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Sirtuins have long been implicated in playing a role in the longevity of various species, including our own, and researchers at the University of Rochester have now discovered more supporting evidence that they do.

What are sirtuins?

Sirtuins are a family of proteins that facilitate cellular function and have long been known to play a role in aging. In particular, they are responsible for functions such as gene expression and are involved in DNA repair. It has long been understood that sirtuins played a role in aging, but the key factor in how well they function is the presence of nicotinamide adenine dinucleotide (NAD+), a coenzyme found in all living cells. NAD+ biology is central to deregulated nutrient sensing and a reason why we age, and sirtuins play a key role in this biology.

While this study focuses on one particular sirtuin, the sirtuins are a group of seven proteins that regulate cellular function and health in multiple ways:

Name Location Activity Function
Sirtuin 1 nucleus, cytoplasm deacetylase metabolism, inflammation
Sirtuin 2 cytoplasm deacetylase cell cycle, tumorigenesis
Sirtuin 3 nucleus and

mitochondria

deacetylase metabolism
Sirtuin 4 mitochondria ADP-ribosyl transferase insulin secretion
Sirtuin 5 mitochondria demalonylase, desuccinylase and deacetylase ammonia detoxification
Sirtuin 6 nucleus Demyristoylase, depalmitoylase, ADP-ribosyl

transferase and deacetylase

DNA repair, metabolism, TNF secretion
Sirtuin 7 nucleolus deacetylase rRNA transcription

However, the sirtuins can only work properly if they have access to NAD+, which, unfortunately, declines with age. Ultimately, the sirtuins act as regulators to ensure how efficient a cell is; thus, when combined with NAD+, they could be a strong determinant of longevity.

While the seven sirtuins occupy differing locations in the cell, their fundamental role is that they remove acetyl groups from other proteins. Acetyl groups control specific reactions and act like tags on proteins that other proteins can identify and react with.

Sirtuins work with acetyl groups in a process known as deacetylation; in other words, they identify when there is an acetyl group on a molecule and remove it, which frees up the molecule to do its job. For example, sirtuins deacetylate histones, proteins that are part of a condensed form of DNA known as chromatin, to help protect DNA from damage. The histone is a large protein which the DNA wraps around, and when histone has an acetyl group, the chromatin is unwound. While the chromatin is in this unwound state, the DNA is being transcribed, the first step in the process of gene expression. However, while it is in this unwound state, it is vulnerable to damage, and so the sirtuins act to close and repack the chromatin to protect it from damage once gene expression is no longer required.

Sirtuins have been known for around 20 years or so, and this key function has earned their encoding genes the reputation of being “longevity genes.” Researchers have been studying them ever since to try to learn how exactly they work and how we might use them in the fight against age-related diseases.

More evidence for the longevity gene

Dr. Vera Gorbunova, Dr. Andrei Seluanov, and Dr. Dirk Bohmann, along with their team and other researchers, have published a new paper showing that sirtuin 6 (SIRT6) is responsible for more efficient DNA repair in species with longer lifespans [1].

As we and other animals age, our DNA is increasingly prone to damage and breakage; this can then lead to mutations and rearrangement of our genes, a precursor for cancer and aging. It has long been proposed that this is why DNA repair plays a key role in how long an organism lives [2].

In particular, double strand breaks (DSBs) are the focus here and are the result of oxidative damage, which is unavoidable. Unfortunately, regardless of how healthy you are, you cannot avoid DSBs, because oxidative damage is a consequence of us breathing and taking in oxygen. This is one of many examples of how the body damages and ages itself through the operation of normal metabolism; fortunately, we also have ways of repairing that damage, and this is where SIRT6 comes in.

SIRT6 is known as a longevity gene due to its key role in DNA repair and metabolism. In studies, it has been shown that mice with additional copies of the gene live longer than their regular counterparts, and mice that have the gene knocked out experience accelerated aging.

The research team hypothesized that if better DNA repair supports longer lifespans, organisms with longer lifespans may have evolved more efficient regulation of DNA repair. So, could this mean that higher SIRT6 activity is present in longer-lived species?

To put this to the test, the researchers examined DNA repair in 18 different rodent species; their lifespans ranged between 3 years for mice and up to 32 years for naked mole rats and beavers. They discovered that the longer-lived rodents did indeed have more efficient DNA repair and that this was due to SIRT6 being both more active and more potent; in longer-lived species, the gene has evolved to become more efficient, showing its role as a key determinant of longevity.

As a final step, the researchers investigated the molecular differences between the SIRT6 proteins found in mice and the more potent ones found in beavers. They found that there were five amino acids in the SIRT6 protein in beavers that made them more potent and better at facilitating cellular DNA repair and enzyme function. The research team also inserted beaver and mouse SIRT6 genes into human cells and found that the beaver SIRT6 was superior at reducing stress-induced DNA damage as compared to cells given the mouse SIRT6. In fruit flies, inserting the beaver SIRT6 gene increased their lifespan better than the mouse SIRT6 did.

Summary

DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.

Conclusion

The team now plans to see if the SIRT6 genes in even longer-lived species than humans have evolved to be even more efficient than our own. The bowhead whale in particular is of interest, as it is known to live more than 200 years and may have even more potent SIRT6 genes than those of humans.

If this is shown to be the case, then it opens to the door to interventions that improve the activity and potency of our own SIRT6 genes. Another approach could be to add additional SIRT6 genes to our cells to increase DSB repair. Finally, another option could be to increase the potency of our own SIRT6 genes by making them work more like the more efficient ones found in even longer-lived species.

Ultimately, the goal is to prevent age-related diseases, and improving how efficiently our body addresses DNA damage, thus making us more robust to age-related damage, is a step in that direction. Developing ways to repair that damage is a good strategy, but so is making ourselves more resilient to the damage in the first place, and the two approaches are not mutually exclusive.

Dr. Vera Gorbunova will be speaking at our second annual Ending Age-Related Diseases conference on July 11th-12th, 2019 in New York City. For more information, check out our conference page.

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Literature

[1] Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., … & Goldfarb, A. (2019). SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell, 177(3), 622-638.

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. April 26, 2019

    I like the idea of ​​improving and strengthening the processes that protect us from deterioration :)

  2. May 1, 2019

    Very interesting. The article did not mention how many active enzymes the human Sirt6 has… is it the same as the mole rat and beaver?

    Also if these enzymes are known could they be supplemented along with NR?

    Off topic but I believe that scientists should seriously pursue testing high potential longevity treatments under right to try legislation (with the person’s consent). If death is eminent and the person is willing to help humanity move forward testing on actual humans makes a lot more sense than mouse studies (it also will propel our progress much quicker). IMHO

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