What Are Sirtuins and How Do They Support Healthy Aging?


What Are Sirtuins and How Do They Support Healthy Aging?

For decades, scientists have sought to better understand why we age. Scientists believed that aging was simply a natural part of our human development and that little could be done to stem the tide of physical deterioration. However, in the 1990s, a groundbreaking discovery revealed that a specific family of genes and their resultant proteins regulate aging; further research indicates that modulation of these genes and proteins may improve the way we age. These genes are known as SIRT genes, and the proteins are called sirtuins. Read on to learn about sirtuins, how they support healthy aging, and what you can do to optimize your sirtuin activity.

What Are Sirtuins, and Why Should You Care About Them?

Sirtuins are a family of seven proteins that play regulatory roles in almost all cellular functions. Sirtuins impact the body’s inflammatory balance, cell growth, circadian rhythms, energy metabolism, neuronal function, and stress resistance.[1] At a biochemical level, their primary mechanism of action is removing acetyl groups from an amino acid called lysine found in proteins throughout the body. Removing this acetyl group in a process called “deacetylation” activates the target protein, allowing it to perform its vital functions in the body. Histones, the proteins around which our DNA is wound, are one group of proteins modified by histone deacetylation. Deacetylation of histones regulates gene expression, ensuring that your genes are turned “on” and “off” at the right time in your body.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor required for the activation and function of sirtuins.[2] Without sufficient NAD+, sirtuins cannot effectively regulate the body’s inflammatory balance, metabolism, and stress response system, leading to a breakdown of bodily functions.

NAD+ levels naturally decline with age. In fact, age-related NAD+ depletion may play a role in age-related health concerns, such as declines in metabolic health and cognitive acuity.

The Car and the Driver: How Sirtuins Drive Our Body Functions

The concept of sirtuins can feel pretty abstract, even to those of us with years of science education! To better understand how sirtuins impact the body, let’s draw a quick analogy.

If we compare the human body to a car, then sirtuins sit squarely in the driver’s seat, deciding when and where to turn a corner, pump the breaks, or increase speed to squeeze through a yellow traffic light. In your own body, sirtuins similarly “drive” numerous body functions.

Using the same car analogy, we can compare NAD+ to a car’s gasoline. Gas provides fuel for the vehicle, enabling the driver to decide where, when, and how to drive the car. Similarly, NAD+ provides power for sirtuins, allowing them to perform their vital activities.

The car’s driver also makes decisions that impact how well the car ages. He or she determines when it’s time to take the car into the shop for repairs and how often the oil is changed, factors that significantly impact how long a car will last. If the driver doesn’t perform these tasks, the car will age poorly and soon be non-functional. Conversely, a conscientious driver can keep a car in good shape well over the 200,000-mile mark, allowing the car to age with grace. A growing body of research indicates that sirtuins act in the same way, exerting a powerful influence on how our bodies age.

Sirtuins Regulate the Way You Age

The aging process is characterized by declines in numerous body systems and function, including:

    • Impaired blood sugar regulation

    • Reduced cognitive acuity

    • Decreased energy and stamina

    • Impaired vision

    • Reduced collagen production in the skin, leading to lackluster skin and wrinkles

At one time, scientists thought that these declines were only typical manifestations of aging. However, a growing body of research indicates that sirtuins intersect with many cellular processes and body functions that decline with age, "rescuing" healthy body functions and restoring youthful vitality. In fact, sirtuins are increasingly being recognized as master regulators of longevity. If you want to age gracefully, then enhancing your sirtuin activity is essential.

How Sirtuins Rescue the Aging Body

Safeguard the Aging Brain

The brain undergoes several changes with aging, including increases in harmful reactive oxygen species, which disrupt the brain’s inflammatory balance. Sirtuin activation may help counteract age-related declines in brain function by protecting the brain from harmful reactive oxygen species (ROS)., supporting healthy cognition across the lifespan.[3]

Support Metabolic Health

Metabolic health, which includes your body’s ability to maintain healthy blood sugar and blood lipid levels, declines with age. Poor metabolic health, in turn, may lead to impairments in heart and brain function.

Sirtuin activation helps reverse metabolic decline, enhancing your body’s ability to use blood glucose and lipids from stored body fat for fuel.[4] Improved metabolism can enhance healthspan - the period in one's life that is lived in good health.

