FOXO3: Longevity Gene?

The role of the FOXO3 transcription factor in aging and healthspan

When researchers study genes and longevity in centenarians, one gene consistently stands out: FOXO3.

FOXO3 plays an important role in controlling cellular processes such as growth, resistance to stress, and aging. It is a transcription factor, meaning it regulates the expression of other genes. FOXO3 gene variants have been consistently linked to human longevity and are associated with a lower risk of age-related diseases.

Why is this interesting right now? Longevity researchers just published a new paper on infusing stem cells enhanced with FOXO3 to roll back the aging clock (in monkeys). The old animals were injected with FOXO3-enhanced stem cells, and positive effects were seen across many organs, showing a system-wide deceleration of aging.[ref]

From the Cell article on FOXO3

Let’s take a look at what all FOXO3 does and why it is key in longevity - and then we’ll jump into the research on increasing FOXO3.

What does FOXO3 do?

FOXO3 is a transcription factor. When activated, it can translocate to the nucleus of a cell where it binds to DNA and regulates gene expression. The key is that it regulates the expression of genes important for healthy aging.

FOXO3 was first identified as a gene involved in lifespan through studies in C. elegans, which is a worm often used in research studies. Researchers found that a mutation that increased the function of a gene similar to the human FOXO3 gene caused a 2.3-fold increase in lifespan.

Let’s take a look at what studies show about FOXO3:[ref]

• Longevity:
  FOXO3 is heavily involved in regulating lifespan and is considered a major gene associated with human longevity. Studies have shown that specific FOXO3 gene variants are linked to living longer due to having a lower risk of death from cardiovascular disease, lower inflammatory cytokine levels, and longer telomeres.[ref] Read the Genetic Lifehacks article on longevity and FOXO3 to check your genes.

• Gut health: Preventing gut inflammation
  Lower FOXO3 activity is associated with obesity, metabolic diseases, inflammatory diseases, and cancer. Animal studies show that this is partly driven by the effect of FOXO3 on gut health. FOXO3 deficiency leads to an “inflammatory immune landscape and dysregulated molecular pathways” in the gut, driving many of the chronic disease pathways seen in humans. [ref]

• Cellular Stress: Activating Antioxidants
  FOXO3 helps cells respond to various stressors, including oxidative stress and metabolic stress. It can activate genes that protect cells from damage, such as those involved in antioxidant production.[ref]

• Maintaining muscle:
  FOXO3 regulates muscle mass in aging, with lower levels of FOXO3 found in aging muscles. Research shows that increasing the activation of FOXO3 can reverse the aging muscle phenotype. [ref]

• Autophagy:
  FOXO3 helps in instigating autophagy, a cellular process that removes damaged or misfolded proteins and cellular components. This is important for maintaining cellular health, especially during aging, as it can remove damaged parts of cells or mitochondria.[ref]

• Stem cells:
  The FOXO3 protein helps maintain the pool of adult stem cells, which are essential for tissue regeneration and repair. This is particularly important since stem cell function declines with age.

• Cancer:
  FOXO3 is considered a latent tumor suppressor because it can inhibit cancer development and progression in certain types of cancer. It can promote cell cycle arrest and apoptosis (programmed cell death) in cancer cells.[ref]

• Osteoporosis and bone health:
  FOXO3 levels are low in osteoporosis (low bone density). Studies show that low FOXO3 allows for higher oxidative stress in the bones, leading to greater bone loss.[ref]

Regulation and Activation of FOXO3:

OK, so FOXO3 as a transcription factor is integral to many of the negative aspects of getting older.

Let’s take a look at what activates FOXO3, and then we will go into the environmental factors that regulate it. [ref]

Oxidative stress or low energy levels: Both can activate FOXO3, moving into the nucleus and increasing the transcription of genes such as catalase and SOD1 (for oxidative stress) or for energy conservation genes for low glucose/ATP.

DNA damage: FOXO3 is also involved in the repair response for DNA damage. This gives it a protective role in cancer and cell proliferation.

