October 27, 2022

A Brief Guide to Sirtuins

September 22, 2023

A Brief Guide to Sirtuins

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A Brief Guide to Sirtuins

The last few decades have seen incredible advances in our understanding of how we age and how we might be able to alter the process for the better. Some of the most exciting breakthroughs have come through research into the sirtuin family of enzymes. In this post we’ll explain how sirtuins work, look at the research that shows they play a key role in longevity, and discuss how you can apply these findings to actions in your own life.

What are sirtuins?

Sirtuins are a family of enzymes that regulate metabolism and a wide range of other processes, including insulin release and DNA repair. They are named after the SIR2 gene (hence sirtu-ins) which was first identified in yeast, but closely equivalent genes have also been found in species including worms, flies, rodents, and humans (who have seven distinct sirtuins, named SIRT1-7). This suggests that sirtuins were present in some of the first living organisms to evolve on earth, so the fact that they’ve been conserved over billions of years and across such disparate forms of life indicates that they’re pretty important!

How are sirtuins linked to longevity?

The first indication that sirtuins play a role in longevity came in 1995, when a mutation in the yeast SIR4 gene was found to extend the organism’s lifespan by more than 30% [1]. Researchers then examined other members of the SIR family and discovered that yeast cells with an extra copy of the SIR2 gene lived 30% longer than normal [2]. A very similar effect was also seen when the sirtuin gene sir-2.1 was over-expressed in the nematode worm C. elegans [3].

Sirtuins have a wide range of complex functions, so working out how they are causing these changes is tricky. However, it appears to be linked to the beneficial effects seen with calorie restriction; when organisms are given at least 20% less nutrition than normal, they have longer lifespans and improved protection against age-related disease. Interestingly, though, organisms that have had sirtuin genes removed do not experience these effects [4], suggesting that calorie restriction extends healthspan by activating sirtuins.

So how are these effects linked? Well, like much of longevity science, it’s complicated! But a crucial factor is that sirtuins require the molecule NAD+ in order to function. NAD+ is a key component in a pathway that cells use to produce energy, so sirtuins' activity changes in response to how much energy is present in a cell, essentially enabling them to act as stress sensors. It appears that when cells are stressed - as they are under calorie restriction, for example - NAD+ levels rise and sirtuins are able to exert their protective effects.

What does this mean for me?

Of course, the big question is: how can we apply these findings to humans? It all comes down to ways we can activate the sirtuins that are present in our bodies.

  1. Calorie restriction: Mimicking calorie restriction using intermittent fasting regimes is one way to stress your cells and activate sirtuins, and there is a growing body of research supporting the health benefits of this approach.
  2. Other types of cell stress: Exercise (particularly high-intensity interval training [HIIT] and resistance training) as well as hot and cold therapy also appear to be effective at ‘shocking the system’ and activating sirtuins.
  3. Sirtuin-activating compounds: Specific supplements and foods can also increase sirtuin activity. For example, resveratrol is a molecule that is produced by plants in response to damage or stress, but research has shown that it can activate the SIRT1 enzyme in humans. It is found in high concentrations in blueberries, raspberries, and grapes (and red wine), but is best taken as a supplement, and numerous studies have linked its consumption to improved healthspan.
  4. SIRT6 activators: Recent research has suggested that SIRT6 could be especially important for longevity. One particularly striking study from 2021 showed that mice with extra copies of the SIRT6 gene have significantly improved healthspans [5]. Supplements including quercetin, fisetin, fucoidan and oleic acid are all thought to activate SIRT6, as are natural plant polyphenols such as cyanidin, which is found in raspberries, cherries, blackcurrants, and blackberries.
  5. NMN supplements: Because sirtuins need NAD+ to function, it’s believed that taking supplements containing NAD+ precursors, such as NMN or NR, will result in increased NAD+ levels and greater sirtuin activity. NAD+ precursor supplements have shown encouraging results in animal models and clinical trials investigating the benefits in humans are currently underway. 

Conclusion

While it’s important to note that there is still a need for robust clinical evidence directly linking sirtuins to positive health impacts in humans, there are many reasons to be excited. As we’ve seen, our current understanding already offers a wide range of practical ways to improve our aging by harnessing the power of sirtuins. It’s clear that we’ve only just scratched the surface of the vast potential of sirtuins, and as this fascinating research area continues to evolve it has the potential to truly revolutionize our approach to human aging.

References

  1. Kennedy, B.K., Austriaco, N.R. Jr., Zhang, J., & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80(3), 485–96 (1995) Link
  2. Kaeberlein, M., McVey, M., & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13(19), 2570–80 (1999) Link
  3. Tissenbaum, H., & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001) Link
  4. Lin, S.J., Defossez, P.A., & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000) Link
  5. Roichman, A., Elhanati, S., Aon, M.A. et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun 12, 3208 (2021) Link

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Oscar Allan

SCIENTIFIC CONTENT WRITER & RESEARCHER

Oscar is a science writer and e-learning developer with a master's degree in longevity-related topics

A Brief Guide to Sirtuins

The last few decades have seen incredible advances in our understanding of how we age and how we might be able to alter the process for the better. Some of the most exciting breakthroughs have come through research into the sirtuin family of enzymes. In this post we’ll explain how sirtuins work, look at the research that shows they play a key role in longevity, and discuss how you can apply these findings to actions in your own life.