Improve the Body’s Response to Exercise

Physical activity is essential for whole-body health and longevity. However, research indicates that the skeletal muscle’s response to exercise is blunted with age, leading to dampened exercise-induced health benefits. Sufficient NAD+ levels along with sirtuin activation offers a solution to this problem by enhancing the generation of mitochondria, your cellular powerhouses, inside skeletal muscle cells. Enhanced mitochondrial production in skeletal muscle is shown to improve both muscle development and exercise capacity, helping you stay active as you grow older.[5]

How to Optimize Your Sirtuin Activity

It turns out that many of the environmental inputs our ancestors experienced throughout human evolution impact sirtuin expression, optimizing the activity of these powerful proteins.


Various phytochemicals found naturally in fruits, vegetables, and other plants, have been found to activate sirtuins. These compounds are frequently referred to as STACs, an acronym for "sirtuin-activating compounds."

One of the most potent STACs is resveratrol, the famous phytochemical found in grapes and red wine.[6] By enhancing sirtuin activity, resveratrol may support metabolic health and brain function. Unfortunately, you would need to drink a LOT of red wine to obtain enough resveratrol to efficiently activate your sirtuins, so this is one situation in which supplementation may be beneficial.

Quercetin is also a sirtuin activator, albeit with milder effects than resveratrol.[7] Quercetin demonstrates multiple benefits for longevity, including antioxidant and metabolic health-promoting effects. Some of these longevity benefits may be attributable to quercetin's impact on sirtuin activation, while others may be mediated by its effects on cellular senescence, another aging mechanism.


Our ancestors frequently experienced periods of food scarcity throughout human evolution that required them to fast for significant periods. Research suggests that these periodic bouts of food scarcity and fasting altered our genome, promoting the expression of genes and proteins that enhance resilience in the face of stressors such as food scarcity. The sirtuins are just one family of proteins bolstered by fasting; this enhanced sirtuin expression likely conferred survival benefits to our hungry hunter-gatherer ancestors. However, periodic fasting may also support our own health in the modern-day world by similarly promoting increased sirtuin expression.

The sirtuins SIRT1 and SIRT3 are activated by fasting.[8] The type of fasting that may best optimize sirtuin expression remains unknown at this time; however, this doesn't mean you should wait until the data is in to begin a fasting routine! We suggest that you start with intermittent fasting, an eating approach in which you eat your meals during a limited time window each day and fast for the remainder of the day. Many people find a 16:8 intermittent fasting approach feasible for their lifestyle; this approach involves fasting for 16 hours and eating within an 8-hour time window each day.


Exercise has been found to increase SIRT3 protein content, thereby enhancing overall sirtuin expression.[9] By enhancing sirtuin expression in skeletal muscle, exercise promotes mitochondrial biogenesis (the production of new, healthy mitochondria), which, in turn, enhances cellular energy production.

What form of exercise is best for activating sirtuins? Currently, the jury is out on this one. However, one study found that a combination of aerobic exercise and resistance training increased NAD+ levels in skeletal muscle, bolstering this vital sirtuin-activating cofactor.[10] Routinely incorporating aerobic exercise, such as running or cycling, with resistance training activity may help support sirtuin expression.

Age-related physical decline may be typical, but it is not inevitable! Through dietary and lifestyle interventions such as fasting, exercise, and strategic use of sirtuin-activating phytochemicals, you can optimize sirtuin activity and your health and vitality as you

[1] Rajman L, et al. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018; 27(3): 529-547.

[2] Imai SI and Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24(8): 464-471.

[3] Jesko H, et al. Sirtuins and their roles in brain aging and neurodegenerative disorders. Neurochem Res. 2017; 42(3): 876-890.

[4] Houtkooper RH, et al. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012; 13(4): 225-238.

[5] Radak Z, et al. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol. 2020; 35: 101467.

[6] Mohar DS and Malik S. The sirtuin system: The holy grail of resveratrol? J Clin Exp Cardiolog. 2012; 3(11): 216.

[7] Rahnasto-Rilla M, et al. Natural polyphenols as sirtuin 6 modulators. Sci Rep. 2018; 8: 4163.

[8] Zhu Y, et al. Metabolic regulation of sirtuins upon fasting and the implication for cancer. Curr Opin Oncol. 2013; 25(6): 630-636.

[9] Vargas-Ortiz K, et al. Exercise and sirtuins: A way to mitochondrial health in skeletal muscle. Int J Mol Sci. 2019; 20(11): 2717.

[10] De Guia RM, et al. Aerobic and resistance exercise training reverses the age‐dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiol Rep. 7(12): e14139.

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