Phosphorylation: FOXO3's activity is regulated by phosphorylation (the addition of phosphate groups), which can be triggered by various signaling pathways. Different parts of the gene being phosphorylated will either promote or prevent FOXO3 from acting on genes in the nucleus of the cell.

Environmental Factors that regulate FOXO3:

FOXO3 is often referred to as a factor for increasing cellular resilience in stressful situations.

One reason that caloric restriction (or intermittent fasting) is associated with longevity is that it activates FOXO3.

Heat also activates FOXO3, as does exercise. Both of these are stressors that result in more FOXO3 activation, which is part of the reason for the benefits from exercise or sauna.

Interestingly, metformin also upregulates FOXO3. Metformin is a diabetes medication that has been studied for life extension.[ref][ref]

Ways to increase FOXO3: Lifehacks for Longevity

Here’s what research shows can help to increase FOXO3 levels in aging. I’m listing all the options so that you can pick what works for your lifestyle. Be sure to check on interactions with prescription medications if you decide to go with a new supplement.

Exercise:
Endurance exercise increases FOXO3 levels.[ref] This is yet one more reason to find an activity that you enjoy and that will keep you actively moving.

Intermittent fasting or calorie restriction:
Animal studies clearly show that FOXO3 is involved in the lifespan-increasing benefits of calorie restriction. However, long-term calorie restriction isn’t a great option for humans or other long-lived primates. Instead, intermittent fasting or time-restricted eating may be a better option as a lever for increasing FOXO3.[ref]

Diet:
Certain compounds found in foods can also influence FOXO3. For example, EGCG (found in green tea) and quercetin (found in onions and apples) have been shown to affect FOXO3 activity by inhibiting kinase activity that would normally lead to its inactivation.

Taurine:
A naturally occurring amino acid, taurine has been shown in studies to increase FOXO3 levels.[ref] Taurine levels decline with age, making it a good target for supplementation in aging.

Taurine is available as a supplement in powdered form* or in capsules. The powder has very little taste, making it easy to add to a drink or yogurt.

*Amazon affiliate link - please read the reviews and choose the brand you’re most comfortable with

Resveratrol:
A natural polyphenol, resveratrol increases FOXO3 by influencing sirtuins and upregulating oxidative stress enzymes such as catalase.[ref][ref]

Resveratrol is also available as a powder or in a capsule.

Curcumin:
A component of the spice turmeric, curcumin has many anti-inflammatory properties. Animal studies show that curcumin increases FOXO3 by influencing sirtuins.[ref][ref]

Curcumin is also available as a supplement.

Astaxanthin:
Astaxanthin is a lipid-soluble red pigment found in shrimp and krill. A study in mice showed that astaxanthin upregulated FOXO3 significantly.[ref]

Circling back: FOXO3 boosted stem cells, miRNAs

I wanted to circle back to the new study in monkeys that used senescent-resistant stem cells to counteract aging on a system-wide level. The researchers used FOXO3-enhanced stem cells and saw a decrease in the aging clock test results for multiple organs.[ref] The idea of an enhanced stem cell therapy delivered by IV to turn back the clock systemically is an intriguing one.

How else could FOXO3 levels be impacted on a broader basis? Gene expression and epigenetic modifications also come into play.

MicroRNAs are short strands of RNA that can block the translation of genes into their proteins. miR-301a-3p is one microRNA that decreases FOXO3 expression. There’s current research into inhibitors for miR-301a that hold potential for lung health, cancer, and aging.[ref][ref] Other miRNAs, including miR-155, miR-132, miR-212, miR-223, and miR-29a, can inhibit its expression.[ref] Lifestyle and environmental factors can also alter miRNAs. For example, miR-132 is increased by stress and fear, so dialing down the stress in life may help to allow more FOXO3.[ref] I have more on miRNAs and the effect on aging here as well as specifics on targeting miR-29a.

Conclusion:

FOXO3 and gene expression are key to health in aging and to extending lifespan. The research studies on using FOXO3-enhanced stem cells point to a real possibility for delaying aging, at some point when it is well tested and the kinks are worked out. In the meantime, consider intermittent fasting, resveratrol, curcumin, astaxanthin, and exercise — all things that we know are protective in aging.