Why Sirtuins Are Important for Vascular Aging

We grow old — at least biologically — due to a combination of environmental, lifestyle, and genetic factors. Father time takes a toll on our organs and tissues at a cellular level, leading to our progressive “decline.” Apologies for starting off on such a depressing note…

Many of these age-related changes occur to our cardiovascular system, with the primary two being the stiffening of our arteries and a loss of blood vessel function — our arteries lose their relaxation capacity, and this sets the stage for atherosclerosis.

There are many potential “causes” of cardiovascular aging, and one pathway gaining recent attention involves proteins known as silent-information regulators — a.k.a. sirtuins. Sirtuins are known as histone deacetylases — they remove certain chemical modifications on our DNA that play a role in aging. This process of DNA modification is called epigenetics.

Sirtuins have earned the spotlight because research shows that these proteins regulate several aspects of aging — and some are even shown to increase lifespan in worms and fruit flies. It is now well-known that sirtuins also regulate the process of many age-related diseases like cardiovascular disease (CVD), cancer, and neurodegenerative diseases (i.e. Alzheimer’s and Parkinson’s disease).

Here, I want to focus on CVD specifically. Humans have seven sirtuins (Sirt1–7), and all of them are found in vascular endothelial cells of our blood vessels. While Sirt1 is the most well-studied, all sirtuins play some role in cardiovascular regulation.

We need sirtuins for proper (healthy) blood vessel function. Research has shown that sirtuins (primarily Sirt1) protect against damaging free-radicals and oxidative stress and prevent the senescence of endothelial cells. In addition, sirtuins stimulate our body to produce nitric oxide (NO) — a molecule that helps blood vessels relax and prevents atherosclerosis/blood platelet aggregation.

Sirtuins block harmful cardiovascular processes by preventing inflammation — they interfere in the signaling pathway of a pro-inflammatory mediator called nuclear-factor-kappa-B (NF-kB). Chronic low-grade inflammation is one of the best-known causes of aging and disease, so anything that can potentially reverse harmful inflammation is a good thing.

The role(s) of sirtuins in healthy/pathological vascular function. From D’Onofrio et al. 2015

Sirtuins also protect against DNA damage in the smooth muscle of our blood vessels, reduce atherosclerotic plaque formation, and prevent the degeneration of our vascular walls.

On the other hand, a loss of Sirt1 with aging reduces our ability to repair damaged vessels, attenuate our beneficial stress responses, and increase senescence of cells. None of this is good.

Thus, a loss of sirtuins — whether through aging or harmful environmental exposures (pollution, poor diet, smoking, etc.) — is a direct CAUSE of aging. These genetic and epigenetic superstars control everything from metabolism to brain health, all the way down to the function of our tiny little blood vessels.

For this reason, maintaining (or better yet, increasing) your levels of sirtuins at all costs should be a primary goal if you want to age successfully and maintain resilience and function throughout your lifespan.

Interestingly, a recent study has actually found evidence (in humans!) that higher levels of sirtuins do in fact protect against blood vessel dysfunction with aging. Perhaps more intriguing is this: it wasn’t only current sirtuin levels that had this protective effect…but sirtuin levels during childhood!


The study, which is published in April in the American Journal of Physiology: Heart and Circulatory Physiology , investigated the hypothesis that lower levels of sirtuins during childhood would be related to vascular dysfunction later on in life (adulthood).

To do this type of study, you need a measure of your “predictor” (or independent) variable at a previous time point. In this study, the independent variable — sirtuin concentrations — were measured in study participants when they were around age 16 (which they refer to as “childhood). These data were gathered as part of a larger longitudinal study on cardiovascular aging called the Augusta Heart Study.

Some participants who had their sirtuin levels measured in childhood then agreed to participate in the current investigation as adults (average age of 34). Their blood samples were retaken to measure current sirtuin concentrations, and many other variables like body fat and cholesterol were assessed.

In addition to sirtuins and metabolic health, the primary outcomes of this study included a suite of measurements to assess micro- and macrovascular health. Function of the microvasculature of each participant was assessed in response to heat, reactive hyperemia, and a chemical stimulus known as acetylcholine (ACh). Function of their larger vessels was assessed using a technique called flow-mediated dilation (FMD). Arterial stiffness — another important cardiovascular marker — was also measured.

The aims of this study were relatively simple. By looking at childhood sirtuin levels in each participant, it would be possible to determine whether lower levels during childhood predicted worse vascular function in adulthood about 20 years later (i.e. are these measures correlated).

By splitting the participants into “low sirtuin” and “high sirtuin” groups, this study also investigated whether people with low levels of sirtuins have lower vascular function compared to “high sirtuin” individuals.

