NAM makes life better, not longer

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Across a wide range of organisms, levels of the key metabolite NAD+ decline with aging, with undesirable consequences at multiple biological scales: In our cells, reduction in NAD+ decreases the activity of the sirtuins, a well-characterized family of pro-longevity proteins. At the systems level, the changing NAD+/NADH balance interferes with the communication between our brains and adipose tissues, resulting in further metabolic dysregulation.

Consequently, a fertile and active area in the broad field of longevity enhancement is the concept of NAD repletion: the idea that, by supplementing the body with molecules that help cells make more of this compound, we can restore (or at least maintain) a more metabolically youthful state, from the cellular level on up.

At present, NAD repletion lies at a busy intersection between basic research, the nutraceutical industry, and translational medicine: A growing number of fundamental studies have demonstrated that supplementation with NAD precursors extends lifespan (and boosts its cellular- and tissue-level correlates) in mice; related compounds are being marketed direct to consumers without FDA regulation; and the first clinical trials are beginning to assess whether we can safely and sustainably increase NAD+ levels in humans.

Because the human data are so preliminary, much of our belief in the potential for NAD repletion relies on results from animal models. Accordingly, it behooves us to keep abreast of the most recent developments. This is especially true when the latest results are partially, but not completely, consistent with previous findings; such discrepancies can reveal cracks in our models and blind spots in our understanding of critical biology.

In the most recent issue of Cell Metabolism, Mitchell et al. report that administration of nicotinamide (NAM), a precursor of NAD+, confers a variety of benefits. In a mouse model, the authors demonstrated that NAM treatment decreased oxidative stress, improved glucose metabolism, and prevented age- and lifestyle-related deterioration of the liver. The supplemented mice benefited at a functional level as well, exhibiting improved coordination and locomotor activity. Thus, NAM (like other NAD+ precursors) increased the ‘healthspan’, that is, the proportion of the adult lifespan free of age-related disease.

Despite these benefits, and in contrast to other NAD repletion studies, NAM treatment had no effect on mean or maximum lifespan, implying that the improvements observed in functional studies occurred in pathways that are not limiting for lifespan, at least in this strain of mouse. Moreover, while there was some evidence that sirtuins were activated, tissue levels of NAD+ did not measurably rise.

This is surprising, given that other NAD precursors have been shown to both extend lifespan (and, for that matter, boost NAD+ levels as expected)— raising the question of why NAM, an orally bioavailable NAD precursor, does not have the same effect. One possible explanation, supported by the authors’ findings in this study, is that NAM administration suppressed uptake of NAM and altered expression of NAD biosynthetic enzymes, although it remains less than clear why this would yield some, but not all, of the previously observed benefits of NAD repletion. Alternatively, high doses of NAM could be inhibiting sirtuin activity, as they do in yeast—but given that NAM is itself produced by enzymes that consume NAD, it is not clear why all methods of NAD repletion would not run afoul of this type of end-product inhibition.

For me, the key point is that there was a strong prior reason to believe that NAM supplementation would have the same healthspan- and lifespanextending benefits as other NAD precursors…but it didn’t, which means that we still have a good bit left to learn about the biology of the NAD pathway, even at the fairly simple level of how to inject material into the system to adjust relative concentrations of compounds of interest in a safe, salutary, and sustainable way.


 

Mitchell et al. “Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice.” Cell Metabolism 27(3):667–676 (2018). DOI: 10.1016/j.cmet.2018.02.001

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