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All About SIRT3 + 20 Natural Ways to Increase it

Written by Joe Cohen, BS | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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Are You…..

  • Tired?
  • Get Fatigued easily?
  • Overweight?
  • Have insulin resistance?
  • Don’t burn fatty acids well?

SIRT3 combats all of these, and if you are suffering from these issues, SIRT3 might be a component of the problem…

Summary of SIRT3

SIRT3 is a mitochondrial protein and has also been studied in regards to longevity and metabolic syndrome.

It is involved in controlling reactive oxygen species in the cell. Higher levels of SIRT3 are connected to longevity.

SIRT3 is also involved in metabolism, and a study with mice lacking SIRT3 had greater obesity and insulin resistance on a high-fat diet.

Reduction of SIRT3 function was found to lead to mitochondrial dysfunction and metabolic syndrome [1].

Lower SIRT3 is also thought to be a causal factor for pulmonary hypertension [2].

SIRT3 and Increased Energy


One major function of SIRT3 is regulation of mitochondrial electron transport chain activity to increase energy production, particularly from fat.

SIRT3 is important for activating enzymes (e.g. LCAD) that break down and burn fat for energy. Simultaneously, SIRT3 decreases carb metabolism [3].

SIRT3 increases increase acetyl-CoA (by increasing acetyl-CoA synthetase 2), which is the fuel for the Kreb cycle [3].

Additionally, SIRT3 directly stimulates the Krebs cycle to increase energy production (especially the conversion of isocitrate to α-ketoglutarate by increasing IDH2 activity) [3].

SIRT3 promotes mitochondrial function by enhancing the activity of the first (NDUFS1&9) and second complexes (SDHA) in the mitochondrial electron transport chain. It might also stimulate the fifth complex [3].

Mice without SIRT3 show reduced ATP levels at baseline and during cellular stress [3].

SIRT3 increases the activity of SOD2 (MnSOD), reducing oxidative and radiation stress in mice and this is one mechanism by which calorie restriction helps combat oxidative stress [3].

SIRT3 is important for getting into ketosis (SIRT3-deficient mice are unable to produce normal levels of ketone bodies upon fasting) [3].

SIRT3 results in increased NADPH increased reduced glutathione in mitochondria (means it’s charged and ready to combat free radicals), and decreased DNA damage in the ear (cochlea) and in other tissues.

SIRT3 activates AMPK [4].

High levels of SIRT3 in mice inhibits hypoxia-inducible factor, which suppresses tumor growth [5].

SIRT3 decreases the synthesis of proteins in the mitochondria (by decreasing the activity of the ribosomal protein MRPL10) [3].

Technical: SIRT3 activates/increases: AceCS2, HMGCS2 (ketogenesis), GDH (converts glutamate to alpha-ketoglutarate), SDH, Ku70, MnSOD, FOXO3a, cyclophilin D (stop mPTP), H3-K56 (causing increased gene expression),ornithine transcarbamylase (OTC -a rate-limiting enzyme in the urea cycle), NDUFA9 (complex I), ICDH2 (promotes regeneration of antioxidants and catalyzes the citric acid cycle) [3]… SIRT3 Suppresses: p53, MRPL10 [3], Skp2 [6]

Natural Ways to Increase SIRT3

Pathways: PGC-1a [7], PPARa [8], Hydrogen Sulfide [9]

  1. Calorie restriction [3]
  2. Cold [10]
  3. Exercise [4]
  4. Estrogen/Estrogen-related receptor alpha [11]
  5. Nicotinamide Riboside [12]
  6. PQQ [13]
  7. Lipoic Acid [14]
  8. Resveratrol [15]
  9. Berberine [16]
  10. Bitter melon [17]
  11. EGCG [8, 18] – but EGCG decreases SIRT3 in cancer cells (good) [18]
  12. Oroxylin A/Chinese Skullcap [15]
  13. Leucine [19]
  14. HMB [19]
  15. ALCAR [20]
  16. Hydrogen Peroxide [21]
  17. Dan shen (Salvianolic acid A) [22]
  18. Kaempferol [23]
  19. Areca nut (keratinocytes) [24]
  20. Caffeic acid prevented decreased SIRT3 in liver injury model [25]… Chlorogenic acid/Green Coffee Extract also has caffeic acid.

What Inhibits SIRT3

A ketogenic diet decreases SIRT3 in mice [26]. Metformin decreases SIRT3 in the liver [11].

SIRT3 Can Contribute to Cancer

SIRT3 and the hallmarks of cancer. SIRT3 can link to six hallmarks of cancer, such as resisting cell death, genomic instability, and mutation, sustaining proliferative signaling, dysregulation of cellular energetics, tumor-promoting inflammation and invading growth suppressors [27].



SIRT3 Genes/SNPs

Check out the SIRT3 gene and SNPs on SelfDecode:

  1. RS11246020 (SIRT3)
  2. RS11555236 (SIRT3)

If you want to analyze your genome, SelfDecode is the best tool out there to do that.

SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thank you for your support.

About the Author

Joe Cohen, BS

Joe Cohen, BS

As a kid, Joe suffered from inflammation, brain fog, fatigue, digestive problems, mood and other issues that were poorly understood in both conventional and alternative medicine. Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health--something that has since become known as “biohacking”. With thousands of experiments and pubmed articles under his belt, Joe founded SelfHacked, the resource that was missing when he needed it. SelfHacked now gets millions of monthly readers. Joe is a thriving entrepreneur, author and speaker. He is the CEO and founder of SelfDecode. His mission is to help people gain access to the most up-to-date, unbiased, and science-based ways to optimize their health.


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