Do you remember the stories about sirtuins, resveratrol and the “French paradox”?
Sirtuins are proteins with a very important role in the cell: they control the enzyme that converts acetate, a source of calories, into acetyl CoA, a key point of entry to cellular respiration. Because of this crucial role, it has been proposed that it may be possible to control age-related disorders in various organisms, and in humans. These disorders include obesity, metabolic syndrome, type II diabetes mellitus, Parkinson’s disease and the “ultimate disorder”: aging.
What is the French paradox? Despite the high consumption of saturated fats like butter, French people have a lower than expected incidence of heart disease, a fact attributed to their higher consumption of red wine. I think this is a very pleasant way to activate sirtuins! Another effective sirtuin activation strategy is calorie restriction (not eating!) and this is not an experiment that I am eager to try.
Sirtuins are evolutionarily conserved aging/longevity regulators, present in humans but also in yeast, worms, flies, and mice. Sirtuins are NAD+-dependent deacylases, which respond to nutritional and environmental perturbations, such as fasting, DNA damage, dietary restriction and oxidative stress. In general, sirtuin activation triggers nuclear transcriptional programs that enhance metabolic efficiency and also stimulate mitochondrial oxidative metabolism and the accompanying resistance to oxidative stress. Sirtuins increase anti-oxidant pathways and facilitate DNA damage repair through chemical modification of repair proteins. Research has shown that sirtuins promote longevity in yeast, worms, flies, and mice, and can mitigate many diseases of aging in mice, including type 2 diabetes, cancer, cardiovascular diseases, neurodegenerative diseases, and pro-inflammatory diseases.
The potential role of sirtuins in aging made them an instant hit with the skin care industry. Research on sirtuin-related pharmaceuticals is still in its infancy, but a famous skin care brand promotes one of its products as “pro-sirtuin” (terms like “youth proteins” and “age decelerators”, have also been used). There is no real pro-sirtuin technology in those products, because there is no such technology yet; the ingredient lists are just more of the same.
There are ways to approach the information now available about sirtuins: add actives than can help activate them or add substrates that are required for their activity. Starving the skin would not work, because it would only accelerate thinning and elasticity loss. What can be done? We can add sirtuin activators like resveratrol to the skin care products we use. Resveratrol, a favorite ingredient which we at SAS use practically pure, will activate sirtuins and promote DNA repair. We can also add NAD+, a coenzyme required for sirtuin activity. NAD+ also affects other enzymes, such as the poly ADP-ribose polymerase (PARP) protein family, and the cyclic ADP-ribose (cADPR) synthases which require NAD+ as a co-substrate to perform their function.
The dependence on NAD+ concentration by crucial enzymes like sirtuins, PARPs and cADPRs makes NAD+ even more relevant from the point of view of human health. So be prepared to see NAD+ in the news. And, for now, keep an eye on Skin Actives, because we are planning to add NAD+ to several of our anti-age products.
Note: What is a coenzyme?
Coenzymes are organic molecules required by certain enzymes to carry out catalysis, i.e. accelerate chemical reactions. Coenzymes are often made up of vitamins, or, seen from a different perspective, we need some of the vitamins because they are part of coenzymes. We need to ingest these vitamins because we are unable to synthesize them from scratch, so they have to come from other sources. One of these vitamins is nicotinamide (a.k.a. niacinamide) and it is a critical part of the coenzyme NAD+ (and also of NADP+ and the reduced forms NADH and NADPH).
NAD+ and its role in electron exchange and protein regulation
Figure: the structure of NAD+
Why is NAD+ so crucial to life? NAD+ acts as an electron/hydrogen carrier that facilitates the transfer of energy between nutrients and the cell’s energy currency, ATP. In these oxidation-reduction reactions, the active part of the coenzyme (the one that gets reduced and oxidized again and again) is the nicotinamide.
Figure: The redox reactions of NAD+.
RH2 + NAD+ → NADH + H+ + R;
From the hydride electron pair, one electron is transferred to the positively charged nitrogen of the nicotinamide ring of NAD+, and the second hydrogen atom transferred to the C4 carbon atom opposite this nitrogen.
The redox couple NAD+/NADH participates in numerous reactions that require electron exchange, such as glycolysis, pyruvate-to-lactate and pyruvate-to-acetyl-CoA interconversions, beta-oxidation, citric acid cycle (TCA cycle), and oxidative phosphorylation. For example, NAD+ is converted to NADH in the glyceraldehyde-3-phosphate dehydrogenase step of glycolysis, a pathway in which glucose is converted to pyruvate. Conversion of NAD+ to NADH is also important in mitochondrial metabolism. In mitochondria, NAD+ is converted to NADH in four steps of the mitochondrial TCA cycle, in which acetyl-CoA is oxidized to carbon dioxide. NAD+ is also converted to NADH during the oxidation of fatty acids and amino acids in mitochondria. In these mitochondrial pathways, the NADH generated is an electron donor for oxidative phosphorylation and ATP synthesis.
NAD+ also plays an important role in the regulation of NAD+-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD+ biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm.
NAD+ levels decline during the aging process, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD+ can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD+ intermediate supplementation may be an effective anti-aging intervention.
Sirtuins are evolutionarily conserved aging/longevity regulators, which are present in yeast, worms, flies, mice and humans. Sirtuins are NAD+-dependent deacylases, which play key roles in responding to nutritional and environmental perturbations, such as fasting, DNA damage, dietary restriction and oxidative stress. In general, sirtuin activation triggers nuclear transcriptional programs that enhance metabolic efficiency and also upregulate mitochondrial oxidative metabolism and the accompanying resistance to oxidative stress. Sirtuins foster this resistance by increasing anti-oxidant pathways and by facilitating DNA damage repair through deacetylation or ADP-ribosylation of repair proteins. Accordingly, many studies have shown that sirtuins promote longevity in yeast, worms, flies, and mice, and can mitigate many diseases of aging in murine models, such as type 2 diabetes, cancer, cardiovascular diseases, neurodegenerative diseases, and pro-inflammatory diseases.
The dependence of crucial enzymes like sirtuins, PARPs, and cADPRs on NAD+ concentration, makes NAD+ even more relevant from the point of view of human health. So, be prepared to see NAD+ in the news. And, for now, keep an eye on Skin Actives, because we are planning to add NAD+ to several of our anti-age products.
-Dr Hannah Sivak
Imai S., Guarente L. (2014) NAD+ and Sirtuins in Aging and Disease. Trends Cell Biol. 2014 Aug; 24(8): 464–471. 10.1016/j.tcb.2014.04.002