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Augmenting NAD+ to Treat Age-related Degenerative Diseases?

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Review of “NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice” from Science by Stuart P. Atkinson

Tissue homeostasis and regeneration requires the normal function of diverse types of resident adult stem cells. However, stem cell function decreases over time, leading to the common symptoms of human aging [1] which includes mitochondrial dysfunction. 

To test whether a reversal of mitochondrial dysfunction could improve aging stem cell function, the laboratory of Keir J. Menzies and Johan Auwerx have studied muscle stem cells (MuSCs) and their reaction to supplementation with nicotinamide adenine dinucleotide (NAD+) which is well-known for its ability to reverse mitochondrial dysfunction (See original study for extensive references). Their new study, published in Science, now demonstrates that this strategy may represent an effective means to treating age-related degenerative diseases [2].

Using both gene expression and metabolic assessment of young and aged mice, the study first confirmed that the senescence of MuSCs correlated with increased levels of mitochondrial dysfunction. Aged mice also had fewer MuSCs and these contained lower levels of NAD+. Augmenting NAD+ via treatment with the NAD+ precursor nicotinamide riboside (NR) led to increased MuSC numbers and accelerated muscle regeneration in young and old mice, and enhanced muscle function in aged animals, and improved overall MuSC transplantation efficiency.

So what’s going on?! It seems that NR-induced NAD+ repletion protected MuSCs against senescence and boosted the function of mitochondria as shown by an increase in oxidative respiration. Furthermore, NR activated the mitochondrial unfolded protein response (UPRmt), a stress-response pathway that mediates adaptations in mitochondrial content and function, and also activated the expression of prohibitins, proteins which sense mitochondrial stress and modulate senescence in fibroblasts in mammals [3] and maintain and promote longevity in worms [4].

Excitingly, the authors also saw the beneficial effects of NR-supplementation to MuSCs in the mdx mouse, which is used as a model for human Duchenne muscular dystrophy. Untreated mdx mice normally present with MuSC depletion and dysfunction; however, NR treatment boosted MuSC function and regeneration.

Finally, the authors assessed the potential for NR-supplementation in other stem cells characterized by a decline in the number and function with age: neural SCs (NSCs) and melanocyte SCs (McSCs). Encouragingly, they found that NR-supplementation boosted NSC proliferation in the subventricular zone (SVZ) and the dentate gyrus of the hippocampus (sites of adult neurogenesis), and rescued the decline of McSCs in hair follicles of aged mice. Additionally, and encouragingly, NR also mediated a small extension of lifespan!

Overall, this study suggests that a simple nutritional intervention has the potential to treat multiple age-related degenerative diseases in human patients and also to extend lifespan. Of note, the study found no deleterious side-effects of NAD+, even at very high doses, and so the path towards human trials seems clear of obstacles……who is next in line for the elixir of youth?!

References

  1. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013;153:1194-1217.
  2. Zhang H, Ryu D, Wu Y, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016;352:1436-1443.
  3. Coates PJ, Nenutil R, McGregor A, et al. Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence. Exp Cell Res 2001;265:262-273.
  4. Artal-Sanz M and Tavernarakis N Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 2009;461:793-797.