What are sirtuins?

Sirtuins are a family of enzymes that regulate metabolism and a wide range of other processes, including insulin release and DNA repair. They are named after the SIR2 gene (hence sirtu-ins) which was first identified in yeast, but closely equivalent genes have also been found in species including worms, flies, rodents, and humans (who have seven distinct sirtuins, named SIRT1-7). This suggests that sirtuins were present in some of the first living organisms to evolve on earth, so the fact that they’ve been conserved over billions of years and across such disparate forms of life indicates that they’re pretty important!

How are sirtuins linked to longevity?

The first indication that sirtuins play a role in longevity came in 1995, when a mutation in the yeast SIR4 gene was found to extend the organism’s lifespan by more than 30% [1]. Researchers then examined other members of the SIR family and discovered that yeast cells with an extra copy of the SIR2 gene lived 30% longer than normal [2]. A very similar effect was also seen when the sirtuin gene sir-2.1 was over-expressed in the nematode worm C. elegans [3].

Sirtuins have a wide range of complex functions, so working out how they are causing these changes is tricky. However, it appears to be linked to the beneficial effects seen with calorie restriction; when organisms are given at least 20% less nutrition than normal, they have longer lifespans and improved protection against age-related disease. Interestingly, though, organisms that have had sirtuin genes removed do not experience these effects [4], suggesting that calorie restriction extends healthspan by activating sirtuins.

So how are these effects linked? Well, like much of longevity science, it’s complicated! But a crucial factor is that sirtuins require the molecule NAD+ in order to function. NAD+ is a key component in a pathway that cells use to produce energy, so sirtuins' activity changes in response to how much energy is present in a cell, essentially enabling them to act as stress sensors. It appears that when cells are stressed - as they are under calorie restriction, for example - NAD+ levels rise and sirtuins are able to exert their protective effects.

What does this mean for me?

Of course, the big question is: how can we apply these findings to humans? It all comes down to ways we can activate the sirtuins that are present in our bodies.

  1. Calorie restriction: Mimicking calorie restriction using intermittent fasting regimes is one way to stress your cells and activate sirtuins, and there is a growing body of research supporting the health benefits of this approach.
  2. Other types of cell stress: Exercise (particularly high-intensity interval training [HIIT] and resistance training) as well as hot and cold therapy also appear to be effective at ‘shocking the system’ and activating sirtuins.
  3. Sirtuin-activating compounds: Specific supplements and foods can also increase sirtuin activity. For example, resveratrol is a molecule that is produced by plants in response to damage or stress, but research has shown that it can activate the SIRT1 enzyme in humans. It is found in high concentrations in blueberries, raspberries, and grapes (and red wine), but is best taken as a supplement, and numerous studies have linked its consumption to improved healthspan.
  4. SIRT6 activators: Recent research has suggested that SIRT6 could be especially important for longevity. One particularly striking study from 2021 showed that mice with extra copies of the SIRT6 gene have significantly improved healthspans [5]. Supplements including quercetin, fisetin, fucoidan and oleic acid are all thought to activate SIRT6, as are natural plant polyphenols such as cyanidin, which is found in raspberries, cherries, blackcurrants, and blackberries.
  5. NMN supplements: Because sirtuins need NAD+ to function, it’s believed that taking supplements containing NAD+ precursors, such as NMN or NR, will result in increased NAD+ levels and greater sirtuin activity. NAD+ precursor supplements have shown encouraging results in animal models and clinical trials investigating the benefits in humans are currently underway. 

Conclusion

While it’s important to note that there is still a need for robust clinical evidence directly linking sirtuins to positive health impacts in humans, there are many reasons to be excited. As we’ve seen, our current understanding already offers a wide range of practical ways to improve our aging by harnessing the power of sirtuins. It’s clear that we’ve only just scratched the surface of the vast potential of sirtuins, and as this fascinating research area continues to evolve it has the potential to truly revolutionize our approach to human aging.

References

  1. Kennedy, B.K., Austriaco, N.R. Jr., Zhang, J., & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80(3), 485–96 (1995) Link
  2. Kaeberlein, M., McVey, M., & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13(19), 2570–80 (1999) Link
  3. Tissenbaum, H., & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001) Link
  4. Lin, S.J., Defossez, P.A., & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000) Link
  5. Roichman, A., Elhanati, S., Aon, M.A. et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun 12, 3208 (2021) Link

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Oscar Allan

Oscar is a science writer and e-learning developer with a master's degree in longevity-related topics