Are Sirtuin Activators Able To Increase Lifespan? - Age Reversal Now

Are Sirtuin Activators Able To Increase Lifespan?

By Chris | Life Extension

May 01
sirtuin molecule

Sirtuin – The Fountain of Youth Protein?

What are they? Sirtuins are proteins activated by nutritional deficiency, stress, and small molecular sirtuin-activating compounds (STACs) that regulate a multitude of cellular functions related to aging and longevity.1

Caloric Restriction, Longevity, and Sirtuins!

It’s been known for over 80 years that reducing the calories fed to mice without malnutrition extends their lifespan considerably.2 To this day, caloric restriction (CR) is the only known method that extends the lifespan of every species studied. There are several theories as to why this is the case. Interestingly sirtuins play a role in the organism’s response to restricted calories. Sirtuins are one of a number of nutrient sensing pathways that modulate the ageing process.3

An important discovery was that the sirtuin found in yeast (Sir2) is activated by calorie restriction.4 In another study, a mutant yeast created with the gene encoding Sir2 removed was shown to possess a 50% shorter lifespan than the normal yeast cell, whereas a mutant with 2 times the amount of Sir2 lived 30% longer than the control group.5 The action of Sir2 in regulating lifespan has been confirmed in studies with other species.6 7 

When SIRT1 (The mammalian version of Sir2) is increased in mammals, it contributes to the health of the organism by delaying the onset of age-related diseases such as diabetes, cancer, and arteriosclerosis.8 9  These studies prove that sirtuins are important in regulating the ageing process. (The topic of cancer and sirtuin activators will be addressed in a later article.)

The mechanism that makes sirtuins powerful anti-aging proteins remains a mystery.  Although we don’t know why, the fact that CR has such an enduring effect on lifespan is striking.  The power of this information is incredible because it gives each of us the tools to extend our own lifespans!  But CR is difficult to do and not very fun.  What if there was a shortcut that would provide the benefits of caloric restriction without the hardship?

Sirtuin Activators and Resveratrol

A major breakthrough was made when evidence was revealed that small molecules, sirtuin activators such as resveratrol can activate sirtuin proteins and effectively slow down the aging process.10   Controversy ensued in the scientific community, with skeptics arguing that the effect was only seen in the test tube, and not in actual living organisms.11 12  Eventually solid evidence was presented that “small molecule sirtuin activators”  (STACs) could really mimic the age extending effects of caloric restriction.13

Next Generation Resveratrol – Pterostilbene

Resveratrol is an important compound that greatly enhanced the understanding of Sirtuins in-vivo (in a living organism) and in-vitro (in a test tube). Although well absorbed by the body, the bioavailability of resveratrol is extraordinarily low due to rapid and extensive metabolism.14 15  Resveratrol has a half-life of about nine hours once it is processed in the liver (by binding it with sulfate or glucoronate). Unbound resveratrol has a very short half-life of about 14 minutes if accompanied by quercetin or piperine.16  

Because of the low bioavailability, resveratrol’s usefulness as an anti-aging compound is limited.  However, new sirtuin activators have been discovered with higher bioavailability than resveratrol that have captured the excitement of the anti-aging community.  Pterostilbene, a natural polyphenol derived from blueberries and almonds is one such compound. 

Pterostilbene is an close analog of resveratrol that possesses powerful anti-oxidant activity.17  Studies show that pterostilbene has an 80% bioavailability versus 20% for resveratrol.  The half-life of pterostilbene is much longer than resveratrol, with 14 mins for unbound resveratrol versus 90-114 minutes for pterostilbene, making pterostilbene a prime target as a therapeutic natural substance with possible anti-aging properties.18

Resveratrol

Resveratrol

Pterostilbene

Pterostilbene

Above is the molecular structure of resveratrol versus pterostilbene.  You can see the striking similarities.  Pterostilbene differs only by the presence of methyl groups on the hydroxyl arms.  The presence of the additional methyl ether groups makes the molecule more hydrophobic (more soluble in oil) and more resistant to degradation in the liver, increasing its bioavailability.  Methylated polyphenols have been shown to have greater bioavailability due to increased intestinal absorption and enhanced hepatic stability.19  Methylated polyphenols such as pterostilbene are not broken down as quickly by the liver as their non-methylated cousins (such as resveratrol), and therefore more available for use in the body. Although blueberries are good for you, you would need to eat an incredibly large number of blueberries to obtain a therapeutic dosage of pterostilbene.20

Where to Find Pterostilbene?

Fortunately, pterostilbene is readily available as a nutritional supplement from a number of sources.  I take Double Wood Pterostilbene.  Double Wood Pterostilbene is third party tested and made in a cGMP facility in the United States.

