NAD Mechanisms Necessary for Calorie Restriction Benefits

Nicotinamide adenine dinucleotide cycles between two forms, NAD+ and NADH, in the course of participating in important cellular processes such as the mitochondrial respiration whose dysfunction is implicated as a cause of aging. Earlier this year researchers showed that NAD levels decline with age and restoring them can improve measures of health in old mice. Here the same research group notes that NAD mechanisms are required for most of the health and longevity benefits produced by the practice of calorie restriction, and their data suggests that this has a lot to do with changing the operation of mitochondria. Alterations to mitochondrial function show up time and again in considerations of aging and longevity, and are a factor in most of the known ways to slow aging in laboratory animals:

Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD+-dependent deacylases known as sirtuins, and increases in NAD+ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol.

DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD+ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption.

We conclude that stress response and NAD+-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD+ salvage. Under DR conditions, NAD+-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.



It's best not to assume that anything reported about intervention in aging in C. elegans is likely to translate to humans, particularly as regards CR (leaving aside the substantial possibility that CR may not even work in humans). The mechanisms driving aging in these organisms and the means that are effective to retard them, are quite different from those of mammals. C. elegans' mature bodies are composed entirely of cells that don't divide, so they don't develop cancer; they don't have hearts or circulatory systems as they occur in mammals and thus don't suffer heart disease or atherosclerosis; they don't live long enough to accumulate mitochondrial DNA deletions, or several other key forms of molecular and cellular damage that contribute to aging in mammals; they almost always die of starvation due to failure of the muscles in their pharynx; and the thing that keeps being equated to CR is the "dauer state," a kind of deep suspended animation, when challenged with food withdrawal or a range of other stressors, which is not a very neat model adapted to carry out ambulatory life under ongoing limited or intermittent energy availability.

Separately, there are quite substantial caveats that should be considered when evaluating the research reviewed in that Rejuvenation Research article

Posted by: Michael at October 13th, 2014 11:33 AM

Will be using a combination of niacin/niacinamide/resveratrol to try to increase NAD levels.

Posted by: roger at October 14th, 2014 1:51 PM

Thanks for this informative important article. I would like more information on this.

Posted by: Ruso Perone at July 28th, 2020 11:46 PM
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