Hopefully the Fight Aging! audience recalls the years-long hype over resveratrol, driven by the self-serving processes that enabled investors in Sitris Pharmaceuticals to make a sizable profit at the expense of GSK, and supplement sellers to open up a new market for the credulous. The only meaningful results from all of that turned out to be an increased knowledge of the biochemistry of sirtuins, one very thin slice of the broad metabolic response to calorie restriction. Resveratrol and its ilk are not meaningful calorie restriction mimetics, and you are far better off cutting a few hundred calories from your daily intake or exercising a little more.
In light of this history I think it is entirely appropriate to be skeptical of the current hype surrounding the role of NAD+ in metabolism, and the various precursor molecules that can increase levels of NAD+ when taken as dietary supplements. When compared with sirtuins and resveratrol, the publicity here involves many of the same people, similar for-profit companies engineering the news cycle, and the same area of cellular biochemistry, which is to say aspects of calorie restriction closely related to sirtuins. My expectation is that, at the end of the day, this will result in nothing more than another increase in the knowledge of this portion of cellular biochemistry, while all the other claims regarding longevity and health are largely smoke and mirrors. Some people will make a lot of money, supplement sellers will prosper, and nothing will meaningfully change in human health as a result of all of this.
The first study in mice noted below is very similar in outcome to past studies of resveratrol, which is to say little in the way of gains in healthy mice, and some compensation for the detrimental effects of being overweight or obese. It is important to remember that mouse longevity is far more plastic than that of humans in response to calorie restriction and interventions that affect the same portions of cellular biochemistry as are involved in the calorie restriction response. Mice live 40% longer when calorie restricted; in humans the gain is unlikely to be larger than a few years, even though the observed health benefits are sizable. So an alleged calorie restriction mimetic that produces no gain in mouse longevity, or only helps to make overweight mice less metabolically abnormal, is not all that interesting. You might compare this with the second paper, which is a commentary from the usual suspects on how great the prospects are for supplementation related to NAD+ levels.
Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice
The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+, is elusive. In the present study, we aimed to characterize the effects of chronic NAM supplementation on the longevity and healthspan characteristics of male C57BL/6J mice fed a synthetic low-fat diet (SD) and the corresponding high-fat diet (HFD). Because of the liver's importance in maintaining metabolic homeostasis, we carried out histological, biochemical, and untargeted metabolomics surveys to provide an unbiased view of the metabolic impact exerted by 62-week NAM supplementation on liver from SD- and HFD-fed mice.
Protein target validation combined with metabolic flux analysis enabled the identification of the underlying mechanisms of enhanced glucose disposal and reduced oxidative stress in response to NAM supplementation. Surprisingly, our data showed that NAM depresses NAD salvage and has complex effects on sirtuin expression and activity. NAM appears to have greater beneficial effects in mice subjected to HFD than SD, which might provide important clues about its therapeutic potential in the fight against obesity and associated comorbidities.
We report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Analysis revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Although neither hepatic NAD+ nor NADP+ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD-fed mice in the absence of survival effects.
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Nicotinamide adenine dinucleotide (NAD) is one of the most important and interesting molecules in the body. It is required for over 500 enzymatic reactions and plays key roles in the regulation of almost all major biological processes. Above all, it may allow us to lead healthier and longer lives. Much of the renewed interest in NAD over the last decade can be attributed to the sirtuins, a family of NAD+-dependent protein deacetylases (SIRT1-7). Sirtuins have been shown to play a major regulatory role in almost all cellular functions. At the physiological level, sirtuins impact inflammation, cell growth, circadian rhythm, energy metabolism, neuronal function, and stress resistance.
By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.
View the full article at FightAging
