Of Yeast and Men: Longevity and Sirtuins

BioViva Science
6 min readJan 18, 2024

Yeast go beyond bread and beer. In fact, they are helping us build inroads into the ravages of aging.

What’s brewing?

Sirtuins are a family of signaling proteins. They are named after their first documented member, Sir2. SIR is an acronym for “Silent Information Regulator.” SIR genes were found to suppress transcription silencing through a genetic screen for mutations (Dang, 2014).

Their silencing function is essential to regulating gene expression, influencing longevity, metabolism, and responses to cellular stress (Wu, 2022).

Although sirtuins were discovered in 1979, it took twenty years for widespread interest to ignite. This was because two studies linked Sir2 activity withextended replicative lifespan in yeast (Sinclair and Guarente, 1997; Guarente, 2000).

Speculation about Sir2’s role in the aging of multicellular organisms was investigated soon after (Imai et al., 2000), and they have since been identified in other cells (Rack, 2015).

Seven are known in humans. Two of which, SIRT6 and SIRT7, are conserved across kingdoms; those studied in fungi, animals, and protozoa are remarkably similar (Frye, 2000).

Sirtuins impact cellular aging on many levels

Caloric restriction is a robust intervention against aging, and sirtuins are largely to thank.

As a lifespan intervention, caloric restriction involves decreasing consumption while maintaining sound nutrition. CR consistently mitigates biological aging; it reliably extends healthspan and lifespan in a myriad of model organisms (Redman, 2011).

Sirtuins, particularly Sir2 and SIRT1, are major players in the desirable effects of caloric restriction (Cantó, 2009).

Yet, as noted elsewhere, there can be drawbacks to fasting and other forms of CR. Upregulating genes like Klotho could be safer and more sustainable.

Ideally, many genes should be targeted at once, and with finesse, which can only be done with BioViva’s CMV delivery system.

The finding that sirtuins are NAD+-dependent protein deacetylases that counter senescence in yeast was followed by several studies detailing physiological changes to caloric intake supervised by sirtuins.

The benefits of CR were eliminated in organisms engineered to have no sirtuins (Guarente, 2013).

The horizon stretches beyond yeast

With exciting results from multiple animal models, researchers have suggested sirtuin-based drugs could be an effective way to mimic the effects of CR (Guarente, 2013).

Sirtuin research is broadening our understanding of the mechanisms behind healthy longevity. SIRT1 activation mitigates the devastating progression of diabetes and bone loss. Mouse studies show that an overexpression of SIRT1 conferred protection from diabetes, including those given high-fat diets (Nakagawa, 2011).

A survey of the Dutch population has echoed animal findings, as variation in SIRT1 was found to impact mortality risks in subjects with type 2 diabetes (Zillikens, 2009).

What about the other sirtuins?

Yes, there are others. SIRT3-deleted mice, for instance, have diminished ATP levels during fasting compared to controls (Hirschey, 2010).

Moreover, SIRT7-deficient mice display heart hypertrophy, kyphosis, and premature death (Nakagawa, 2011).

Nakagawa proposes that “(SIRT2 to SIRT7) might need to be modulated in concert with SIRT1 to extend life span.” For complex organisms like ourselves, a careful symphony must be conducted.

So while they show promise, it should be noted that translating this research will take time.

Still, there are things we can do right now!

What can we do now?

The conventional methods of sirtuin activation are diet and exercise. Together they are the formula for not only sirtuin expression but many beneficial molecules.

However, diet and exercise always fail in the long run. As we get older, it becomes harder to glean the full benefits of lifestyle changes.

Genetic differences in sirtuin levels can be combated directly and indirectly gene therapy. While targeted gene therapy can produce very specific results, the hallmarks of aging are intimately intertwined.

Tackling certain facets of aging, like Klotho depletion, telomere shortening, or the loss of muscle mass, can have numerous desirable downstream effects. It may be more prudent to address these issues than to tweak something as fundamental as sirtuins.

SIRT1 administered through AAV7m8 vectors to target optic nerve disease improved outcomes for age-related retinal degeneration (Ahmara, 2019).

