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FOXO proteins are members of the FOX family of highly conserved transcriptional regulators. They play important roles in human lifespan and healthy aging, both of which are influenced by environmental and genetic factors. The genetic contribution to lifespan and aging increases as an individual gets older, suggesting that people who live long lives might carry so-called “protective genes.”

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Background

FOX proteins are named for a gene found in fruit flies that causes the insects to have forked structures on their heads (supplying the “F”) and a particular group of specialized genes – known as a “box” (supplying the “OX”). They are named alphabetically, from FOXA to FOXS. FOX proteins act as transcription factors by binding to specific regions on DNA, thereby controlling the transmission of genetic information and influencing the chemical "blueprint" for proteins.

Members of the “O” class of FOX proteins provide the instructions for genes responsible for the regulation of cellular replication and senescence, resistance to oxidative stress, metabolism, and DNA repair. They play an integral part in both tumor suppression and in longevity.^[1] Four FOXO genes have been identified in mammals: FOXO1, FOXO3, FOXO4, and FOXO6. Due to certain genetic redundancies, FOXO2 is identical to FOXO3, and FOXO5 (an ortholog of FOXO3) is found only in fish. Orthologs are genes found in different species that evolved from a common ancestral gene by speciation. Typically, orthologs retain the same function across species.

FOXO regulation

FOXO proteins are regulated by the insulin/PI3K/Akt signaling pathway, a complex biological signaling system that is conserved across multiple organisms, from worms to mammals.^[2] The pathway is initiated with the intake of food, which raises blood glucose. When blood glucose levels are high, the pancreas releases insulin into the bloodstream. Insulin, in turn, induces the activation of the enzyme PI3K, which subsequently phosphorylates the enzyme Akt. This pathway sets in motion a complex cascade of biological events that have a wide range of effects on the body’s cells. It is noteworthy that insulin and IGF-1, a hormone similar in structure to insulin, share similar downstream signaling pathways leading to several shared outcomes, including activation of the PI3K/Akt pathway (insulin/PI3K/Akt).

FOXO responsiveness

FOXO functions much like a highly calibrated sensor that is very responsive to different environmental conditions within the cell. It is found predominantly in the nucleus of the cell, where it binds to DNA and influences transcription, but it can also be found in the cytoplasm – the watery part of the cell. A unique characteristic of FOXO is that it can shuttle back and forth between the two locations in response to signaling cues.^[3] FOXO proteins translate these cues into changes in gene expression that modulate and coordinate an organism’s longevity and overall health. In addition, FOXO is subject to a variety of chemical modifications, including phosphorylation, acetylation or deacetylation, and ubiquitination, all of which influence where FOXO is located and how it behaves.^[4]

FOXO proteins sit at the nexus of cellular processes

FOXO proteins’ ability to shuttle between sites within the cell places them at the nexus of essential cellular processes. They orchestrate the expression of a vast number of genes, ultimately regulating an exhaustive list of important processes, including aspects of the cell cycle, apoptosis, autophagy, tumor suppression, longevity, appetite regulation, and many others.

Cell cycle arrest: Cells constantly monitor their cell cycle status at various checkpoints. These checkpoints help ensure the accuracy of DNA replication and division and provide time for DNA repair. In some scenarios, FOXO blocks the cell cycle by either switching on cell cycle inhibitors (such as p21 and p27) or by switching off cell cycle activators (cyclin D1/D2).^[5] But FOXO is highly sensitive to physiological context and needs, and under conditions of cellular stress, it mediates cell cycle arrest to allow time for repair of damaged DNA and cellular detoxification.

Apoptosis: A key role of FOXO is to switch on genes that protect against stress. However, it demonstrates [a kind of specificity in response to the microenvironment within the cell, perhaps in a hormetic fashion.^[6] For example, moderate stressors may switch on stress-resistant genes, while more intense stressors may switch on genes that drive apoptosis by recruiting death cytokines like Fas ligand and TRAIL.^[5]

Autophagy: A key player in the aging process is autophagy, an intracellular system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy has been described as a type of cellular quality control. Defects in autophagy have been linked with premature aging and age‐related disorders. FOXO proteins regulate many genes responsible for autophagy and activate mechanisms in many different cell types including those in the nervous system, heart, kidneys, and muscles.^[7]

Learn more about autophagy in this overview article.

Tumor suppression: Due to FOXO’s ability to alter the cell cycle, promote DNA repair, and induce apoptosis, loss of FOXO activity is linked with tumor development.^[8]

Longevity: Human longevity and healthy aging are influenced by both environmental and genetic factors. People who live long lives might carry so-called “protective genes.”

