What Are Sirtuins? A Guide to Sirtuins and Their Role in Human Health

Written and Reviewed by: Elysium Health

What Are Sirtuins? A Guide to Sirtuins and Their Role in Human Health

Key Takeaways:

  • Sirtuins are a family of seven proteins that are essential for human health. They play a critical role in cell metabolism and gene expression and are often referred to as "the guardians of the genome."
  • Sirtuins can only function in the presence of the coenzyme NAD+. As we age, NAD+ levels decline, diminishing the activity of sirtuins.
  • Two of the most characterized sirtuins are SIRT1 and SIRT3, which play a variety of roles in DNA maintenance, chromatin modification, healthy glucose metabolism, mitochondrial function, and cellular energy production.

Related Products:

  • Basis for cellular aging: Designed to activate SIRT1 by boosting NAD+ levels with the NAD+ precursor NR and direct activation with pterostilbene.
  • Signal for metabolic aging: Combines the NAD+ precursor NMN and a SIRT3 Activation Complex to boost NAD+ levels and simultaneously activate SIRT3 for mitochondrial health.


Sirtuins are a family of seven proteins that play an essential role in our health—from DNA maintenance to mitochondrial biogenesis and cellular energy production. This article explains the science of sirtuins with a focus on two of its members, SIRT1 and SIRT3.

Proteins: They’re one of four main biological macromolecules, including lipids, carbohydrates, and nucleic acids. There are an estimated 80,000 to 400,000 types of proteins in the human body. More than 2,700 of these are a particular type of protein called enzymes, which catalyze chemical reactions to carry out important biological tasks, from digestion to replicating DNA. And seven of these enzymes are sirtuins, SIRT1-SIRT7. They play such a critical role in health, from metabolism to gene expression, that researchers have described them as “guardians of the genome” and even “the magnificent seven.” 

Sounds important (and a little dramatic), right? Let’s take a closer look at the role of sirtuins in your body to see why scientists are so interested. 

Genes or proteins? We just said that sirtuins are proteins, but you’ve probably heard of sirtuin genes, too—so which is it? Many of our genes code for proteins, providing instructions to the cell on how to make a specific protein. Proteins are the form that participate in enzymatic activities. So, there are both sirtuin genes and sirtuin proteins. For example, SIRT1 is the gene that codes for SIRT1 proteins. In scientific writing, italics are used when talking about the gene; no italics when referring to the protein


What are sirtuins? 

The scientific definition of sirtuins is NAD+-dependent histone deacetylases—a mouthful. What does it mean to be NAD+-dependent? Sirtuins can only function in the presence of NAD+. In fact, they consume one molecule of NAD+ each time they do their work of deacetylation (which we’ll explain shortly). The relationship to NAD+ is important: NAD+ stands for nicotinamide adenine dinucleotide, a coenzyme found in all living cells that’s essential for cellular metabolism, mitochondrial function, and hundreds of other biological processes. The concentration of NAD+ is determined by the nutritional state of the cell and by other factors, like age; NAD+ levels decline with age. So in their relationship with NAD+, sirtuins act as metabolic sensors, able to understand the metabolic state of the cell and act accordingly to help keep things in balance.  

Deacetylation is how they do it. Sirtuins remove acetyl groups from other proteins—mainly histones, but also non-histone proteins, and in doing so they regulate gene transcription and protein activity. Here’s how it works: Acetyl groups are physical tags on proteins that modify their properties, from stability to intra-cellular localization, and interactions with other molecules. Importantly, these tags are dynamic. In other words, they can come off and on. Sirtuins will recognize acetyl groups on specific molecules and remove the tag, resulting in a variety of effects depending on the substrate

Histones are proteins that form a complex with DNA, called chromatin. The histone is a large bulky protein that the DNA wraps itself around. When the histones have an acetyl group, the chromatin is open, or unwound. This unwound chromatin means the DNA is being transcribed and the gene expressed; when the histones are deacetylated by sirtuins, the chromatin is closed, or tightly and neatly wound, meaning gene expression is stopped, or silenced. In non-histone proteins, de-acetylation by sirtuins modifies the activity of the protein.

deacetylation activity of sirtuins

Putting it all back together—NAD+-dependent histone deacetylases—we now understand that sirtuins sense the metabolic state of the cell and then regulate gene expression or protein activity in response. Sirtuins are thought to do this mainly in response to stress of various kinds: genotoxic, metabolic, and even aging. One challenge, as we mentioned earlier, is that NAD+ levels and consequently sirtuin function actually decline with age, making it more difficult to respond to various stressors over time. 

