; GCN1l1, general control of amino acid synthesis 1-like 1; mTOR, mechanistic target of rapamycin; O-GlcNAc, O-linked N-acetylglucosamine’ OXPHOS, oxidative phosphorylation; PPARγC1α, peroxisome proliferator activated receptor γ coactivator 1α; TCA, tricarboxylic acid; TORC1, mTOR complex 1; TORC2, mTOR complex 2.