A subsequent study implied that SIRT1 administration by AAV is neuroprotective in a chronic glaucoma animal model. The authors point to its possible use in other neurodegenerative diseases (Yue, 2023).

AAVs are a wonder in the medical field, but they have limitations. The need to deliver multiple genes, as well as safety concerns surrounding multiple administrations, must be addressed.

BioViva is addressing these issues.

The Power of CMV

BioViva has brought the gene therapy industry its CMV delivery platform, which solves the aforementioned issues with other vectors. Already capable of administering three times the material of AAV, it can potentially deliver ten times as much genetic material.

Sirtuins are part of the aging process, but there are many others. This is why a large and potentially redosable vector is absolutely necessary.

Aging must be treated as a disease. To do this, we have to understand its hallmarks and have the right toolkit to tackle them simultaneously.

Authored by Ryan Hall

Ryan is an independent writer, and an avid enthusiast of emerging technologies.

He received his University education at Northern Michigan University, as a history major, where he was inducted into the Phi Beta Kappa Society for academic excellence. While in Michigan, he also trained as an athlete at the United States Olympic Education Center, where he achieved the status of a multiple-time University All-American in Greco-Roman wrestling.

He has authored several plays and a collection of poetry. Some of his major areas of interests include: Biblical and Classical studies, FinTech, medical innovation, and nutritional science.

References and Works Cited

  1. Ahmara Gibbons Ross, Devin McDougald, Reas Sulaimankutty, Kimberly Dine, Kenneth S Shindler; Creating Gene Therapy With SIRT1 Signaling for Neuro-protection in Optic Nerve Disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):637.
  2. Cantó C, Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab. 2009 Sep;20(7):325–31. doi: 10.1016/j.tem.2009.03.008. Epub 2009 Aug 25. PMID: 19713122; PMCID: PMC3627124.
  3. Dang W. The controversial world of sirtuins. Drug Discov Today Technol. 2014 Jun;12:e9-e17. doi: 10.1016/j.ddtec.2012.08.003. PMID: 25027380; PMCID: PMC4101544.
  4. Frye, R. A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochemical and biophysical research communications, 273(2), 793–798.
  5. Guarente, L. (2000). Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 14, 1021–1026.
  6. Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013 Oct 1;27(19):2072–85. doi: 10.1101/gad.227439.113. PMID: 24115767; PMCID: PMC3850092.
  7. Hirschey M. D., Shimazu T., Goetzman E., Jing E., Schwer B., Lombard D. B., Grueter C. A., Harris C., Biddinger S., Ilkayeva O. R., et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125
  8. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb 17;403(6771):795–800. doi: 10.1038/35001622. PMID: 10693811.
  9. Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci. 2011 Mar 15;124(Pt 6):833–8. doi: 10.1242/jcs.081067. PMID: 21378304; PMCID: PMC3048886.
  10. Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, Qu Y, Ortmayer M, Leidecker O, Cameron DR, Matic I, Peleg AY, Leys D, Traven A, Ahel I (July 2015). “Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens”. Molecular Cell. 59 (2): 309–20. doi:10.1016/j.molcel.2015.06.013. PMC 4518038. PMID 26166706.
  11. Redman LM, Ravussin E. Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes. Antioxid Redox Signal. 2011 Jan 15;14(2):275–87. doi: 10.1089/ars.2010.3253. Epub 2010 Aug 28. PMID: 20518700; PMCID: PMC3014770.
  12. Sinclair, D. A., and Guarente, L. (1997). Extrachromosomal rDNA circles — a cause of aging in yeast. Cell 91, 1033–1042. doi: 10.1016/s0092–8674(00)80493–6
  13. Wu, Qi-Jun, et al. “The sirtuin family in health and disease.” Signal Transduction and Targeted Therapy 7.1 (2022): 402.
  14. Yue J, Khan RS, Duong TT, Dine KE, Cui QN, O’Neill N, Aravand P, Liu T, Chaqour B, Shindler KS, Ross AG. Cell-Specific Expression of Human SIRT1 by Gene Therapy Reduces Retinal Ganglion

--

--

BioViva Science

BioViva Science is a gene therapy company that treats aging as a disease.