A growing body of evidence suggests that FOXO genes may increase lifespan; however, much of the research linking FOXO and longevity has been conducted in worms. Worms have only one FOXO ortholog, DAF-16, which simplifies pinpointing the gene’s activities and roles. Worms that have mutations in either their insulin receptors or PI3K (which would prevent Akt-driven phosphorylation of DAF-16) live two to three times longer than normal worms.^[9] As in humans, this FOXO ortholog switches on genes that protect against oxidative stress, pathogens, and protein structural damage, all of which promote disease and decrease longevity.

Scientists are currently on the cusp of learning about FOXO and longevity in mammals. The bulk of the evidence comes from studies in mice and appears to be linked to the insulin/PI3K/Akt pathway. For example, mice that lack the insulin receptor or the IGF-1 receptor live longer and are more resistant to oxidative stress than normal mice.^[10] However, mice lacking the FOXO3 gene do not live any longer than normal mice. Since it is possible that the multiple forms of FOXOs in humans provide a layer of biological redundancy in which [one FOXO form compensates for the absence of another, developing better animal models for studying the role of FOXO in mammals, especially in humans, is critical to its understanding.^[5]

Appetite regulation: FOXO also plays a role in regulating food intake. Early research shows that FOXO switches on neuropeptides in the hypothalamus – the region of the brain that serves as the link between the nervous system and the endocrine system. FOXO switches on transcription of neuropeptide Y and Agouti-related protein – two hormones that increase appetite; but it switches off transcription of POMC, a hormone that decreases appetite, suggesting that hypothalamic FOXO is an important regulator of food intake and energy balance.^[11]

FOXO proteins influence metabolism

FOXO proteins influence various aspects of metabolism that may have health effects in humans. For example,

• FOXO1 promotes microsomal triacylglycerol transfer protein expression (involved in chylomicron synthesis), augments VLDL production, and elevates plasma triglyceride levels.^[12]
• FOXO1 binds to insulin-response elements to increase hepatic gluconeogenesis^[13], a robust contributor to hyperglycemia in the setting of diabetes.^[14]
• FOXO1 represses PPARγ1 and PPARγ2 promoter activity, driving insulin resistance.^[15]
• FOXO3 promotes triglyceride synthesis and subsequent hepatic triglyceride accumulation.^[16]

Focus on FOXO3

FOXO3 is a master regulator of many genes involved in stress tolerance. It increases the production of genes that combat cellular aging, such as damage to DNA, proteins, and lipids, and loss of stem cell function. It also increases the production of genes including those that regulate DNA repair, tumor suppression, stem cell function, immune function, protein aggregation, and more, which is how FOXO3 staves off aging.

FOXO3 is activated by caloric restriction and intermittent fasting, and by dietary components, such as EGCG, which is found in green tea, and by quercetin, which is found in onions and apples. Heat stress, such as from using the sauna, also activates FOXO3.^[5]

Genetic variants of FOXO

Single-nucleotide polymorphisms, or SNPs, of the FOXO genes, may influence how longevity. SNPs in FOXO3, in particular, increase lifespan and improve overall health. For example, in a study of more than 1,700 German adults, those who carried a variant of the FOXO3 gene were 1.5 times more likely to live to the age of 100 years or older.^[17] In addition, in a study of more than 600 men of Japanese ethnicity, those who carried a variant of the FOXO3 gene were 2.75 times more likely to live to the age of 95 years or older.^[17] The men who lived the longest tended to be leaner and had overall better health than their younger counterparts.

Similarly, in a genome-wide association study, people carrying a variant of the FOXO3 gene tended to have a reduced inflammatory response (downregulation of TNFα and several other pro-inflammatory cytokines and upregulation of IL10, a cytokine associated with anti-inflammatory effects).^[18] A reduced inflammatory response may be beneficial in some diseases, such as those closely associated with inflammation (e.g., Crohn’s disease or rheumatoid arthritis), but it may be harmful in others (e.g., malaria).

Lifestyle influences and FOXO

Lifestyle choices, such as exercise and diet, also play a role in how active FOXO is. For example, how smoking, lack of exercise, and an unhealthy diet (especially one that is based on animal protein) can increase the risk of certain diseases, including cancer. High protein intake is the most potent nutritional regulator of serum IGF-1 levels in humans, and IGF-1 inhibits the actions of FOXO3. Exercise also has a wide range of effects on longevity, possibly due to increased interaction between FOXO3 and SIRT1.^[19] This might be one mechanism by which exercise could be involved in preventing cancer and potentially other diseases associated with aging.