Dr. Raul Mostoslavsky—SIRT6 and the Hallmarks of Aging

By Longevity by Design, November 9, 2022

LBD_Header Image_Dr. Raul Mostoslavsky

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In this episode of Longevity by Design, our hosts, Dr. Gil Blander and Ashley Reaver, MS, RD, CSSD, are joined by Dr. Raul Mostoslavsky, the Laurel Schwartz Professor of Oncology at Harvard Medical School. 

Dr. Raul Mostoslavsky has studied sirtuin functions in cancer for many years and has identified a pathway responsible for tumor growth in 30% to 40% of pancreatic cancer patients and more recently identified metabolism as a heterogeneous feature of cancer. Dr. Raul Mostoslavsky discusses the role of sirtuins in aging and explains how the mechanisms that protect us from cancer may also preserve our longevity on a cellular level.


Meet Longevity by Design’s podcast guest, Dr. Raul Mostoslavsky

Dr. Raul Mostoslavsky is the Laurel Schwartz Professor of Oncology at Harvard Medical School. Dr. Raul Mostoslavsky’s research primarily focuses on cancer. However, he also studies the phenomenons of aging due to the surprising connections between the two. 

Dr. Raul Mostoslavsky has worked closely in his lab with SIRT6, a protein-coding gene that is intimately related to aging and cancer. A growing body of evidence indicates that SIRT6 may have roles in aging because of the gene's ability to protect against genomic instability. Dr. Mostoslavsky further explains, "If you overexpress or activate sirtuins, you can get an extension of lifespan. This has really revolutionized the field."

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The impact of SIRT6 on cancer

In his lab at Mass General hospital, Dr. Raul Mostoslavsky began to study how SIRT6 is related to cancer. A defining characteristic of cancer cells is that even in the presence of oxygen, they prefer to produce lactate. This is known as aerobic glycolysis or the Warburg effect. Dr. Mostoslavsky’s lab was the first to show that in the absence of SIRT6, normal cells undergo aerobic glycolysis. This finding led him to believe SIRT6 evolved to be a tumor suppressor. 

To further prove the link between SIRT6 deficiency and cancer, Dr. Mostoslavsky went to cancer genome databases to examine the available data. Not surprisingly, he found that SIRT6 is downregulated in many cancer types.

His lab initially identified eight mutations that inactivate or destabilize SIRT6. He found that these mutations were evolutionarily selected for in specific cancers. As this field has grown, hundreds more mutations have been identified. It is believed that some tumors inactivate SIRT6 by point mutation, while most tumors silence SIRT6 expression. 

Interestingly, cancer development is strongly correlated with age. In 2011, the renowned cancer review article "The Hallmarks of Cancer" was published, and two years later, "The Hallmarks of Aging" was published. What's fascinating is that many of these hallmarks overlap. So, the mechanisms that protect us from cancer also promote longevity—a major one being genomic integrity.


How SIRT6 contributes to DNA repair

As Dr. Raul Mostoslavsky explains, any mechanism protecting our cells from DNA damage also protects us from cancer. This is because our cells become less fit as they accumulate mutations. Additionally, stem cells are not exhausted when the human body faces fewer mutations. Many theories state that the longer we keep our stem cells, the longer we will live. Dr. Mostoslavsky explains how protecting your DNA from mutations promotes longevity and decreases the likelihood of developing cancer. 

The specific role of SIRT6 in DNA repair is quite intriguing. Dr. Mostoslavsky's lab published a paper on SIRT6 in 2013 showing the ability of  SIRT6 to move from its place in chromatin to sites where cells are experiencing DNA damage. Within seconds, SIRT6 will move to a damage site and bring other important chromatin factors for opening chromatin around the DNA break. Opening chromatin allows for repair factors to come more efficiently. SIRT1 also has this ability. 


SIRT6 and telomere length, a conflict in cancer research

Extensive research has been conducted on telomere length. Cells that manage to maintain healthy telomere lengths tend to live longer. Although sirtuins are not the primary regulators of telomere length, they contribute to maintaining healthy telomeres in normal cells. Specifically, SIRT6 regulates deacetylation in histones, and depletion of SIRT6 leads to shortened telomeres. 

Dr. Mostoslavsky says, "If you can keep your telomeres long, your cells will be happier. However, it is a double-edged sword because cancer cells tend to activate mechanisms to keep their telomeres long as well. Companies are developing drugs to maintain the length of our telomeres for healthspan or lifespan purposes, although it could be a double-edged sword because this may also promote cancer."

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SIRT6's metabolic impact

Nicotinamide adenine dinucleotide (NAD), a coenzyme central to metabolism, is found in all living cells. All sirtuins use NAD as a cofactor for their enzymatic activity. Research supports that both intracellular and circulating levels of NAD decrease with age. Recent models suggest that maintaining NAD levels in our cells is a way to keep cells and our bodies optimal. 

Interestingly, maintaining NAD levels is also correlated with maintaining sirtuin activity. SIRT6 has a unique relationship to NAD. Among the seven sirtuins, SIRT6 binds to NAD with the highest affinity. And even low cellular NAD levels can maintain SIRT6 activity.

Free fatty acids also influence SIRT6 activity. When you eat fat-containing foods, your body doesn’t utilize glycolysis to produce glucose for energy. IIn talking about fatty acids and SIRT6, Dr. Mostoslavsky explains the two main reasons high fat intake can be cancer-promoting. First, cancer cells can utilize fat as a source of energy. Additionally, excess fat inactivates SIRT6. The inactivation of SIRT6 leads to the Warburg effect (cancer promotion/aerobic glycolysis), so in combination, these two mechanisms can be deleterious to health.


Caloric restriction's impact on cancer and aging

Some studies show that calorie restriction can be associated with a longer lifespan. Dr. Raul Mostoslavsky notes, ''Calorie restriction—where you are decreasing the availability of carbohydrates and fat as an energy source—has many beneficial effects in the context of cancer and lifespan. A lot of the original experiments on calorie restriction relate to cancer more than aging, and we know that this has apparent effects on protecting against cancer.'' 

Dr. Raul Mostoslavsky recommends decreasing refined carbohydrates while promoting whole grain-rich foods and decreasing saturated fats. “We know that diet has health implications; anything you can do to make your diet healthier will benefit how you age and contribute to avoiding cancer.”

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Advice on living a healthier longer life

The benefits of exercise on health are universally accepted. Down to the molecular level, there are a host of reasons that exercise promotes healthspan and longevity. When asked for lifestyle tips, Dr. Mostoslavsky reponds, “The magic pill for me is exercise, for a multitude of reasons.” 

More specifically, Dr. Mostoslavsky discusses the benefits of endurance running. The metabolic studies of marathoners compared to sedentary individuals is astounding, "If I have one piece of advice, it would be to try to run every day, between 30 to 60 minutes per day."



Longevity by Design

Longevity by Design is a podcast for individuals looking to experience longer, healthier lives. In each episode, Dr. Gil Blander and Ashley Reaver join an industry expert to explore a personalized health journey. The show helps you access science-backed information, unpack complicated concepts, learn what’s on the cutting edge of longevity research and the scientists behind them. Tune into Longevity by Design and see how to add years to your life, and life to your years.


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