Sirtuins, Aging, and Mitochondrial Function

Healthy aging is just as important as how long we live. Many of the chronic illnesses we face are simply general problems associated with aging due to a decline in mitochondrial function.

This article will examine how sirtuins play a part in the aging process by how they regulate our cellular health. Genetic SIRT3 variants are important in oxidative stress and fat metabolism.[ref]

Mitochondria, Energy Production, and Sirtuins:

Your mitochondria (the ‘powerhouse of the cell’) are vital to healthy longevity. In the mitochondria, molecules convert into energy and then store as ATP (adenosine triphosphate). When other parts of your cells need energy, a bond breaks in the ATP molecule, releasing energy and creating ADP (adenosine diphosphate) + a phosphate molecule.

Cells have anywhere from dozens to thousands of mitochondria in them, depending on the type of cell. Cells that need a lot of energy, like heart muscle cells and liver cells, have more mitochondria.

Mitochondria cross-section showing inner and outer membranes. Wikimedia Commons – C/C license

The inner membrane of the mitochondria is where a lot of the magic takes place. It is where a series of reactions change the electrical potential (think energy) across the membrane.

The source of chemical energy for the mitochondria is the food you eat or your own stored fat. In addition, you need ways of moving the electrons – molecules that will accept and donate electrons – across the membrane. NAD+ and FAD are the two crucial molecules here, which we get from riboflavin and B3.

But we also need a way to turn on and off the production of the required proteins inside the mitochondria and take care of oxidative stress. That is where sirtuins come into play — along with NAD+.

What do sirtuins have to do with aging?

Sirtuins are a family of seven proteins that are important in removing acetyl groups from molecules.

Acetyl groups within the cell nucleus attach to the DNA at specific points, marking and opening up the DNA for transcription. They are like a chemical post-it note, pointing to what needs to be transcribed and then turned into a protein.

Sirtuins remove that acetyl group at the right time, which allows the DNA to compact again and protects it from damage.

The ability to turn on and off genes for transcription is what allows your body to work. But your genes also need ways to protect the DNA. Preventing damage to DNA is vital for healthy aging. (Damaged DNA can lead to cellular death or cancer.)

Sirtuin activation occurs by NAD+ (nicotinamide adenine dinucleotide). NAD is also a vital component of mitochondrial energy production; it elevates in response to calorie restriction.

Related Article: NAD+, nicotinamide riboside, and NMN)

In addition to removing acetyl groups in the nucleus, other sirtuins are active in the mitochondria and the cell’s cytoplasm. Your mitochondria contain their own DNA, which codes for a few mitochondrial-specific proteins.

What is SIRT3?

SIRT3 is a mitochondrial protein and has also been studied in regards to longevity and metabolic syndrome. It involves turning on and off several important mitochondrial genes. Higher levels of SIRT3 have connections 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. Reduced SIRT3 function leads to mitochondrial dysfunction and metabolic syndrome.[ref][ref]

Mice with the gene deleted are more likely to have tumors, and human breast cancer tissue shows deletion of SIRT3 in 40% of carcinomas.[ref] SIRT3 function is significant in preventing cancer.

What activates SIRT3?

Researchers have found that both exposures to the cold and reducing calories upregulate SIRT3.[ref]

A December 2014 study in Cell Metabolism found that nicotinamide riboside, a precursor to NAD+ (nicotinamide adenine) dinucleotide) and a derivative of vitamin B3 could prevent noise-induced hearing loss in mice. The researchers found that nicotinamide riboside activated SIRT3 in the mitochondria. This increase in SIRT3 prevented the noise-induced hearing loss. Moreover, the addition of nicotinamide riboside (NR) was effective either before or after the hearing loss.[ref]

Other studies show that calorie restriction slows age-related hearing loss through increasing SIRT3 “by promoting the glutathione-mediated  mitochondrial antioxidant defense system.” [ref][ref]

SIRT3 may be involved in longevity through interaction with FOXO3, which “modulates mitochondrial mass, A/TP production, and clearance of defective mitochondria”.[refFOXO3 genetic variants are also associated with increased longevity.


SIRT3 Genetic Variants

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Check your genetic data for rs11555236 (23andMe v4 only):

  • C/C: typical
  • A/A: increased longevity, increased SIRT3[ref]

Members: Your genotype for rs11555236 is .

