More than You Wanted to Know About NAD+ in Metabolism and Aging

Manipulating levels of nicotinamide adenine dinucleotide (NAD+) so as to improve mitochondrial function in older individuals is a popular topic these days, particularly now that numerous groups are selling supplements alleged to raise NAD+ levels usefully. These might be thought of as a form of exercise mimetic drug, in the cases where they actually perform. Even given an intriguing early human trial, this is most likely a road to only minor benefits in the matter of aging. At 90, even the best of former athletes looks like a 90-year old, with a significant degree of dysfunction, and a high chance of failing to live to see 91. The research community can and must achieve better results than this class of intervention, by focusing on repair of underlying damage rather than compensatory adjustment of faltering cellular machinery.

In recent years, interest in nicotinamide adenine dinucleotide (NAD+) biology has significantly increased in many different fields of biomedical research. A number of new studies have revealed the importance of NAD+ biosynthesis for the pathophysiologies of aging and aging-related diseases. NAD+ is an essential component of cellular processes necessary to support various metabolic functions. The classic role of NAD+ is a co-enzyme that catalyzes cellular redox reactions, becoming reduced to NADH, in many fundamental metabolic processes.

There are five major precursors and intermediates to synthesize NAD+: tryptophan, nicotinamide, nicotinic acid, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). In mammals, a major pathway of NAD+ biosynthesis is the salvage pathway from nicotinamide. Nicotinamide is converted to NMN, a key NAD+ intermediate, by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway. NMNATs then convert NMN into NAD+. NAMPT plays a critical role in regulating cellular NAD+ levels.

It is now becoming a consensus that NAD+ levels decline at cellular, tissue/organ, and organismal levels during the course of aging. Activities of NAD+-consuming enzymes are affected by this NAD+ decline, contributing to a broad range of age-associated pathophysiologies. Sirtuins are a family of NAD+-dependent deacetylases/deacylases which have central roles in translating NAD+ changes to the regulation of many regulatory proteins for metabolism, DNA repair, stress response, chromatin remodeling, circadian rhythm, and other cellular processes.

A significant cause for this age-associated NAD+ decline is the decrease in NAMPT-mediated NAD+ biosynthesis. It has been shown that the expression of Nampt at both mRNA and protein levels is reduced over age in a variety of tissues. This age-associated decrease in Nampt expression causes a reduction in NAD+ in those same tissues, affecting the activities of NAD+-dependent enzymes and redox reactions within the cell and leading to functional decline. Therefore, supplementation with NAD+ intermediates, such as NMN and NR, can effectively restore the NAD+ pool and cellular functions in aged animals.



The last paragraph in the article above indicates the importance of NAMPT in providing adequate levels of NAD+ in many tissues of the body. NAMPT plays a critical role in regulating the availability of NAD+ by using nicotinamide to increase NAD+ levels. This function declines during aging, which is why it is necessary for most to supplement with NR or AMN with aging. One particular rare SNP variant of NAMPT (rs10487818 AA) apparently keeps on producing NAD+ and is very protective of obesity and T2D. I happen to be homozygous for this rare AA variant found in less than 2% of the population. Perhaps in the future, with CRISPR technology, people without this variant could theoretically have it transplanted to their genome.

Posted by: Biotechy Marcks at July 11th, 2018 10:12 AM

On a related note. A couple of years ago there was a lot of noise about urolitin facilitation mitochondria recycling. And now there are only crickets.

Was it confirmed or debunked for humans?

Posted by: cuberat at July 11th, 2018 11:38 AM

My above referenced rare SNP variant in the NAMPT gene is a longevity gene SNP as it keeps producing NAD+ from nicotinamide in humans. The reference is Blakemore, 2009, Obesity (Silver Spring), A rare variant in visfatin is associated with protection of obesity.

Posted by: Biotechy Marcks at July 11th, 2018 2:03 PM

PS I might point out that 23andme was wondering why I only weigh 140 lbs, when their study of about 500 obesity and weight control SNP's show that persons my age and height have an average weight of 185 lbs. I think the rare SNP I cited above probably answers that question, at least in part.

Posted by: Biotechy Marcks at July 11th, 2018 2:06 PM

Thanks Adrian.

This study is for a proprietary molecule and it didn't publish any improvement in the physical conditions. At least it is safe. I am not even sure the proprietary formula is any better than the naturally occurring urolutin.

What strikes me is that it is assumed that elagic acid is converted to urolutin by gut bacteria but yet nobody did the research to isolate the exact bacteria species and reproduce the process in vitro( at least I didn't find any publication). The elagic acid has quite bad water solubility hence low bioavailability.
Low soluble concentration of the precursors makes bacteria synesis in the intestines very hard, even if the subjects were taking bacteria culture pills with the elagic acid.
While Elagic acid is fairly cheap , the only available urolutin costs arm and leg, for the lab grade quality. I guess it wood be quite ready and cheap to isolate the bacteria and new fermented elagic acid with high concentration of urolutin. Yet nobody is doing that. Of course you cannot patent urolutin but can still have probable production....

Posted by: Cuberat at July 12th, 2018 7:15 AM

Adrian, Culberat: There is a good summary of the benefits of Urolithin A in the September 2017 Life Extension Magazine (available online) and a good natural source in Pomegranate fruit. They discuss the various health aspects and diseases by use of it and the ongoing research efforts with Urolithin A, particulariy increased mitophagy, better health outcomes like less frailty, anticancer properties, and exciting promise in AD and PD dementia, among other things.

Posted by: Biotechy Marcks at July 12th, 2018 7:41 AM

Hi Biotechy,
I tried the magazine, which has good summary. However, nothing concrete on humans. urolitin but not urolitin per se.

While the rodent examples are impressive, I cannot find any publication on actual results in humans . The study done by amazentis is about safety. And the efficacy is measured by some metabolical markers. But there was no mentioning about stamina and health improvements.

And the the pommegrenade extracts are souce of elagic acid , a precursor for

Posted by: cuberat at July 12th, 2018 9:29 AM
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