Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

Chromosome 6.

FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-binding domain. 

FOXO3A (Forkhead box O3A) is a protein that plays a critical role in regulating cellular processes such as cellular differentiation, apoptosis, and oxidative stress. 

It belongs to the Forkhead family of transcription factors, which are known to play a role in regulating gene expression. 

FOXO3A is particularly known for its role in promoting longevity and has been linked to the lifespan extension in several animal models. 

The protein’s activity can be regulated by various signaling pathways, including the insulin and PI3K/AKT pathways.


There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. 

These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway

Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.

The use of FOXO3a knockout mice has revealed a diverse range of functions in both health and disease, namely infertility, lymphoproliferation, adenoma, organ inflammation, metabolism etc.; yet despite the purported importance of FOXO transcription factors in aging, FOXO3A knockout mice do not show an obvious shortening of lifespan or accelerated aging [7]

FOXO3a activation in vascular smooth muscle cells induces prominent apoptosis and extracellular matrix breakdown in vitro and exacerbates atherosclerosis and vascular remodelling in vivo. 

FOXO3a also functions as a trigger for apoptosis through upregulation of genes necessary for cell death, or downregulation of anti-apoptotic proteins.

FOXO3 is a regulator of Notch signaling pathway, an essential regulator of quiescence in adult stem cells, in the self-renewal of stem cells during muscle regeneration.

It is thought that FOXO3a is also involved in protection from oxidative stress

Deregulation of FOXO3a is involved in tumorigenesis.

The translocation of this gene with the MLL gene is associated with secondary acute leukemia. 

Downregulation of FOXO3a activity is often seen in cancer.

FOXO3 is known as a tumor suppressor.

Genetic variation in FOXO3 has been shown to be associated with healthspan and longevity in humans.

FOXO3 is found in most centenarians across a variety of ethnic groups around the world.

In a meta-analysis of 78,308 individuals of European descent, a particular single nucleotide polymorphism (SNP) in an intronic region of FOXO3 and neighboring SNPs in the promoter region, have the strongest associations with intelligence.

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