FOXO3
Forkhead box O3
Gene Number: 2309
Location: 6q21
Key Functions: Transcription factor activity, regulation of oxidative stress response, modulation of apoptosis, promotion of autophagy, lifespan regulation
FOXO3 encodes the forkhead box O3 transcription factor, a pivotal member of the FOXO subfamily within the forkhead transcription factor family. These proteins are characterized by a conserved DNA-binding domain known as the forkhead box, enabling them to regulate gene expression critical for cellular homeostasis. FOXO3 plays a central role in modulating various cellular processes, including oxidative stress response, apoptosis, autophagy, metabolism, and DNA repair. Its activity is tightly regulated through post-translational modifications such as phosphorylation, acetylation, and ubiquitination, which influence its nuclear localization and transcriptional activity [R].
FOXO3 regulates the expression of genes involved in [R]:
1. Cellular stress resistance:FOXO3 enhances the expression of genes that mitigate oxidative stress and other damaging agents, thereby improving cellular survival under adverse conditions. This includes the upregulation of antioxidant enzymes like catalase and manganese superoxide dismutase (MnSOD), which neutralize reactive oxygen species (ROS) and protect cellular components from oxidative damage.
2. Apoptosis:By modulating apoptotic pathways, FOXO3 ensures the elimination of damaged or dysfunctional cells, thereby preventing the development of diseases such as cancer. It upregulates pro-apoptotic genes such as Bim and PUMA, while downregulating anti-apoptotic proteins like FLIP, facilitating programmed cell death in response to cellular stress.
3. Metabolism:FOXO3 influences metabolic processes, including the regulation of glucose and lipid metabolism, which are crucial for maintaining energy homeostasis and overall metabolic health. It integrates signals from insulin/IGF-1 pathways to modulate gene expression involved in gluconeogenesis, lipogenesis, and mitochondrial function.
4. DNA repair:The gene also plays a role in activating DNA repair mechanisms, which are essential for maintaining genomic stability and preventing mutations that could lead to malignancies. FOXO3 induces the expression of genes involved in DNA damage response pathways, such as those regulated by p53 and ATM, facilitating the repair of DNA lesions and maintaining genomic integrity.
FOXO3 is particularly significant in the context of longevity and healthy aging. Numerous genetic variants of FOXO3 have been repeatedly associated with exceptional lifespan in various human populations, suggesting a strong evolutionary advantage linked to this gene. For instance, specific single nucleotide polymorphisms (SNPs) within FOXO3 have been identified as significant contributors to longevity. Studies have highlighted associations between these SNPs and extended lifespan across different populations, indicating that FOXO3 may play a role in promoting healthspan and delaying the onset of age-related diseases [R].
Beyond its role in aging, the activity of FOXO3 has profound implications for numerous health aspects, including immune regulation, where it modulates the immune response to ensure a balanced reaction to pathogens; cancer suppression, as it helps in the prevention of tumorigenesis by promoting apoptosis in potentially cancerous cells; cardiovascular health, where it contributes to the maintenance of heart function and vascular integrity; and neuroprotection, which is crucial for preserving cognitive function and preventing neurodegenerative diseases. Thus, the multifaceted roles of FOXO3 underline its importance as a key player in the intricate balance of cellular functions that contribute to health and longevity [R].
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs9400239 | No matching variant or no valid DNA data | T | No interpretation available |
rs2802292 | No matching variant or no valid DNA data | G | No interpretation available |
rs9400239
TT – Longevity-associated genotype; carriers show increased odds of reaching advanced age and healthier stress-response regulation (R).
CT – Heterozygous; partial longevity benefit, moderate protection compared to C/C (R).
CC – Common genotype; not associated with enhanced lifespan in current studies (R).
Functional effect: The T allele has been linked to exceptional longevity in several cohorts, often in strong linkage with other FOXO3 SNPs (rs2802292, rs2764264). It is thought to promote better cellular stress resistance and metabolic regulation.
rs2802292
TT – Reference genotype; less likely to reach extreme old age compared to carriers of the G allele (R).
TG – Heterozygous; moderate longevity benefit with one copy of the protective allele (R).
GG – Strongly longevity-associated genotype; up to ~2.7× higher odds of living to 100; improved insulin sensitivity and stress resilience (R).
Functional effect: The G allele of rs2802292 is the most robust FOXO3 longevity variant replicated across multiple populations (Japanese, German, Italian centenarians, etc.). It enhances FOXO3 expression in skeletal muscle and liver, boosting oxidative stress defense, autophagy, and metabolic homeostasis. The T allele is more common globally and represents the baseline lifespan trajectory.
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