Another option is Life Extension Resveratrol with Pterostilbene. for those who prefer the benefits of the combination of resveratrol and pterostilbene.

Another option is Relentless Improvement Pterostilbene, which they specify as 99.9% trans-pterostilbene.  Relentless Improvement is a trusted brand with good products.

I will be sharing more about pterostilbene’ s antioxidant benefits, including its potential effect of reducing the risk of cancer in another article soon.

 References

  1. Wang Y. Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation. Diabetes & Metabolism Journal. 2014;38(5):321-329. doi:10.4093/dmj.2014.38.5.321. [PMC free article]
  2. McDonald RB, Ramsey JJ: Honoring Clive McCay and 75 years of calorie restriction research. J Nutr 2010,140(7):1205–1210. 10.3945/jn.110.122804  PubMed Central PubMed
  3. Wang Y. Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation. Diabetes & Metabolism Journal. 2014;38(5):321-329. doi:10.4093/dmj.2014.38.5.321. [PMC free article]
  4. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289:2126–2128. [PubMed]
  5. Kaeberlein M, Hu D, Kerr EO, Tsuchiya M, Westman EA, Dang N, Fields S, Kennedy BK. Increased life span due to calorie restriction in respiratory-deficient yeast. PLoS Genet. 2005;1:e69. [PMC free article] [PubMed]
  6. Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A. 2004;101:15998–16003. [PMC free article] [PubMed]]
  7. Wang Y, Tissenbaum HA. Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech Ageing Dev. 2006;127:48–56. [PubMed]
  8. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390–392. [PubMed]
  9. Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010;1:3. [PMC free article] [PubMed]
  10. Konrad T. Howitz, Kevin J. Bitterman, Haim Y. Cohen, Dudley W. Lamming, Siva Lavu, Jason G. Wood, Robert E. Zipkin, Phuong Chung, Anne Kisielewski, Li-Li Zhang, Brandy Scherer & David A. Sinclair; Small molecule STACs extend Saccharomyces cerevisiae lifespan; Nature volume 425, pages 191–196 (11 September 2003; doi:10.1038/nature01960 [PubMed]
  11. Kaeberlein M., McDonagh T., Heltweg B., Hixon J., Westman E.A., Caldwell S.D., Napper A., Curtis R., DiStefano P.S., Fields S., et al. Substrate-specific activation of sirtuins by resveratrol. J. Biol. Chem. 2005;280:17038–17045. doi: 10.1074/jbc.M500655200. [PubMed] [Cross Ref]
  12. David Stipp;Thinning the Fog around Sirtuins;Scientific American;March 7, 2013 [Blog Post]
  13. Hubbard BP, Gomes AP, Dai H, et al. Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Science (New York, NY). 2013;339(6124):1216-1219. doi:10.1126/science.1231097. [PMC free article]
  14. Almeida L, Vaz-da-Silva M, Falcão A, Soares E, Costa R, Loureiro AL, Fernandes-Lopes C, Rocha JF, Nunes T, Wright L, Soares-da-Silva P. Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol Nutr Food Res. 2009;53(Suppl 1):S7–S15. doi: 10.1002/mnfr.200800177. [PubMed] [Cross Ref]
  15. Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, Beaudeux JL. Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res. 2010;54:7–16. doi: 10.1002/mnfr.200900437. [PubMed] [Cross Ref]
  16. Kapetanovic IM, Muzzio M, Huang Z, et al. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemotherapy and Pharmacology. 2011;68(3):593–601. [PMC free article] [PubMed]
  17. Rimando AM, Cuendet M, Desmarchelier C, Mehta RG, Pezzuto JM, Duke SO. Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. J Agric Food Chem. 2002;50:3453–3457. [PubMed]
  18. Kapetanovic IM, Muzzio M, Huang Z, et al. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemotherapy and Pharmacology. 2011;68(3):593–601. [PMC free article] [PubMed]
  19. Wen X, Walle T. Methylated flavonoids have greatly improved intestinal absorption and metabolic stability. Drug Metab Dispos. 2006;34:1786–1792. [PubMed]
  20. McCormack D, McFadden D. A Review of Pterostilbene Antioxidant Activity and Disease Modification. Oxidative Medicine and Cellular Longevity. 2013;2013:575482. doi:10.1155/2013/575482. [PMC Free Article]
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About the Author

Chris is a citizen researcher with an avid interest in Anti-Aging. Chris earned a BA degree in Biochemistry from the University of California, Berkeley and has studied Enzyme Kinetics and Bio-Physical Chemistry.

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