Exercise really does influence how we age, and a new study shows how regular exercise in later life can help offset the decline of NAD+ and NAMPT, two important molecules that facilitate cellular energy production, in skeletal muscle.
NAD+ and mitochondria
The mitochondria are the power stations of the cell and provide the energy that our cells need in order to function. As we age, our mitochondria become increasingly dysfunctional and inefficient, and they produce excessive waste in the form of free radicals, which bounce around the interior of the cell, striking and damaging the cellular machinery within.
Mitochondria rely on a supply of nicotinamide adenine dinucleotide (NAD+) in order for them to produce a form of cellular energy known as adenosine triphosphate (ATP). NAD+ is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.
In metabolism, NAD+ facilitates redox reactions, carrying electrons from one reaction to another. This means that NAD+ is found in two forms in the cell: NAD+ is an oxidizing agent that takes electrons from other molecules in order to become its reduced form, NAD+H. NAD+H can then become a reducing agent that donates the electrons it carries.
The transfer of electrons is one of the main functions of NAD+, though it also performs other cellular processes, including acting as a substrate for enzymes that add or remove chemical groups from proteins in post-translational modifications, performing cellular signaling, regulating metabolism, facilitating DNA repair, and engaging in many other functions within the cell. Quite simply, without NAD+ and its supporting precursors, life would not be possible.
Three pathways, one molecule
Given how critical NAD+ is to cellular function, our cells have a number of ways to obtain it; this redundancy in the system is likely to be due to how important NAD+ is.
NAD+ can be created de novo, going through multiple enzymatic steps in the de novo pathway (kynurenine pathway), ultimately producing nicotinic acid mononucleotide (NaMN) as the final step in this process. The term “de novo” means that one biomolecule, in this case, NAD+, is produced anew from a different molecule. Essentially, the NaMN molecule is built from scratch, starting with the essential amino acid L-tryptophan (Trp). The de novo pathway is the only non-vitamin B3-based pathway that allows the creation of NAD+.
Niacins, such as nicotinic acid- and niacinamide-containing compounds, are taken in via dietary sources or supplements and can be used to create NAD+, with each form entering the system at different points. Nicotinic acid (NA) and nicotinic acid riboside (NAR) produce NAD+ via the Preiss-Handler pathway. This pathway begins with NA or NAR and converts both into NAD+ via a series of enzymatic steps. As this diagram shows, NaNM is an intermediate in the pathway, meaning that the de novo pathway shares several common enzymatic steps with the Preiss-Handler pathway on the road to NAD+ creation.
The final pathway is the salvage pathway, which converts niacinamide (NAM) into NAD+ through a series of steps that continually cycle and recover the NAD+ once it has been used by the cell, turning it back into NAM to create NAD+ again; hence, it is called the salvage pathway. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) also both feed into the salvage pathway and are converted into NAD+.
Nicotinamide phosphoribosyltransferase (NAMPT) is also a precursor for NAD+ and part of the salvage pathway and, as recent research shows, can also influence lifespan when levels are increased in mice.
Exercise can restore NAMPT and NAD+ in older adults
One reason that mitochondria functionally decline with age is the decline of both NAD+ and NAMPT levels; however, the reason for this decline is not yet fully understood, though the chronic age-related inflammation known as inflammaging appears to play a role.
It is well known that it is possible to maintain strength and fitness until quite late in life and that exercise can help counteract the typical loss of muscle mass associated with aging. However, regular fitness routines are not something everyone does and, as a result, they may suffer from strength and mobility issues later in life. The good news is that this decline can be reversed through regular exercise, even for previously sedentary people.
Exercise can restore NAMPT and NAD+ levels in older people who take up exercise, at least in skeletal muscle, as this recent study shows .
Aging decreases skeletal muscle mass and strength, but aerobic and resistance exercise training maintains skeletal muscle function. NAD+ is a coenzyme for ATP production and a required substrate for enzymes regulating cellular homeostasis. In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate‐limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown. We assessed the effects of 12 weeks of aerobic and resistance exercise training on skeletal muscle abundance of NAMPT, nicotinamide riboside kinase 2 (NRK2), and nicotinamide mononucleotide adenylyltransferase (NMNAT) 1 and 3 in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age (r2 = 0.297, P < 0.001, n = 57), and VO2peak was the best predictor of NAMPT levels. Moreover, aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. None of the other proteins changed with exercise training. In a separate cohort of young and old people, levels of NAMPT, NRK1, and NMNAT1/2 in abdominal subcutaneous adipose tissue were not affected by either age or 6 weeks of high‐intensity interval training. Collectively, exercise training reverses the age‐dependent decline in skeletal muscle NAMPT abundance, and our findings highlight the value of exercise training in ameliorating age‐associated deterioration of skeletal muscle function.
There is a myriad of NAD+ precursor supplements available, some at eye-watering prices, but simple exercise may offer a cheaper alternative for people willing to put in the time and effort. Even if the benefits of exercise only apply to skeletal muscle, it is worth doing to resist the age-related loss of strength and mobility. It will be interesting to see if the same holds true for other tissue types following regular exercise.
If you are serious about living a long and healthy life and potentially living long enough to see the arrival of more advanced therapies that may effectively target aging, then exercise is quite simply the most reliable and cost-effective anti-aging measure that you can take right now, alongside a balanced diet and plenty of quality sleep.
 de Guia, R. M., Agerholm, M., Nielsen, T. S., Consitt, L. A., Søgaard, D., Helge, J. W., … & Treebak, J. T. (2019). Aerobic and resistance exercise training reverses age‐dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiological reports, 7(12), e14139.