Of the seven sirtuins in the cell, three of them work in the mitochondria, three of them work in the nucleus and one of them works in the cytoplasm, each playing a variety of roles. Two of the sirtuins, SIRT1 and SIRT3, are the most characterized in scientific literature and, therefore, the focus of this article.





Nucleus, cytoplasm

DNA maintenance, chromatin modification, glucose metabolism, differentiation, neuronal function, mitochondrial function


Cytoplasm, nucleus

Cell cycle


Mitochondria, nucleus, cytoplasm

Mitochondrial metabolism, mitochondrial biogenesis and protection, ATP production



Mitochondrial metabolism


Mitochondria, cytoplasm, nucleus

Urea cycle



DNA maintenance, genome maintenance, telomere maintenance, metabolism



rDNA transcription



What does SIRT1 do? Master regulator of DNA maintenance and much more.

SIRT1 is the most studied of the sirtuins because it’s the human equivalent of SIR2, the sirtuin first discovered in yeast cells. SIRT1 is located in the nucleus and the cytoplasm, and it’s expressed in most parts of the body—brain, heart, kidney, liver, pancreas, spleen, skeletal muscle, endothelial tissue, and white adipose tissue. 

SIRT1 plays a role in a variety of cellular responses and processes, including DNA maintenance, energy metabolism, apoptosis and cell survival, proliferation, differentiation, inflammation, neuronal function, cardiovascular function, ion channel regulation, and even mitochondrial function. We’ll focus here primarily on DNA maintenance and touch briefly on one aspect of energy metabolism, the cell’s response to nutrient stress or fasting. 

DNA maintenance refers broadly to a set of processes responsible for maintaining the stability and integrity of our genome. That’s right: We have finely calibrated processes for tuning up our DNA. That’s important because our genome isn’t perfectly stable as a result of endogenous and exogenous factors. DNA replicates constantly in our bodies, creating duplicate genomes each time a cell divides. This intricate process of replication and transcription can break down, causing errors in the code as it’s copied. Our DNA can also be affected by factors like radiation, carcinogens, heavy metals, and reactive oxygen species that are a normal byproduct of metabolism.

There are many ways that SIRT1 plays a role in DNA maintenance and genomic stability by interacting with both histone and non-histone proteins. For example, in the presence of DNA affected by stressors, SIRT1 can interact with histones to keep the chromatin compacted around the affected site to prevent it from replicating with the errors. In the presence of a double-strand DNA break, SIRT1 can recruit non-histone proteins like KU70 and members of the FOXO family and deacetylate them to increase DNA maintenance activity. 

Another important and well-studied function of SIRT1 is to coordinate the cell’s response to nutrient stress—what happens under conditions of calorie restriction or fasting. Preclinical research suggests that NAD+ levels and sirtuin function (especially SIRT1 and SIRT3) actually increase during fasting. The activation in particular of SIRT1 has a variety of positive downstream effects, influencing processes that include gluconeogenesis, cholesterol efflux, fat mobilization, and insulin secretion. One of the many mechanisms by which SIRT1 responds to nutrient stress is by binding to the non-histone protein PPARγ and lowering its activity, which helps to reduce fat storage. Further studies are needed to see if the beneficial effects of calorie restriction also involve sirtuin activation in humans.

While SIRT1 is expressed in times of cellular stress, it’s also possible to activate SIRT1 intentionally. Our product Basis contains two ingredients—nicotinamide riboside (NR) and pterostilbene—designed to stimulate SIRT1 in synergistic ways. The first is by increasing levels of NAD+ with NR, a precursor to NAD+. Basis was studied in our double-blind, randomized, placebo-controlled clinical trial, which demonstrated that it can increase NAD+ levels by an average of 40 percent from baseline in adults taking the recommended daily dose. 

The second way Basis targets SIRT1 is with pterostilbene, a polyphenol found in grape skins and blueberries that’s similar to resveratrol but more bioavailable. Preclinical research suggests that pterostilbene activates SIRT1 by binding to its enzymatic active pocket. By increasing NAD+ levels and activating SIRT1, Basis combats cellular aging, supports cellular energy, helps maintain healthy DNA, and supports hundreds of other integral processes in the cells.


