Variants of the FOXO3 gene multiply by 1.5–2.75 the probability of reaching centenarian age in German and Japanese cohorts.
View the study (cohort) →FOXO blocks the cell cycle and activates apoptosis in cells with genomic damage; a high intake of animal protein raises IGF-1, which inhibits FOXO.
Regulates insulin sensitivity via the PI3K/Akt cascade; activates autophagy under low-insulin conditions.
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FOXO proteins are members of the FOX family of transcriptional regulators, highly conserved throughout evolution from worms to mammals, and they play essential roles in longevity and healthy aging by acting as molecular sensors that translate signals from the cellular environment into changes in gene expression that modulate and coordinate the survival and health of the organism.
FOXO proteins are regulated by the insulin/PI3K/Akt signaling pathway, a complex and conserved biological system that is activated when we eat: elevated glucose levels stimulate the release of insulin, which activates PI3K, which in turn phosphorylates Akt, triggering a cascade of effects that includes the temporary inactivation of FOXO proteins, which means that eating directly inhibits the longevity mechanisms that FOXO activates.
A unique feature of FOXO is its ability to move between the nucleus, where it binds to DNA and influences transcription, and the cytoplasm of the cell, in response to specific signals, which places it at the nexus of essential cellular processes such as the cell cycle, apoptosis, autophagy, tumor suppression, longevity, and appetite regulation, with an exquisite sensitivity to the physiological context that allows differentiated responses depending on the intensity of the stress.
FOXO blocks the cell cycle by activating cell cycle inhibitors under stress conditions, allowing time to repair damaged DNA; it activates stress resistance genes in response to moderate stressors and apoptosis genes in response to intense stressors; it regulates autophagy, the cellular recycling system critical for healthy aging, in multiple cell types including neurons and cardiac, kidney, and muscle cells; and it participates in appetite regulation through neuropeptides in the hypothalamus.
FOXO3 is a master regulator of many genes involved in stress tolerance, and it increases the production of genes that combat cellular aging, including damage to DNA, proteins, and lipids, loss of stem cell function, DNA repair, tumor suppression, and immune function; single nucleotide polymorphisms in FOXO3 are associated with increased longevity in multiple human populations studied.
In a study of more than 1,700 German adults, carriers of a variant of the FOXO3 gene were 1.5 times more likely to live to 100 years or older; in another study of more than 600 men of Japanese ethnicity, carriers of the same variant were 2.75 times more likely to live to 95 years or older, and those who lived longer tended to be leaner and enjoyed better overall health than their younger peers.
FOXO3 is activated by caloric restriction, intermittent fasting, and dietary components such as EGCG from green tea and quercetin found in onions and apples; heat stress such as that from a sauna also activates FOXO3; whereas smoking, lack of exercise, and a diet high in animal protein may inhibit it, since high protein intake is the most potent nutritional regulator of serum IGF-1 levels in humans, and IGF-1 inhibits the actions of FOXO3.
Information, not medical advice. Scientific evidence reflects the quality of the studies.