Can You Hack This Gene to Live Longer? (SIRT1)

The sirtuins are a group of enzymes heavily implicated in aging, cell death, inflammation, mental and physical stress resistance, and energy metabolism. They regulate and “turn off” other genes, especially those involved in the process of aging [R, R, R, R].

When your cells experience stress, acetyl groups are added to proteins as a response to changes induced by inflammation and oxidation. Sirtuins (like SIRT1) remove these acetyl groups to keep the protein in service longer than usual [R, R].

Many age-related and degenerative diseases are characterized by low sirtuin activity, including [R, R]:

• Cancer
• Alzheimer’s disease
• Parkinson’s disease
• Huntington’s disease
• Amyotrophic lateral sclerosis (ALS)
• Kennedy’s disease

Sirtuin activity is also unusually low in chronic inflammation. Some researchers believe that activating the sirtuins—and especially SIRT1—may help manage obesity, atherosclerosis, diabetes, and other inflammatory diseases [R].

Given all of this, it’s not surprising that SIRT1 has been touted as a longevity gene.

Research on SIRT1 originates in yeast, of all things: the first sirtuin ever identified was a gene called sir2, which is required for yeast to grow and divide. From sir2, researchers discovered the animal and mammalian sirtuins, SIRT1 through SIRT7 [R, R].

Today, SIRT1 is among the best-known of the longevity genes, which also include FOXO3, FOXO1, PON1, and others.

SIRT1 Knockouts and Duplications

One of the best ways to study the function of a particular gene is to see what happens when it’s not working and when it’s working too much. Mice and rats can be genetically modified to delete (knock out) or duplicate one gene at a time for this purpose [R].

When SIRT1 is knocked out of mice, many die before they are born, and only 20% reach maturity. Those who make it are small, infertile, and prone to diseases of the eye, brain, and heart [R].

When SIRT1 is doubled in mice, they experience less DNA damage and other markers of aging. Excess SIRT1 activity also protected heart tissue from damage after a heart attack [R].

Together, these mouse studies demonstrate not only that SIRT1 is necessary for a healthy life, but that more SIRT1 is better for healthy aging.

SIRT1 and Human Longevity

A handful of studies have shown that people with certain SIRT1 variants are more likely to live very long lives. One of the variations with the strongest effect so far is rs12778366: even one copy of the ‘C’ allele may reduce all-cause mortality risk by as much as 30% [R].

Another SNP with a large potential impact on lifespan is rs7895833: the ‘G’ allele here is almost twice as common in older people as it is in the average adult [R].

Animals and humans with increased SIRT1 activity tend to have fewer age-related diseases, possibly because SIRT1 prevents DNA damage.

SIRT1 is active in every tissue in your body, working tirelessly to maintain cell function and prevent disease [R, R, R].

NAD+, SIRT1, and DNA Damage

The exact mechanism by which SIRT1 affects aging is still under intense investigation. However, we do know a few things [R, R]:

• SIRT1 activity (especially in the liver and cardiovascular system) decreases as we age
• NAD+, which is required for SIRT1 function, decreases as we age
• Decreases in NAD+ and SIRT1 coincide with DNA damage and age-related diseases
• When SIRT1 activity is low, the activity of genes associated with aging increases
• SIRT1 activity is closely linked with antioxidant status in the elderly

Together, this paints a picture wherein high SIRT1 activity could prevent age-related DNA damage and disease.

Interactions with FOXO1, FOXO3, and PON1

SIRT1 appears to have an effect on lifespan on its own, but it works best in concert with other longevity genes.

SIRT1 and FOXO1, for example, are both required to activate the antioxidant enzyme MnSOD. On the other hand, FOXO1 can bind to and turn off SIRT1, which is one of the reasons why FOXO1 should be kept in balance by AMPK [R].

SIRT1 also directly activates FOXO3, perhaps the best-studied human longevity gene. FOXO3 suppresses tumors, promotes insulin sensitivity, repairs DNA, and improves immune function [R].

SIRT1’s relationship with PON1 is more complex. Some researchers believe that SIRT1 and PON1 have similar or overlapping functions, and that the activity of one can compensate for the activity of the other. Since both SIRT1 and PON1 are highly beneficial, there’s no harm in trying to increase both [R].

SIRT1 works together with other longevity genes like FOXO1, FOXO3, and PON1 to repair DNA, flush toxins, and prevent oxidative stress.

Important SNPs:

SIRT1 rs12778366 [R]

• ‘C’ = Increased SIRT1 activity, reduced risk of diabetes, longer lifespan
• ‘T’ = Reduced SIRT1 activity, increased risk of diabetes, average lifespan
• Only about 1% of people worldwide have the most beneficial ‘CC’ genotype!

SIRT1 rs7895833 [R]

• ‘G’ = More common in long-lived populations, may increase lifespan
• ‘A’ = Less common in long-lived populations
• About 18% of people worldwide have the most beneficial ‘GG’ genotype

SIRT1 rs3758391 [R]

• ‘T’ = Lower cardiovascular mortality risk, less cognitive decline during aging, may increase lifespan
• ‘C’ = Normal cognitive decline during aging, normal aging
• About 29% of people worldwide have the most beneficial ‘TT’ genotype

SIRT1 rs7896005 [R]

• ‘A’ = More common in long-lived populations, may increase lifespan
• ‘G’ = Less common in long-lived populations
• About 51% of people worldwide have the most beneficial ‘GG’ genotype

At rs12778366, the SIRT1 variant with the best-established impact on lifespan, only about 20% of the world’s population has at least one copy of the beneficial ‘C’ allele. Furthermore, only 1% of the world’s population has the ‘CC’ genotype.

At the other relevant SNPs, the most beneficial genotypes are considerably more common. However, if your genotype file only has rs12778366 and you see a red face in the table below, don’t worry! That just means you have room to improve your SIRT1 function.