Supplements That Increase Sirtuins for Cellular Health and Longevity

December 8, 2025 •

4 min read

Research into sirtuin activators suggests that certain compounds can influence these vital regulatory proteins. Often called 'longevity proteins,' sirtuins are NAD+-dependent enzymes that play key roles in cellular energy optimization, DNA repair, and managing inflammation.

Quick Summary

This article explores key supplements that boost sirtuin activity, including NAD+ precursors like NMN and potent polyphenols. It explains the crucial role of sirtuins in cellular health and aging and details how these compounds work synergistically to support longevity pathways.

Key Points

NAD+ Precursors: Supplements like NMN and NR are highly effective for boosting sirtuin activity by increasing the cellular NAD+ fuel source.
Resveratrol: A polyphenol found in grapes and berries, resveratrol directly activates SIRT1, though its poor bioavailability in supplement form is a significant limitation.
Quercetin: This flavonoid modulates sirtuin pathways, with research confirming its ability to activate SIRT1 and SIRT6, particularly to reduce inflammation and oxidative stress.
Curcumin: The active ingredient in turmeric, curcumin activates SIRT1 and SIRT3, offering anti-inflammatory and neuroprotective benefits, though bioavailability can be a challenge.
Synergistic Strategy: For optimal results, combine NAD+ precursors with polyphenol activators and integrate healthy lifestyle practices like exercise and calorie restriction.
Sirtuins are Longevity Proteins: Known as 'cellular watchmen,' sirtuins are NAD+-dependent enzymes crucial for DNA repair, metabolism, and combating inflammation, all linked to longevity.

Understanding Sirtuins and Their Function

Sirtuins are a family of seven enzymes (SIRT1-7) found in mammals that function as metabolic sensors, linking cellular energy levels to gene expression and cell survival. These proteins are highly dependent on nicotinamide adenine dinucleotide (NAD+) as a cofactor. As NAD+ levels decline with age, so does sirtuin activity, which is linked to a number of age-related health issues. Activating sirtuins through diet, lifestyle, and supplementation is a primary focus of longevity research.

The Critical Role of NAD+ in Sirtuin Activation

NAD+ is a crucial coenzyme for all sirtuin functions. Its levels are a major determinant of sirtuin activity; as cellular NAD+ decreases with age, sirtuin function diminishes. This relationship is why supplements designed to increase NAD+ levels are often considered effective ways to boost overall sirtuin activity. NAD+ precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), have been the subject of extensive study for their ability to restore NAD+ levels and subsequently activate sirtuins.

Key Supplements That Increase Sirtuins

Multiple supplements, primarily falling into two categories—NAD+ boosters and polyphenol activators—are known to influence sirtuin activity. It is important to note that clinical outcomes vary between compound types and bioavailability is a key consideration.

NAD+ Precursors

These supplements provide the raw materials for the body to produce more NAD+, thereby indirectly activating all seven sirtuins. This approach works with the body's natural regulatory systems.

Nicotinamide Mononucleotide (NMN): NMN is a well-researched NAD+ precursor that has shown promise in animal and some human studies. It effectively increases NAD+ levels and supports sirtuin activity, mitigating age-related decline in energy metabolism and physical function.
Nicotinamide Riboside (NR): Similar to NMN, NR is another precursor that boosts NAD+ levels. It has been shown to improve various markers of metabolic health and combat age-related decline by supporting mitochondrial health through SIRT3 activation.

Polyphenol Activators

These plant-based compounds can directly or indirectly activate specific sirtuins, though their bioavailability often varies.

Resveratrol: One of the most studied polyphenols, resveratrol is found in grape skins, blueberries, and peanuts. It acts as an allosteric activator of SIRT1, and to a lesser extent SIRT3 and SIRT5. However, studies note its poor bioavailability in humans, with better efficacy often seen with improved formulations or derivatives.
Quercetin: A flavonoid found in many fruits and vegetables, quercetin has been shown to interact with sirtuins. It can activate SIRT6 and SIRT1 in certain contexts, with research showing it can modulate inflammatory responses and support antioxidant pathways via SIRT1. Its bioavailability can be a limiting factor.
Curcumin: The active compound in turmeric, curcumin is a potent anti-inflammatory agent that can also activate sirtuins. It is known to stimulate SIRT1 and SIRT3, with research pointing to its neuroprotective effects and ability to combat oxidative stress through sirtuin pathways. Similar to other polyphenols, its bioavailability can be low.
Fisetin: This flavonoid, found in fruits like strawberries, has been shown to extend lifespan in some animal models and has senolytic properties. Fisetin activates multiple sirtuins, including SIRT1, SIRT3, and SIRT6, and helps suppress oxidative stress.
Pterostilbene: A methylated derivative of resveratrol found in blueberries, pterostilbene exhibits higher bioavailability than resveratrol. It activates SIRT1 and other longevity pathways, supporting metabolic health and mitochondrial function.