What does SIRT3 do? Mitochondrial metabolism and quality control.

As we mentioned previously, three of the seven sirtuins are located in the mitochondria, which serve as a hub for metabolic reactions and produce roughly 95% of the cell’s energy in the form of ATP. SIRT3 is the most studied of the mitochondrial sirtuins and is the major deacetylase in mitochondria, affecting the status of at least 165 proteins in the mitochondria. Among its many roles, SIRT3 directly associates with multiple components of the ATP synthase–the mitochondrial machinery responsible for making ATP, and is shown to regulate multiple steps in the ATP production process. 

SIRT3 is also in charge of “quality control” in the mitochondria, playing a role in the mitochondrial unfolded protein response, mitochondrial fission and fusion, mitophagy, and mitochondrial biogenesis. Mitochondrial biogenesis, for example, is the process by which cells increase the amount of mitochondria in response to cellular stress—most notably, to exercise. This function is important because mitochondria are impaired during aging and various health issues. SIRT3 is thought to play a role in mitochondrial biogenesis as a downstream target of PGC-1α, the so-called “master regulator of mitochondrial biogenesis.”

More broadly, SIRT3 is involved in glucose metabolism, ATP production, fatty acid oxidation, ketone production during fasting, and amino acid cycling. It has even been implicated in nutrient sensing. Both mitochondrial function and levels of mitochondrial sirtuins decline as we age, contributing to aging through impaired metabolism. 

Our product Signal combines NMN with a SIRT3 Activation Complex to simultaneously activate SIRT3. NMN, or nicotinamide mononucleotide, is a direct precursor of NAD+, capable of efficiently replenishing our NAD+ supply lost with aging, activating SIRT3, and restoring metabolic balance. Studies show that NMN may work differently than NR, the NAD+ precursor in Basis—by using different transporters and affecting different tissues. 

Signal’s SIRT3 Activation Complex includes honokiol and viniferin. Honokiol is a natural compound derived from the bark of magnolia trees; it’s been shown in preclinical studies to promote mitochondrial function. Viniferin is derived from grapevine and is a derivative of resveratrol—the naturally occurring polyphenolic compound found in grapes and wine with antioxidant, and immunomodulatory properties. In preclinical models, viniferin has been shown to increase mitochondrial SIRT3 levels and enhance mitochondrial biogenesis.

The complementary ingredients in Signal help maintain overall mitochondrial health and promote optimal cellular energy production and utilization.


Background: What is the history of sirtuins?

Geneticist Dr. Amar Klar discovered the first sirtuin, SIR2, in the 1970s, identifying it as a gene that controlled the ability of yeast cells to mate. Years later, in the 1990s, researchers found other genes that were homologous (similar in structure) to SIR2 in other organisms like worms, fruit flies, and these SIR2 homologues were named sirtuins. While it turned out that organisms have a different number of sirtuins— bacteria only one, yeast have five, mice and humans have seven—they are evolutionarily conserved, meaning their structure and function has remained consistent throughout evolution.

In 1991, Elysium co-founder and MIT biologist Dr. Leonard Guarente, Ph.D., alongside graduate students Nick Austriaco and Brian Kennedy, conducted experiments to better understand how yeast aged. By chance, Austriaco tried to grow cultures of various yeast strains from samples he had stored in his fridge for months, which created a stressful environment for the strains. Only some of these strains could grow from here, but Guarente and his team identified a pattern: The strains of yeast that survived the best in the fridge were also the longest-lived. This provided guidance for Guarente so he could focus solely on these long-living strains of yeast.

Guarente and his team identified SIR2 as a gene that promoted longevity in yeast. It’s important to note that to date, there is no evidence that this study can be extrapolated to humans and more research is needed on SIR2’s effects in humans. Shortly thereafter, Guarente and his team discovered that SIR2 in yeast could only deacetylate other proteins in the presence of NAD+. In Guarente’s own words: “Without NAD+, SIR2 does nothing. That was the critical finding on the arc of sirtuin biology.” 

Without NAD+, SIR2 does nothing. That was the critical finding on the arc of sirtuin biology.” 

These early findings set the stage for all of today’s research on the role of sirtuins in metabolism and aging. Today there are more than 14,000 papers published about sirtuins, as well as products like Basis and Signal that can activate them to support general health and wellness.


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