Reviewing Efforts to Develop NAD+ Therapies to Reverse Age-Related Loss of Mitochondrial Function

Increasing levels of NAD+ in mitochondria, is a class of therapy that probably produces most of its benefits in animal models and human trials by restoring mitophagy. This may well be true of mitochondrially targeted antioxidants as well. Mitophagy removes damaged mitochondria, but is hampered by age-related changes in mitochondrial dynamics, among other reasons. Mitochondria are responsible for packaging chemical energy store molecules to power cellular operations. Mitochondrial function is critical to tissue function throughout the body, but is of particular note in the energy-hungry tissues of muscle and brain.

NAD+ declines with aging for causes that are not well understood, not well linked to the underlying molecular damage that causes aging. Methods of increasing NAD+ are operating on proximate causes at best. They can reverse some degree of the decline, as demonstrated in human trials focused on the function of smooth muscle in major blood vessels. Not all of these trials produced benefits, however, and in those that did, NAD+ upregulation so far doesn't achieve more than "some degree" of improvement. Thus assessment of the field of prospective NAD+ interventions is still very much an ongoing project.

Over the last decade, the importance of NAD+ in healthy ageing and longevity has been recognised, detailed molecular mechanisms unveiled, and many clinical trials explored. Studies from laboratory animals, such as in nematodes and mice, and in human primary cells and post-mortem tissues, as well as human brain imaging, indicate that there is an age-dependent reduction of NAD+ in cells and tissues. Mechanistically, it is suggested that ageing-induced NAD+ reduction may result from reduced production - as there is an age-dependent reduction of key enzymes involved in NAD+ metabolism - or increased consumption by NAD+-consuming enzymes, such as PARPs, CD38, and Sirtuins. All three classes of enzymes compete for NAD+ during ageing, ultimately leading to a bioavailability level insufficient to sustain all NAD+-requiring cellular activities.

Intriguingly, NAD+ repletion, by the supplementation of NAD+ precursors, such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinamide (NAM), or even NAD+ itself, delay ageing phenotypes and promote healthy longevity in both normal and accelerated ageing models in Caenorhabditis elegans (roundworms), Drosophila melanogaster (fruit flies), and mice. Encouraged by animal studies, more than 20 clinical studies exploring whether NR may alleviate pathological ageing and age-predisposed diseases have been initiated.

At least 5 clinical trials have been completed showing that 1-2 g/day of NR for up to 1-3 months is safe. While there were encouraging results in some NR-based phase I clinical trials aiming to reduce blood pressure in healthy middle-aged and older adults and to slow disease progression in amyotrophic lateral sclerosis (ALS) (NR + pterostilbene), no effect was reported in trials of short-term (up to 2-3 months) NR supplementation in obese, insulin-resistant men and nondiabetic males with obesity, nor muscle-mitochondrial bioenergetics in aged men. Of note, all three reports were from the same study and reported different outcomes from the same set of obese men. Possible considerations include a much higher dose of NR (2 g/day) than other trials (mostly 1 g/day) and the sensitivity of the enzymatic, assay-based NAD+ detection method. Thus, these studies emphasise some of the challenges with clinical trials of NAD+-boosting compounds with regards to dose and assessment of NAD+ bioavailability.