NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice

Significant new findings about the effects of boosting NAD+ with nicotinamide riboside were published yesterday in Science.

The researchers demonstrated that treatment with the NAD+ precursor nicotinamide riboside (NR) rejuvenated muscle stem cells in aged mice. NR also prevented muscle stem cells senescence in a mouse model of muscular dystrophy. It was also demonstrated that NR delays senescence of neural stem cells and melanocyte stem cells and ultimately increased mouse lifespan. It should be noted here that the increase was small as compared to the mouse entire lifetime, but when looking at the graphs comparing the remaining lifetime from the start of the NR treatment late in the mouse life at 24 months it was significant with an estimated 20%.

The research also concluded that the view that oxidative stress is thought to be circumvented in stem cells by their reliance on glycolysis as a primary energy resource may not cover all functional aspects. The novel research demonstrates that mitochondrial oxidative respiration is in fact important for the functional maintenance of multiple types of adult stem cells during aging and that the reduction in cellular NAD+ pools blunts the adaptive UPRmt pathway. This ultimately leads to a loss of mitochondrial homeostasis with a concurrent reduction in the number and the self-renewal capacity of muscle stem cells. By boosting the muscle stem cells concentration of NAD+ the proteotoxic stress (=toxicity caused by proteins, usually of misfolded proteins) resistance may be restored due to the activation of the UPRmt pathway, stimulating the prohibitin family of mitochondrial stress sensors and effectors. This in turn improves mitochondrial homeostasis, protecting muscle stem cells from senescence and safeguarding muscle function in aged mice. Impressively the research showed in vivo the importance and nature of the relationship between the NAD+-SIRT1 pathway, mitochondrial activity and muscle stem cells function.

The analyses also showed that boosting NAD+ stores brings beneficial effects beyond muscle stem cells  and also protects neural stem cells and melanocyte stem cells populations from aging.

Overall these results add a new exciting dimension to the discussion about benefits of NAD+ boosting and improving mammalian lifespan.

The mice were fed with a diet contaning Nicotinamide Riboside at a dose of 400 mg/kg/day for 6-8 weeks. This enables us to calculate the Human Equivalent Dose (HED) for the NR diet given to the mice. The FDA has specified guidelines for this conversion to Human Equivalent Dose (HED). Using this guideline 400 mg/kg dosing in mice translates into a HED of approx. 32mg/kg. Or into approximately 2.1 gram daily nicotinamide riboside dose for a person weighing 70kg. Typical supplements on the market have serving sizes of 250mg. It should be noted that this dose is on the high end wrt to side effects and safety and therefore a therapeutic approach likely to be done under medical supervision.

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