María Monterrubio

Get a glimpse of the mechanisms through which resveratrol works within our bodies and how it can improve your metabolism, energy levels, and biological age.

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Welcome, my wellbeing enthusiast! Let’s dive into resveratrol as part of a healthy and vigorous lifestyle.

What is resveratrol and how does it work?

Resveratrol is a natural polyphenol of vegetal origin. Certain plants or fruits that experience adversity from environmental stressors (such as intense ultraviolet light exposure, physical injury, etc.) or contact with pathogens are rich in resveratrol.

In plants, resveratrol has a defensive purpose. It is synthesized de novo upon exposure to the aforementioned stressors and has antimicrobial or antioxidant roles, among others.

You can find significant resveratrol levels in grapes (especially the skin of red or blue grapes), pure cocoa, peanuts, or various berries (including blueberries, blackberries, raspberries, and cranberries).

But what does resveratrol do within our cells? Why is it so precious for us humans? Let’s follow with that!

Resveratrol activates enzymes called sirtuins

Resveratrol is a potent sirtuin activator. Sirtuins are enzymes that control longevity. They are found in organisms from yeast to humans and need a chemical named NAD+ to function.

NAD+, or nicotinamide adenine dinucleotide, is a derivative of vitamin B3 (also named niacin or niacinamide). Hundreds of biochemical reactions within our body require NAD+. Without it, we would be dead.

Sirtuins require NAD+ (the “+” sign at the end signifies it is not bearing a hydrogen atom) to remove acetyl or acyl chemical groups from other proteins. For example, from histones.

Histones are the proteins that help pack the DNA into chromosomes in our cells. When sirtuins eliminate acetyl groups from histones, the latter wrap the DNA more tightly.

As a result, the genes in the specific chromosomal areas where the sirtuins operate get turned off. That is called gene silencing.

Sirtuins also act on proteins different from histones and, through their activity, instruct them to guard cells against adversity, sickness, and death.

In 2003, biologists discovered that resveratrol enhanced the affinity of sirtuins for the acetylated substrate (protein) and NAD+, leading to increased cell survival².

Then, the researchers saw that resveratrol stimulated the sirtuin-dependent deacetylation of p53 (a well-established tumor suppressor), which promoted cellular longevity.

Mild stress also turns on sirtuins (hormesis effects) 

Resveratrol and other polyphenols produced by stressed plants have a xenohormesis effect on us, which has to do with the capacity of our bodies to sense the stress signs of another species (xeno- means foreign) to protect themselves from adversity.

Plants produce resveratrol to defend themselves from mild stress and prolong their survival and wellbeing. And when we humans take resveratrol, we also use it to stimulate sirtuins and thus protect ourselves.

That may explain why so many medicinal substances arise from plants. Those foreign stress molecules like resveratrol (which come from other species, not us) are therefore called xenohormetics (or xenohormesis molecules).

In the last twenty years, we have also learned that resveratrol and other xenohormesis molecules (such as quercetin, present in red onions) can mimic the hormetic or advantageous outcomes that calorie restriction or intense exercise intervals have upon us. 

In other words, xenohormetics like resveratrol can simulate the health benefits that controlled biological damage or adversity in the form of intermittent fasting (the avoidance of food intake, usually for twelve hours up to a few days) or physical exercise, for instance, have on us.

How does resveratrol impact our metabolism and longevity?

In diverse organisms, calorie restriction slows the pace of aging and increases the maximum lifespan.

In yeast, resveratrol mimics calorie restriction by stimulating a sirtuin named Sir2, increasing DNA stability and extending lifespan by 70%. 

The homolog of the Sir2 protein in mammals is called SIRT1 (sirtuin 1). There are seven sirtuins in mammals, known as SIRT1 to 7.

The effects of enhanced sirtuin activity in mammals (such as rodents or humans) are similar to those found, in the first instance, in yeast.

For example, mice with extra copies of the sirtuin genes in their DNA and those treated with Sirtuin-Activating Compounds (STACs) – such as resveratrol – or NAD+ precursors (which also enhance sirtuins activity) have improved organ function, physical endurance, and disease resistance.

