The TL;DR
Sirtuins (SIRT1–SIRT7) are a family of enzymes that protect the genome. They are the “repair crew” of the cell. When they are busy fixing broken DNA, they cannot regulate gene expression, leading to aging. They require NAD+ to function. Without NAD+, sirtuins are like a carpenter without a hammer.
Accessibility Level
Level 3 (Advanced): You cannot measure sirtuin activity directly. You support them by maintaining NAD+ levels (diet/supplements) and activating them via stress (exercise/fasting).
The Science of Maintenance
The 7 Sirtuins
- SIRT1: The most famous. Regulates metabolism, inflammation, and circadian rhythms in the nucleus.
- SIRT3: The “mitochondrial” sirtuin. Protects against oxidative stress.
- SIRT6: The “longevity” sirtuin. Critical for DNA repair and telomere maintenance.
The NAD+ Dependency
Sirtuins are NAD-dependent deacetylases. This means they consume NAD+ fuel to remove chemical tags (acetyl groups) from DNA and proteins. This turns off bad genes (like inflammation) and turns on good ones (like stress resistance).
- Young: High NAD+ → High Sirtuin activity → Tightly coiled, protected DNA.
- Old: Low NAD+ → Low Sirtuin activity → Unraveled, unstable DNA (Aging).
The “Information Theory of Aging”
David Sinclair proposes that aging is a loss of epigenetic information. Sirtuins are the distraction. When DNA breaks (from UV, radiation), SIRT1 rushes to fix it. If it gets distracted too often, it forgets to go back to its day job (silencing genes), and the cell loses its identity.
Evidence Matrix
| Source | Verdict | Notes |
|---|---|---|
| David Sinclair | Champion | Demonstrated that activating SIRT1 (via Resveratrol/NAD+) mimics calorie restriction. |
| Leonard Guarente | Discoverer | Discovered that SIR2 (yeast version) extends lifespan. |
| Clinical Data | Mixed | While strong in mice, human trials on sirtuin activators (like Resveratrol) have been inconsistent. |
How to Optimize
1. Boost NAD+
Sirtuins cannot work without fuel.
- Precursors: NMN or NR (Nicotinamide Riboside).
- Recycling: Exercise boosts the salvage pathway (NAMPT), making more NAD+.
2. Sirtuin Activators (STACs)
- Resveratrol: Found in red wine (but you’d need 100 bottles). Supplements are debated.
- Pterostilbene: A more bioavailable cousin of resveratrol (found in blueberries).
- Olive Oil: Contains Oleic Acid, a potent SIRT1 activator.
3. Hormetic Stress
Sirtuins are stress-response genes. They are activated by:
- Cold exposure.
- Heat (Sauna).
- Fasting.
References
Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology.
Sinclair, D. A., & Guarente, L. (2006). Small-molecule allosteric activators of sirtuins. Annual Review of Pharmacology.
Kane, A. E., & Sinclair, D. A. (2018). Sirtuins and NAD+ in the development and treatment of metabolic and cardiovascular diseases. Circulation Research.