Nampt Overexpression Reduces Age-Related Loss of Exercise Capacity in Mice

NAD, nicotinamide adenine dinucleotide, plays a central role in energy metabolism, and of late has attracted more attention from researchers who aim to modestly slow aging by adjusting the operation of metabolism. Tinkering with NAD levels though any number of different ways appears to produce some benefits in mice, but these are not sizable outcomes. Essentially this looks only incrementally better for normal animals than the marginal results produced for many forms of dietary supplementation in mouse studies.

Researchers examined the role of NAD precursor molecules on mitochondria by specifically disrupting the "NAD salvage pathway," in mouse skeletal muscle. This pathway consists of a series of enzymes that recycles building block molecules to make fresh NAD to power reactions throughout the cell, and especially within the mitochondria, the cell component that makes energy for the body from ingested food. Chemical reactions involving NAD are fundamental to metabolizing all fats and carbohydrates, yet NAD is degraded in response to such physiological stresses as DNA damage, and its concentration declines in several tissues over the natural course of aging.

The team generated mice in which they could restrict the amount of NAD in specific tissues in order to simulate this aspect of normal aging in otherwise healthy mice. Surprisingly, young knockout mice were found to tolerate an 85 percent decline in intramuscular NAD content without losing spontaneous activity or treadmill endurance. However, when these same mice hit early adulthood (three to seven months of age), their muscles progressively weakened and their muscle fibers atrophied. "Their muscle tissue looked like that of Duchenne muscular dystrophy [DMD] patients. The genes that were turned on and the presence of inflammatory immune cells in the muscles lacking NAD looked very similar to what we see in DMD." The team next sought to test whether a dietary NAD precursor might remedy the muscle pathology in the mice. The muscle decline was completely reversed by feeding the mice a form of vitamin B3, called nicotinamide riboside (NR).

Additionally, the team found that induced lifelong overexpression of Nampt, an enzyme important in making NAD, prevented the natural decline in NAD and partially preserved exercise capacity in aged mice. "This was supporting evidence that strategies to enhance muscle NAD synthesis might help to combat age-associated frailty." Researchers plan to follow up on the unexpected muscular dystrophy finding, asking if NAD is also depleted in some forms of dystrophy and if restoring NAD might help ameliorate certain features of the disease. Though the researchers previously found that enhanced NAD synthesis does not benefit muscle performance in young mice, these new findings suggest that it may be useful for combating age-related declines in muscle function.



Looking at the data NR is the least effective of the NAD precursors. Niacin seems to be more effective at increasing the NAD ratio. Of course as David Sinclair identifies CD38 is one of the main things that reduces NAD levels with age and CD38 is of course a component of SASP from senescent cells, the 2012 Sinclair paper strongly suggests that inflammation is the key reason we loose NAD and the associated cascade downstream to the PCG-1a-P53-Mitochonrial Axis of aging (Dephino et al 2012).

So for me the results simply confirm that removing senescent cells and senescent associated Macrophages (SAMS) should be more effective than simply upregulating NAD levels. That said Niacin is cheap and I take it for the time being until better ways arrive to control NAD ratio either via senolytics and or via TFAM gene therapy ala George Church.

Posted by: Steve Hill at August 10th, 2016 8:57 AM

I'm 63, lean, and exercise regularly. I took 500 mg niacin for a year and noticed no muscle changes nor exercise benefit. From reading comments on a Longecity thread on NR supplementation I saw no strong indications that people were seeing benefits. My conclusion was that at a healthy, fit 63 neither niacin nor NR would boost my NAD+ levels enough to make a difference. (I also "water" fast for 6 days once each month, restrict my eating to a 4 hour window each day, and eat a low glycemic index diet which minimizes inflammation and might also increase NAD+ levels.) When I'm older I might benefit from NR.

The Anti-Aging blog says extracellular NAMPT increases inflammation through cytokine signaling. Chronic inflammation in the brain appears to accelerate aging. On the other hand, properly timed inflammation seems to be a necessary part of wound repair and tissue regeneration. So determining dose, timing, and tissue expression might be critical for benefit.

Posted by: Annonymous at August 10th, 2016 12:56 PM

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