And they also show extended and healthy longevity.

Influence of resveratrol on your energy levels

Apart from stimulating the activity of sirtuins, resveratrol activates another longevity pathway in mammals – the AMPK (Adenosine Monophosphate-activated Protein Kinase) route⁴ –.

AMPK fires up in response to low energy (or caloric restriction) and regulates glucose levels in the blood. Hence it positively affects our overall metabolism and longevity.

Indeed, years ago, an astounding thing happened when researchers included resveratrol in the meals comprising the heavy diet of obese mice (a high-fat regime resembling the modern Western diet).

Those mice lived as long and healthy as lean mice (aka their skinny siblings, the control group of mice). 

Thus, resveratrol mimicked the favorable effects of calorie restriction on the metabolism. Indeed, those obese yet healthy mice on resveratrol had perfectly healthy organs by the end of their lives³.

More recently, other well-done studies in humans have uncovered similar outcomes. Among other metabolic benefits, resveratrol reduces fasting glucose (the glucose levels in the blood after an overnight fast)⁵.

It also increases insulin sensitivity (the capacity of our cells to uptake glucose from the blood after a meal).

Now we know (from animal and human studies) that resveratrol raises the metabolic rate and positively impacts glucose levels, body composition, and cardiovascular health.

It also improves the function of mitochondria (the little energy-producing factories inside our cells that provide us with the energy we need)⁴.

Therefore, resveratrol – through the activation of sirtuins or the stimulation of the AMPK pathway – boosts our metabolism and energy levels.

Those – alongside the ability to protect and defend the body – are mechanisms through which resveratrol promotes our organism’s youth extension (and biological age reversal).

Resveratrol as a youth booster and aging-reversal agent 

Fasting increases our NAD+ levels and hence the activity of sirtuins. And so does resveratrol, which can mimic the effects of caloric restriction. 

When activated, the sirtuins defend the body, raise the metabolic rate, protect us against free radicals and oxidative damage, and help reduce unwanted inflammatory processes (that tend to be harmful).

However, fasting, resveratrol, or NAD+ boosters (which we could discuss in another blog post) have even more profound effects on the body. 

And that’s because sirtuins, though deacetylation, can tell histones (remember, the proteins that package the DNA in structures called chromosomes) to wrap the DNA more firmly and therefore keep specific genes silenced, which is crucial to preserve the identity and youth of any cell and tissue in the body. 

Specific chemical changes above the DNA – for example, on histones and not in the DNA itself – are collectively known as epigenetic changes (as opposed to genetic). You may have heard that term, which is quite trendy nowadays!

Indeed, the loss of the original acetylation patterns (epigenetic patterns) of the cellular DNA is a fundamental cause of aging.

You can read the book Lifespan¹ (see the link included in the references at the bottom of this article) by Dr. David Sinclair for a deeper grasp of that.

Through their histone deacetylation activity, sirtuins maintain the youthful epigenetic makeup of cells. And avoid the inappropriate expression of specific genes (that is, their translation into proteins). 

In other words, sirtuins can prevent (and reverse) cell aging. That’s one of the core mechanisms through which resveratrol can boost our youth, maintaining and even reversing our biological age.

Aside from their role in epigenetics, sirtuins 1, 6, and 7 are directly involved in DNA repair, which is also essential to prevent cancers and for our survival, wellbeing, and longevity.

In my next post (right here!), I will disclose how you should take resveratrol to actually reap its health & youth benefits. Don’t forget to subscribe to my newsletter to not miss out on that!

Take care and see you next time!

With love,

María

For your reference:

¹ Lifespan: Why We Age – And Why We Don’t Have To (book). David A. Sinclair, PhD, with Matthew D. LaPlante. 2019.

² Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Konrad T Howitz et al., Nature, 2003; 425(6954): 191-6.

³ Resveratrol improves health and survival of mice on a high-calorie diet. Joseph A Baur et al., Nature, 2006; 444(7117): 337-42.

⁴ SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Nathan L Price et al., Cell Metab, 2012; 15(5): 675-90.

⁵ The effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease. Asma Hoseini et al., Food Funct, 2019; 10(9):6042-6051.

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