Energy-Carrying Molecules to Boost Aging Mitochondria?

Here I'll point out the latest in the Question of the Month series from the SENS Research Foundation, in which the staff are far more polite than I regarding the unmerited hype that seems to accompany both supplement research in general and research emerging from the Sinclair lab at Harvard in specific:

Q: In recent months, I've seen quite a lot of promotional material for a dietary supplement called nicotinamide riboside (NR). The companies involved say that Harvard researchers showed that this supplement restores mitochondrial function in the cells of aging mice, completely reversing the aging process in muscles. Some of them add that other research has shown that it improves metabolism, fights fat and obesity, and is protective of brain function. What do you think of this supplement?

A: It must be clarified that the substance used in the Harvard research was not actually NR, but another compound called nicotinamide mononucleotide (NMN). But NMN is unsuitable for oral supplementation, so the Harvard researchers injected their mice with NMN rather than giving it to them in their feed. With the excited coverage that greeted the research, supplement companies have promoted NR as a substitute, because it was already in production and can be taken orally. Because NR is a precursor to NMN, which in turn is used for the synthesis of the energy shuttle molecule nicotinamide adenine dinucleotide (NAD), many supplement vendors assert or imply that the results with NMN can also be gained with NR.

That all may sound promising, and it certainly makes for effective marketing copy. But no study has actually been done demonstrating that NR has similar effects to NMN in the muscles of otherwise-healthy aging mice. In fact, one study found that high-dose NR supplementation was unable to increase NAD+­ levels in muscle tissue or the mitochondrial fraction of normal, healthy mice. Additionally, overexpressing the gene that converts NR to NMN in these animals' muscles still didn't affect muscle mitochondrial function in the way that the Harvard researchers reported with NMN, suggesting that the effects observed with injected NMN may involve some kind of systemic response to having NMN itself circulating in the bloodstream. This casts considerable doubt on the assumption that either NR, or some other supplement that raises cellular NAD+­ levels, will replicate the effects of NMN on aging muscle. Additionally, interpretation of the Harvard report is greatly hampered by the lack of information of the animals' weight or food intake, which raises the possibility of effects mediated by calorie restriction or (contrariwise) by the simple overfeeding of all the animals in the study.

It's also important for readers of the press coverage to understand just what was involved when such stories reported that NMN treatment "reversed the effects of aging" on the mice's muscles. Readers would be forgiven for imagining the muscles of frail, elderly mice suddenly swelling to youthful size, able to perform tiny rodent bench presses with the strength and endurance of much younger animals. In reality, though, as the investigators were careful to point out in the original scientific paper, while their treated animals' muscle cells exhibited biochemical evidence of improved ("rejuvenated") metabolism and insulin-stimulated glucose uptake, "we did not observe an improvement in muscle strength." This important detail was missing from almost all of the reporting in the popular press. While it's possible, as the scientists speculate, that longer-term treatment would have led to some recovery of muscle function, the lack of any observed improvement in actual muscle strength calls into question the functional significance of the biochemical "rejuvenation" they report.