Check your genetic data for rs11246020 (23andMe v4; Ancestry DNA):

  • C/C: typical
  • C/T: increased risk of metabolic syndrome
  • T/T: 50% increased risk of metabolic syndrome, reduced function[ref][ref]

Members: Your genotype for rs11246020 is .

Check your genetic data for rs185277566 (23andMe v4 only):

  • C/C: decreased SIRT3, increased risk of heart attack[ref]
  • C/G: decreased SIRT3
  • G/G: typical

Members: Your genotype for rs185277566 is .

 


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Revised and updated 2/11/19

References:

Airhart, Sophia E., et al. “An Open-Label, Non-Randomized Study of the Pharmacokinetics of the Nutritional Supplement Nicotinamide Riboside (NR) and Its Effects on Blood NAD+ Levels in Healthy Volunteers.” PloS One, vol. 12, no. 12, 2017, p. e0186459. PubMed, https://doi.org/10.1371/journal.pone.0186459.
Albani, Diego, et al. “Modulation of Human Longevity by SIRT3 Single Nucleotide Polymorphisms in the Prospective Study ‘Treviso Longeva (TRELONG).’” Age, vol. 36, no. 1, Feb. 2014, pp. 469–78. PubMed Central, https://doi.org/10.1007/s11357-013-9559-2.
Brown, Kevin D., et al. “Activation of SIRT3 by the NAD+ Precursor Nicotinamide Riboside Protects from Noise-Induced Hearing Loss.” Cell Metabolism, vol. 20, no. 6, Dec. 2014, pp. 1059–68. www.cell.com, https://doi.org/10.1016/j.cmet.2014.11.003.
Could a Vitamin Supplement Prevent Hearing Loss? 3 Dec. 2014, https://www.medicalnewstoday.com/articles/286408.
Han, Chul, and Shinichi Someya. “Maintaining Good Hearing: Calorie Restriction, Sirt3, and Glutathione.” Experimental Gerontology, vol. 48, no. 10, Oct. 2013, pp. 1091–95. PubMed Central, https://doi.org/10.1016/j.exger.2013.02.014.
Hirschey, Matthew D., et al. “SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome.” Molecular Cell, vol. 44, no. 2, Oct. 2011, pp. 177–90. PubMed Central, https://doi.org/10.1016/j.molcel.2011.07.019.
—. “SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome.” Molecular Cell, vol. 44, no. 2, Oct. 2011, pp. 177–90. PubMed Central, https://doi.org/10.1016/j.molcel.2011.07.019.
Kane, Alice E., and David A. Sinclair. “Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases.” Circulation Research, vol. 123, no. 7, Sept. 2018, p. 868. www.ncbi.nlm.nih.gov, https://doi.org/10.1161/CIRCRESAHA.118.312498.
—. “Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases.” Circulation Research, vol. 123, no. 7, Sept. 2018, pp. 868–85. PubMed, https://doi.org/10.1161/CIRCRESAHA.118.312498.
Lombard, David B., and Bernadette M. M. Zwaans. “SIRT3: As Simple as It Seems?” Gerontology, vol. 60, no. 1, 2014. www.ncbi.nlm.nih.gov, https://doi.org/10.1159/000354382.
Marcus, Joshua M., and Shaida A. Andrabi. “SIRT3 Regulation Under Cellular Stress: Making Sense of the Ups and Downs.” Frontiers in Neuroscience, vol. 12, Nov. 2018, p. 799. PubMed Central, https://doi.org/10.3389/fnins.2018.00799.
Reiter, Russel J., et al. “Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3.” International Journal of Molecular Sciences, vol. 19, no. 8, Aug. 2018, p. 2439. PubMed Central, https://doi.org/10.3390/ijms19082439.
Someya, Shinichi, et al. “Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction.” Cell, vol. 143, no. 5, Nov. 2010, pp. 802–12. PubMed, https://doi.org/10.1016/j.cell.2010.10.002.
Tseng, Anne H. H., et al. “SIRT3 Deacetylates FOXO3 to Protect Mitochondria against Oxidative Damage.” Free Radical Biology & Medicine, vol. 63, Oct. 2013, pp. 222–34. PubMed, https://doi.org/10.1016/j.freeradbiomed.2013.05.002.
Yin, Xiaoyun, et al. “Genetic and Functional Sequence Variants of the SIRT3 Gene Promoter in Myocardial Infarction.” PLOS ONE, vol. 11, no. 4, Apr. 2016, p. e0153815. PLoS Journals, https://doi.org/10.1371/journal.pone.0153815.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.