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The Longevity Gene (SIRT1), NAD+ and Cellular Metabolism: What You Should Know

By Max Cerquetti maggio 24, 2020

As you age, the level of NAD+ (Nicotinamide adenine dinucleotide) in your body naturally declines. Because NAD+ is essential for optimal cellular functioning and repair, this decline contributes to many of the often distressing changes you are likely to experience as you grow older, such as a decrease in cognitive functioning, a reduction in bone density and a decline in muscle strength.

Increasing your levels of NAD+ by supplementation has been clearly shown to have a wide variety of powerful anti-aging effects, including the promotion of brain health and cellular regeneration as well as decreased inflammation. But what exactly is NAD+ and how does it work in your body to slow and in some cases, reverse many of these detrimental aging effects? 

Understanding the role of NAD+, as well how it’s produced and used in your body, will help you make the best decisions regarding supplementation and taking control of your health and your future well-being.

NAD+ is shorthand for a compound called Nicotinamide adenine dinucleotide and it acts as a coenzyme, also sometimes known as a cofactor. Coenzymes are substances that are necessary for enzymes, a type of protein, to do their work in the cell, which is to modulate the rate at which chemical reactions within the cell proceed. Without these coenzymes, many of these vital biochemical reactions would progress at such a slow rate they would be rendered virtually ineffective.


The Sirtuins

One of the vital biochemical reactions that NAD+ mediates is the function of sirtuins (say “sir-TWO-ins”) a family of proteins known as the longevity genes. Sirtuins, first discovered in nematodes and yeast in the 1980’s, are made by nearly every cell in your body and they control aging by turning genes on and off, specifically turning off genes that are involved with aging.

Sirtuins fill a wide variety of roles as they help to repair DNA damage, assist your mitochondria (the “power plants” of your cells) to function more efficiently, inhibit inflammation, regulate the release of insulin and play a role in the mobilization of fats among other processes. Plus, the loss of sirtuins has been implicated in the development of various malignancies, including breast and ovarian cancer.

Sirutins also protect your telomeres. These structures are DNA “caps” within your cells that keep your chromosomes from fraying. The length of an individual’s telomeres has been associated with longevity.

There are seven of these sirtuins found in mammals but the one that has been most researched is SIRT1 and among other roles, has been implicated in how caloric restriction helps to prolong life. Caloric restriction (CR) is one of the most studied and reliable ways to prolong lifespan in such organisms as diverse as nematode worms, fruit flies, mice and even monkeys.

CR as a method of prolonging human lifespan has understandably been difficult to research using scientific studies, but has conclusively been shown to reduce some of the risk factors for age related diseases that can shorten human life. Interestingly, when the SIRT1 gene in mice was disabled and these same mice were put on a calorie restricted diet, the increases in lifespan, as well as blood markers indicating an anti-aging effect, did not occur, showing how CR depends on sirtuins to activate the mechanism that prolongs lifespan.

Not only is SIRT1 required to produce calorie restriction’s anti-aging effects, CR itself boosts the production and levels of sirtuin in the human body. This is true for intermittent fasting as well. Both CR and intermittent fasting are linked to lower insulin levels as well as lower levels of IGF-1(insulin like growth factor).

As you grow older, the proteins in your cells get acetyl groups added to them as a result of stressors that come with aging such as inflammation as well as oxidation. Acetyl groups are small molecules composed of two carbon, three hydrogen and one oxygen atom. This increase in the rate of acetylation can lead to damaged proteins and an increase in the number of errors in the expression of vital genetic information which can result in disease.

 

Sirtuins And NAD+

SIRT1 works by removing these acetyl groups which serves to keep the protein healthy and functioning. But SIRT1 cannot do its work without the presence of NAD+, which is the necessary coenzyme that catalyzes the reaction that removes the acetyl group.

The sirtuins are often described as being able to “sense” NAD, as NAD concentrations in the body fluctuate due to the effects of circadian rhythm, nutritional deficits, environmental conditions and the stress of aging. NAD works by facilitating what are known as redox reactions which transport electrons from one reaction to another.

This is why you sometimes see the “plus” symbol written after NAD, as NAD is found in the cell in two different forms: NAD+ takes electrons from other molecules and becomes NADH, which can then donate the electrons it is carrying to another molecule. These redox (reduction/oxidation) reactions are one of the main ways in which NAD functions to assist the sirtuins in carrying out their roles.

The sirtuins, the levels of NAD+ and your circadian rhythms are all intertwined in a complex network. SIRT1 cannot work without the presence of NAD+ and it’s your circadian rhythm that determines when NAD+ is available for use. If your levels of NAD+ go down or your levels of sirtuins decrease, your circadian rhythm will become unbalanced.

As you can see, sirtuins, particularly SIRT1, are crucial mediators of many vital metabolic body processes and cannot function properly without adequate levels of NAD+. As NAD+ naturally declines with increasing age, it is important to boost the availability of this powerful anti-aging coenzyme. You could increase your level of NAD+ through the use of caloric restriction or a strict regimen of intermittent fasting, but for most people, these methods are simply not sustainable.

Increasing Your NAD+ Levels

Supplementation with a high quality NAD+ product is the most reliable, practical and effective way to increase your levels. There is evidence that for some types of cells, NAD+ and NADH are able to be directly imported into the cells. In other cell types, there seems to be a reliance on importing the precursors of NAD+ (such as NMN) into the cell before conversion into the active molecule, so these findings may be a reason to consider taking more than one type of NAD+ supplement.

You can find more information on all of our NAD+ supplements here, including NAD+ as well as its precursor NMN. Taken daily, NAD+ supplementation will increase your levels of this powerful coenzyme and ensure you have the best protection against the detrimental effects of the aging process.


References -

- Hou Y, Lautrup S, Cordonnier S, et al. NAD+ addition normalizes Alzheimer’s features. Proceedings of the National Academy of Sciences Feb 2018, 115 (8) E1876-E1885; DOI:10.1073/pnas.1718819115

- Kiss T, Giles C, Tarantini S. et al. Nicotinamide mononucleotide (NMN) supplementation promotes anti‐aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti‐atherogenic effects. FASEB Journal 18 April 2020 https://doi.org/10.1096/fasebj.2020.34.s1.04769

- Xiayu Wu, Neng Cao, Michael Fenech, and Xu Wang. DNA and Cell Biology. Role of Sirtuins in Maintenance of Genomic Stability: Relevance to Cancer and Healthy Aging
Oct 2016.542-575. http://doi.org/10.1089/dna.2016.3280

- Chang H.-C., Guarente L. SIRT1 and other sirtuins in metabolism (2014) Trends in Endocrinology and Metabolism, 25 (3) , pp. 138-145.

-Cantó C, Auwerx J. Caloric restriction, SIRT1 and longevity. (2009) Trends in Endocrinology & Metabolism, 20 (7), pp. 325-331.


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