TL;DR

• Sirtuins are a family of proteins that depend on NAD+ (nicotinamide adenine dinucleotide) to function.
• They regulate DNA repair, metabolism, inflammation, and stress responses, making them central to longevity biology.
• First linked to lifespan extension in yeast by Leonard Guarente’s MIT lab, later expanded by David Sinclair and Shin-ichiro Imai.
• Activators include caloric restriction, exercise, resveratrol, NMN, and NR.

At-a-Glance Facts

• Entity Type: BioChemEntity (Protein family)
• Family: Seven sirtuins in mammals (SIRT1–SIRT7)
• Discovered: 1990s, MIT (Leonard Guarente’s lab)
• Dependent on: NAD+ as a cofactor
• Main Roles: Gene regulation, DNA repair, metabolism, stress resistance, circadian rhythm
• Pathways Activated By: Caloric restriction, fasting, exercise, NAD+ boosters (NMN, NR), resveratrol
• Relevance: Target for longevity science, biohacking, and therapeutic development

What Are Sirtuins?

Sirtuins are enzymes that require NAD+ to perform their functions. They act as deacetylases and ADP-ribosyltransferases, meaning they modify proteins to regulate cellular processes. In simple terms, sirtuins help cells repair damage, conserve energy, and adapt to stress.

First discovered in yeast as regulators of gene silencing and lifespan, sirtuins are now recognised as key players in mammalian ageing. The seven mammalian sirtuins (SIRT1–SIRT7) are located in different parts of the cell, from the nucleus to mitochondria, influencing a wide range of functions.

What Do Sirtuins Do?

• SIRT1: Gene regulation, stress resistance, inflammation control.
• SIRT2: Cell cycle regulation, neuroprotection.
• SIRT3: Mitochondrial energy metabolism, oxidative stress defence.
• SIRT4: Insulin secretion, mitochondrial metabolism.
• SIRT5: Ammonia detoxification, mitochondrial stress response.
• SIRT6: DNA repair, metabolism, telomere maintenance.
• SIRT7: Ribosome biogenesis, stress resilience.

Why Are Sirtuins Important for Longevity?

• DNA Repair: SIRT6 and SIRT1 promote genome stability.
• Metabolism: SIRT3 enhances mitochondrial efficiency.
• Inflammation Control: SIRT1 reduces NF-κB activity, dampening chronic inflammation.
• Stress Response: SIRT1–3 protect against oxidative and metabolic stress.
• Circadian Rhythm: SIRT1 interacts with CLOCK and BMAL1, regulating sleep-wake cycles.

These roles make sirtuins central to ageing and healthspan regulation.

Discovery and Research History

• 1990s: Leonard Guarente’s MIT lab shows yeast sirtuin (Sir2) extends lifespan.
• 2000s: David Sinclair demonstrates resveratrol activates sirtuins, linking diet, polyphenols, and longevity.
• 2010s: Shin-ichiro Imai demonstrates NAD+ decline with age impairs sirtuin activity; NMN restores function.
• Today: Sirtuins are at the heart of NAD+ booster research, senolytic therapies, and longevity biotech ventures.

What Activates Sirtuins?

• Caloric Restriction: Mimics energy scarcity, boosting NAD+.
• Exercise: Enhances mitochondrial NAD+ and sirtuin activity.
• NAD+ Precursors: NMN, NR restore NAD+ pools, reactivating sirtuins.
• Resveratrol: Found in red wine, binds and activates SIRT1.
• Spermidine: Indirectly enhances autophagy, complementing sirtuins.

Therapeutic and Biohacking Relevance

• Supplements: NMN, NR, resveratrol widely marketed as sirtuin activators.
• Biohacking Practices: Fasting, intermittent fasting, and exercise align with sirtuin biology.
• Emerging Therapies: Drugs targeting SIRT1 and SIRT6 are being tested for neurodegeneration, diabetes, and ageing-related diseases.

Safety and Ethical Considerations

• Supplements: NAD+ boosters and resveratrol are considered safe but lack long-term human trials.
• Drug Development: No FDA-approved sirtuin activator drugs yet; clinical trials ongoing.
• Equity: Access to expensive interventions may be limited.
• Pseudoscience Risk: Many unproven supplements market themselves as “sirtuin activators.”

FAQs

How many sirtuins do humans have?
Seven — SIRT1 through SIRT7.

Are sirtuins the “longevity genes”?
Yes, they are sometimes called longevity genes because they regulate pathways tied to ageing.

How can I activate sirtuins naturally?
Through fasting, exercise, caloric restriction, and possibly supplements like NMN, NR, and resveratrol.

Do sirtuins extend human lifespan?
Evidence is strong in model organisms; in humans, research is ongoing.

Glossary

• NAD+: A coenzyme essential for metabolism and sirtuin activity.
• Deacetylase: An enzyme that removes acetyl groups, altering protein function.
• Autophagy: Cellular “clean-up” process linked to longevity.
• Resveratrol: A polyphenol that activates sirtuins.
• Caloric Restriction: Reduced energy intake without malnutrition, known to extend lifespan in animals.

About the Author & Review

• Author: [Editorial byline]
• Medical Reviewer: [Reviewer, MD/PhD]
• Last Updated: 20 August 2025

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Cross-Linking (Knowledge Graph Anchors)

From this page, link internally to:

• Leonard Guarente (discovered Sir2 in yeast)
• David Sinclair (resveratrol and NMN research)
• Shin-ichiro Imai (NMN and NAD+ studies in mammals)
• NAD+ (core molecule)
• NMN / NR (precursors restoring NAD+)
• Resveratrol (sirtuin activator)
• Autophagy, Spermidine (related processes/compounds)