Comparison of Key Sirtuin-Activating Supplements


Feature	NMN/NR (NAD+ Precursors)	Resveratrol	Quercetin	Curcumin
Mechanism	Replenishes NAD+, the fuel for all sirtuins.	Directly activates SIRT1 (allosterically).	Modulates multiple sirtuins, including SIRT1 and SIRT6.	Stimulates SIRT1 and SIRT3.
Sirtuins Targeted	Supports all 7 sirtuins.	Primarily SIRT1; also SIRT3, SIRT5.	SIRT1, SIRT6.	SIRT1, SIRT3.
Bioavailability	Good; reliably increases cellular NAD+.	Poor; low absorption limits effectiveness.	Low; limits clinical efficacy.	Low; often requires special formulations for absorption.
Clinical Evidence	Strong and emerging for metabolic health.	Mixed; limited by bioavailability issues.	Limited human trials focusing specifically on sirtuin activation.	Some evidence, but low bioavailability is a major challenge.

The Importance of a Synergistic Approach

While some supplements offer targeted effects, a synergistic approach is often most effective for comprehensive sirtuin support. For instance, combining NAD+ boosters like NMN or NR with polyphenol activators can provide both the necessary fuel (NAD+) and specific enzyme activation. In addition, lifestyle interventions such as regular exercise and caloric restriction naturally increase NAD+ and activate sirtuins, enhancing the effects of supplementation. For optimal cellular health, a combination of targeted supplements and healthy lifestyle habits is likely the most robust strategy. The interplay between dietary intake, exercise, and supplementation creates a powerful synergy that promotes long-term vitality.

Conclusion

Sirtuins are a family of NAD+-dependent enzymes that are critical to cellular health, metabolism, and longevity. Their activity declines with age due to decreasing NAD+ levels. Fortunately, specific supplements can effectively boost sirtuin activity. NAD+ precursors like NMN and NR provide the necessary fuel for all sirtuins, reliably increasing cellular NAD+ pools. Meanwhile, polyphenols such as resveratrol, quercetin, and curcumin act as direct or indirect activators, often targeting specific sirtuin isoforms. While direct activators like resveratrol can suffer from poor bioavailability, targeted formulations and higher bioavailable derivatives like pterostilbene exist. Ultimately, a balanced approach combining potent supplements with healthy lifestyle habits offers the best pathway to maximize sirtuin function and support healthy aging.

Frequently Asked Questions

NAD+ boosters, such as NMN and NR, are indirect activators that provide the necessary fuel for sirtuins to function, thereby supporting all seven isoforms. Polyphenol activators like resveratrol or quercetin, on the other hand, are direct or indirect activators that can specifically target certain sirtuin enzymes.

While resveratrol directly activates SIRT1 in laboratory studies, its effectiveness in humans is limited due to poor oral bioavailability. Better results may be achieved with more bioavailable derivatives like pterostilbene or by focusing on NAD+ precursors.

Sirtuins are entirely dependent on NAD+ as a cofactor to perform their enzymatic functions, including deacetylation. Declining NAD+ levels with age are a primary reason for reduced sirtuin activity, making NAD+ repletion a key strategy for boosting sirtuins.

Yes, many foods contain sirtuin-activating compounds. For example, red grapes and blueberries contain resveratrol and pterostilbene, green tea contains EGCG, and turmeric provides curcumin. However, achieving the high concentrations used in some studies often requires supplementation.

NAD+ precursors, like NMN and NR, are the most scientifically validated approach, as human studies confirm they safely increase NAD+ levels. This provides the cellular fuel needed for all sirtuins to operate efficiently.

Yes, lifestyle changes can effectively boost sirtuin activity. Regular exercise and caloric restriction, or intermittent fasting, naturally increase the NAD+/NADH ratio, which strongly activates sirtuins and supports cellular repair.

A synergistic approach is often more effective. Combining NAD+ precursors to ensure sufficient fuel for all sirtuins with specific polyphenol activators can provide comprehensive support for cellular health and longevity pathways.