What did they find?

Firstly — childhood and adulthood sirtuin levels were highly correlated. Basically, children with “high” sirtuin levels maintained higher sirtuin levels compared to children with “low” sirtuin levels. Whether this is genetic or lifestyle-related, however, is unknown; but interesting to ponder.

However, regardless of one’s childhood sirtuin levels, there was an overall decline in sirtuins with age. And, the lower one’s sirtuins were, the higher levels of a pro-inflammatory marker called C-reactive protein they had.

Consistent throughout all of the tests of microvascular function, the group with low childhood levels of sirtuins exhibited a poorer response to heat, reactive hyperemia, and acetylcholine compared to the high sirtuin group.

Comparison of microvascular function tests between low sirtuin (LowCS) and high sirtuin (HighCS) groups.

Put another way, having high sirtuins in childhood was related to better microvascular function in adulthood. The blood vessels of the high sirtuin children functioned better as adults.

Meanwhile, arterial stiffness and large-vessel function (measured using FMD) were not different between the high and low sirtuin groups — suggesting that these measures might not be as intricately connected to sirtuins with aging.

These findings stress the importance of early life health interventions and suggest that what you do as a child/teen/young adult have a lasting impact later on in life.

To me, this isn’t a revelation. Of course these things matter! However, I think we often discount the influence that everything we do NOW has an impact LATER. When it comes to cardiovascular health, the sirtuin family might be playing a huge role. #ProtectYourSirtuins

Relationships between sirtuin concentrations in childhood and microvascular function tests.

What can we do about this? How can we impact our levels of sirtuins? Three interventions have pretty strong evidence behind them.

Exercise

Research shows that a single bout of exercise activates sirtuin 1. Exercise training also increases levels of sirtuins (primarily 1 and 3). In turn, these sirtuins act in a big way to increase mitochondrial biogenesis and antioxidant function.

Go workout.

Caloric Restriction

Also known as CR, calorie restriction — taking in about 25–30% fewer calories per day than normal — has been shown to extend the lifespans of many animal models including yeast, worms, flies, and rodents. The benefits of CR have been heavily studied and occur, in part, because CR activates sirtuins. It could also be hypothesized that intermittent or prolonged fasting would also increase sirtuins by activating many of the same pathways as CR.

Resveratrol Supplementation

Resveratrol is a polyphenol with potent antioxidant qualities. Often claimed as the reason for the “French Paradox” (why French people seem so healthy despite drinking an inordinate amount of wine) — resveratrol is found in the skins of grapes and other fruits, plus peanuts and some other plant foods.

Yes…and red wine…if you drink enough (not recommending).

Potential beneficial pathways of resveratrol on reduced CVD risk. From Mohar et al. 2012

In many animal models, resveratrol is shown to enhance lifespan, and this is hypothesized to occur at least in part by activating the sirtuins. Resveratrol has been studied in human clinical trials for things like cardiovascular disease — where it shows some promise.

Is it “news” that exercise, a diet rich in plant polyphenols, and the occasional calorie-restriction protocol or fast is beneficial? Not really.

But, the implications of the study discussed above, paired with the research on the benefits of sirtuin-activating interventions, paints an interesting picture surrounding early-life interventions.

Starting to “biohack” (i.e. make good habits) early in life might be a potent way to stall aging. Right now, aging research really just involves late-life interventions to improve health or reduce some aspect of aging. What we DON’T know is what happens if we apply these interventions in childhood or early adulthood. The data we DO have comes from studies in non-human models (i.e. rodents or other model organisms).

This is partially due to ethics — taking children and subjecting them to lifespan-enhancing interventions isn’t exactly a study likely to be approved by your institutional review board. But…it is pretty tempting to think that what we do as parents (even before children are born) could (and will) impact their adult lives.

Just as there is an “open window” for learning skills like language, maybe there is an “open window” during childhood when our genetic landscape is more malleable. If we take advantage of this period before aging “begins”, who knows how our concept of human longevity could change?

Studies referenced

Sirt1 during Childhood is Associated with Microvascular Function Later in Life. Paula Rodriguez-Miguelez, Jacob Looney, Jeffrey Thomas, Gregory Harshfield, Jennifer S. Pollock, and Ryan A. Harris. American Journal of Physiology-Heart and Circulatory Physiology 0 0:0

D’onofrio N, Vitiello M, Casale R, Servillo L, Giovane A, Balestrieri ML. Sirtuins in vascular diseases: Emerging roles and therapeutic potential. Biochim Biophys Acta. 2015;1852(7):1311–22.

Mohar DS, Malik S. The Sirtuin System: The Holy Grail of Resveratrol?. J Clin Exp Cardiolog. 2012;3(11)

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