Sirtuin Modulating Compounds: Influencing the Function of Key Proteins for Longevity

Individually targeting the seven types of sirtuins with molecules to activate or inhibit their function has a wide range of beneficial effects against age-associated conditions like cancer and diabetes.

By Bennett M. Sherman
  1. Introduction: Explaining Sirutins
  2. Targeting Sirtuins for Different Age-Related Conditions
    1. SIRT-1 Modulators
      1. Sirt-1 Activation
      2. Synthetic Sirtuin Activators
      3. Naturally-Occurring SIRT-1 Activators
    2. Other Sirtuin modulators
    3. Choosing a Sirtuin Modulator for Use

Sirtuins are a family of enzymes that depend on the molecule nicotinamide adenine dinucleotide (NAD+) for their function. In mammals, there are seven known sirtuins named SIRT-1 to SIRT-7. These enzymes function by removing protein tags called “acetyl” groups from DNA-organizing proteins called histones, along with cell proteins regulating cell structure and DNA repair.

Sirtuins play key roles in different biological pathways, ranging from DNA reading (transcription) to metabolism to genome stability, giving them essential roles and implicating them in many age-associated diseases. Such diseases include cancer, neurodegenerative conditions, diabetes, cardiovascular and autoimmune diseases. Along those lines, pharmacological modulation of their enzymatic activity has become a promising way to modify disease onset and progression. Extensive research has been conducted on sirtuin modulators that activate or inhibit sirtuins. Sirtuin modulators act specifically on each of the seven types of sirtuins to alleviate age-related diseases.

History of Sirtuin Modulating Compounds

Leonard P. Guarente, a famous American biologist known for lifespan research, is known as the leading propenent of the hypothesis that coloric restriction slows aging through sirtuin activation. Through research on activating sirtuins, Konrad Howitz of Biomol Inc. and biologist David Sinclair discovered sirtuin activating compounds (STACs). Howitz and Sinclair published a highly-touted paper in September, 2003 reporting that polyphenols like resveratrol activate human SIRT1 and extend the lifespan of yeast.

Sirtris Pharmaceuticals, David Sinclair’s company that extensively researched STACs, was purchased by GlaxoSmithKline in 2008 and was subsequently shut down by GlaxoSmithKline for undisclosed reasons.

Targeting Sirtuins for Different Age-Related Conditions

SIRT-1 is the best studied and characterized sirtuin. Located in the nucleus, it regulates gene stability, stress responses, and apoptosis.

SIRT-1 Activation

Sirtuin activating compounds (STACs) increase mammalian SIRT1 activation and have demonstrated success in animal models and clinical trials. In 2003, David Sinclair’s laboratory discovered the first generation of SIRT-1 activators in a drug screening. Several plant polyphenols were shown activate SIRT-1 and to extend the lifespan of yeast, such as butein, piceatannol, and isoliquiritigenin. The most effective of the STACs, which activated SIRT-1 by more than 10-fold, is resveratrol, a naturally-occurring molecule in grapes and red wines. Since then, another naturally-occurring STAC similar to resveratrol with even more potent SIRT-1 activating abilities called pterostilbene has been identified.

Screening Synthetic Sirtuin Activators

The implication that STACs benefit aging and age-associated diseases along with the discovery of shortcomings with natural STACs, such as limited blood availability after consumption (bioavailability) and unspecific action of the STACs prompted the search for synthetic STACs. From the search for synthetic STACs, compounds like SRT1720 were identified that activate SIRT-1 more potently than resveratrol. These sirtuin activators have been used in research studies with the most advanced compound in the series, SRT2104, holding promise for psoriasis treatment. Other sirtuin activators like thiazolopyridine, benzimidazole, and bridged urea have been developed for improved potency and also have promising therapeutic potential. These examples along with STACs activating SIRT-1 make SIRT activation a promising approach for promoting longevity.

Naturally-Occurring SIRT-1 Activators

The naturally occurring SIRT-1 activators, including berberine, resveratrol, curcumin, quercetin, and fisetin, are found in various fruits, nuts, and vegetables. These SIRT-1 activators have been shown to promote cardiovascular health, suppress inflammation, and inhibit tumor growth. Moreover, the SIRT-1 activator fisetin has been shown to increase healthy mouse lifespan by ~20%. As such, naturally occurring SIRT-1 activators are possibly the most promising of all SIRT-modulating compounds.

SIRT2 Modulators

SIRT-2 is located in the cell’s aqueous interior (the cytoplasm) and plays key roles in several cellular processes like cell metabolism. Interestingly, no SIRT-2 activators have been discovered, leaving only SIRT-2 inhibitors as possible treatment options.

SIRT3 Modulators

SIRT-3 localizes to the mitochondria, the cell’s power-generating structure, and has been shown to regulate the function of various metabolic enzymes. Additionally, SIRT-3 can regulate the clearance of toxic, oxygen-containing molecules called reactive oxygen species that drive oxidative stress in cells.

SIRT-4 Modulators

SIRT-4 also localizes to the mitochondria within its interior matrix. SIRT-4 controls various activation pathways for different proteins. Currently, no specific SIRT-4 modulators are available.

SIRT-5 Modulators

SIRT-5 is located in the mitochondria and controls several cellular pathways, including the regulation of cell energy production. Only a few SIRT-5 modulators are specific and have been tested on diseases.

SIRT-6 Modulators

SIRT-6 localizes to the cell’s nucleus and influences energy metabolism, DNA repair, aging, inflammation, and immunity. Both SIRT-6 activators and inhibitors have been identified and evaluated.

SIRT-7 Modulators

SIRT-7 localizes to the nucleus and is important for cell viability. Very few reports are available for SIRT-7.

Sirtuin Modulators that Influence Activity of Multiple Sirtuins

Several sirtuin modulators that influence the activation of all seven sirtuins, dubbed pan-sirtuin modulators, mainly have sirtuin inhibitory action. The main issue regarding these non-specific sirtuin inhibitors is their ineffectiveness of treatment due to inhibiting two or more sirtuins that exert opposite effects in cells. Along those lines, it is preferable not to use pan-sirtuin modulators, and someone should use extra caution if they decide to use a pan-sirtuin modulator.

Choosing a Sirtuin Modulator for Use

With the wide array of sirtuin modulators that activate or inhibit each of the seven sirtuins, along with the pan-sirtuin modulators, finding effective sirtuin modulators for consumption may prove difficult. For this reason, consulting a medical professional before choosing a sirtuin modulator is paramount.

The majority of sirtuin modulators under investigation affect the activation of SIRT-1 since its activation or inhibition affects a multitude of cellular processes. Moreover, naturally-occurring sirtuin activators like berberine, quercetin, and curcumin all influence SIRT-1. Since these SIRT-1 activators can be found in fruits, nuts, and berries, along with supplements, they are the easiest to obtain. What’s more, all of the naturally-occurring SIRT-1 activators have a strong safety profile.


Abbotto E, Scarano N, Piacente F, Millo E, Cichero E, Bruzzone S. Virtual Screening in the Identification of Sirtuins’ Activity Modulators. Molecules. 2022; 27(17):5641.

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