Are You Destined to Live Longer? (FOXO1)

FOXO1 is a strange, doubled-edged little protein. It is a transcription factor, meaning that it binds to DNA and regulates the activity of other genes. More specifically, it regulates insulin production, DNA repair, cell suicide (apoptosis) and parts of the human body’s antioxidant response [R, R].

High FOXO1 activity can be good or bad, depending on the circumstance. On the bright side, this protein [R, R, R]:

• Protects many cells from oxidative stress
• Suppresses the growth and metastasis of cancer cells
• Promotes DNA repair
• Improves wound healing
• Stimulates cellular recycling (autophagy) to destroy and replace damaged proteins

On the other hand, FOXO1 enhances the inflammatory response and reduces insulin sensitivity. In fact, FOXO1 tends to be highly expressed in atherosclerotic plaques (fatty buildup in blood vessels), and mice with overactive FOXO1 tend to develop diabetes [R, R, R, R, R].

With such a broad and complex role, it’s not surprising that FOXO1 mutations may significantly change a person’s health outcomes and even lifespan.

FOXO1 protects cells from oxidative stress and promotes DNA repair, making it an important cancer suppressor gene. It also stimulates autophagy and improves wound healing, but too much FOXO1 activity may increase risk of diabetes and atherosclerosis.

The link between FOXO1 and lifespan is controversial so far. Some studies have found that certain alleles are more common in people who live to be 100 years old or older; other studies have found no correlation [R, R, R].

FOXO1 may have more of an impact on longevity in some populations than others. In a Chinese study, for example, people with the ‘C’ allele at rs2755209 and the ‘T’ allele at rs2755213 were more likely to live over a century. In German and Italian studies, by contrast, there was no such link [R, R].

Some of the variation and apparent contradiction in these studies may be due in part to FOXO1’s double-edged effects. It is possible that people with moderate FOXO1 activity (neither very high nor very low) benefit the most; no studies have yet investigated this possibility.

Some studies have found that certain FOXO1 variants are more common in people who live a very long time, but the link is controversial. People with balanced FOXO1 activity may have the most benefits.

Many of FOXO1’s core functions make it seem likely to promote longevity, while others are counter-intuitive. 

The Bright Side: Antioxidants, DNA Repair & Healing

FOXO1 activates in response to oxidative stress, promoting the expression of antioxidant genes like MnSOD (superoxide dismutase). Accumulated oxidative stress over time can cause progressive tissue damage and is one of the hallmarks of aging. Naturally, then, reducing oxidative stress is important for increasing lifespan [R, R, R].

An improved antioxidant response is also good for wound healing. FOXO1 helps new skin cells grow and move into a wound [R].

FOXO1 promotes DNA repair and prevents cancer cells from growing and migrating throughout the body. This function’s benefit to lifespan is clear: in 2018, 21% of all deaths in the United States were caused by cancer [R, R].

FOXO1 also stimulates autophagy, the process by which your cells recycle old and damaged proteins and re-use their parts. In animal models, increasing autophagy almost universally increases lifespan; meanwhile, people who live to be over a hundred years old are more likely to have genes that turn on or increase autophagy [R, R].

Finally, FOXO1 has a role in maintaining stem cells, which your body uses to produce new tissues and repair damaged ones [R].

The Dark Side: Inflammation & Insulin Response

All of the above sounds great, so you’d think that more FOXO1 function is better—but that’s not necessarily the case.

FOXO1 is highly expressed in atherosclerotic plaques, the fatty buildup that hardens arteries and can cause dangerous clots, heart attacks, and strokes [R].

FOXO1 is also involved in the inflammatory response. TNF-α stimulates FOXO1, which in turn increases the expression of inflammatory cytokines like IL-6. If FOXO1 remains active for a long period of time, chronic inflammation (and a serious decline in health) may result [R, R].

Finally, in animal models, overexpressed FOXO1 in the pancreas leads to insulin resistance and type 2 diabetes; people with diabetes have a life expectancy 5-6 years lower than those without [R, R].

FOXO1 is a double-edged sword that stimulates many longevity-promoting processes, but may increase inflammation, insulin resistance, and atherosclerosis.

Interactions with Other Genes

FOXO1 has many vital functions on its own, but it may only really shine in combination with other important longevity genes. For example, FOXO1 and SIRT1 form a positive feedback loop: they stimulate each other’s expression. Thus, people with naturally high FOXO1 and SIRT1 function may live longer than others [R, R].

The Big Picture: Balancing FOXO1

Ultimately, FOXO1 may do its best work when its activity is balanced: not too high and not too low. For example, FOXO1 as expressed in healthy people is beneficial to wound healing; in people with diabetes, it is destructive and may increase lesions, ulcers, and inflammatory complications [R].

FOXO1 can be both stimulated and suppressed by the master energy regulator, AMPK. AMPK has been shown to induce FOXO1 in healthy animals and to suppress it in animals with diabetes; thus, AMPK activity may be the key to balancing and optimizing FOXO1 [R, R].

AMPK, the master energy regulator, can either increase or decrease FOXO1. It may be the key to balancing FOXO1: harnessing its benefits without amplifying its drawbacks.

Primary SNP: FOXO1 rs10507486

• ‘G’ = More common in longer-lived people (higher FOXO1 activity)
• ‘A’ = Less common in longer-lived people, decreased risk of heart disease and organ failure

Population frequency:

• 71% of people have ‘GG’

Other Important SNPs:

FOXO1 rs2755209

• ‘C’ = More common in longer-lived people (higher FOXO1 activity) 
• ‘A’ = Less common in longer-lived people

Population frequency:

• 34% of people have ‘CC’

FOXO1 rs2755213

• ‘T’ = More common in longer-lived people (higher FOXO1 activity)
• ‘C’ = Less common in longer-lived people

Population frequency:

• 60% of people have ‘TT’