By Dr Dan Plews
In this blog I am going to discuss an essential metabolic coenzyme called NAD+, and why it is so essential to your health. Some of you may be aware of NAD+, but it is fair to say that NAD+ metabolism is one of the trickier areas of physiology I have discussed so far. Taking some time to discuss NAD+ is definitely worth it though, as changes in NAD+ appear to have strong implications in the negative effects of ageing and health benefits of exercise.
The physiology of NAD+
Nicotinamide adenine dinucleotide (NAD) is a metabolic coenzyme critical to the physiological function of all living cells. NAD exists in two forms: in an oxidised form as NAD+, and in a reduced form as NADH. Those of us that have studied exercise physiology and metabolism may be familiar with the concept of NAD as a means of linking the citric acid cycle to oxidative phosphorylation in the aerobic energy system. Specifically, in the oxidation of fats and carbohydrates, and in the citric acid cycle, NAD+ is reduced to NADH. NADH subsequently moves across into the mitochondria, where NADH is oxidised along the electron transport chain for ATP generation. Further up the chain, NAD+ and NADH are important in determining the metabolic of pyruvate, which is produced as a result of carbohydrate metabolism. To enter the citric acid cycle, and subsequently aerobic metabolism, pyruvate is first converted to acetyl CoA. This conversion requires the reduction of NAD+ to NADH. If NAD+ availability is low, pyruvate can instead be converted to lactate; this process converts NADH to NAD+. Therefore, it should be remembered that this pyruvate-to-lactate pathway is an important mediator of cellular NAD+ availability during exercise. NAD is also critically involved in DNA repair, and, likely consequently, the reduced cellular NAD+ availability observed with ageing is likely involved in reduced health and cellular function with age (as we will discuss in this blog).
The complicated physiology of NAD+/NADH is perhaps none more apparent than when considering research concerned with the effects of acute exercise on NAD+ and NADH availability. Early animal studies reported that exercise acutely increases NAD+ and decreases NADH availability; in contrast, data in human muscle has generally suggested the opposite (3). Increased mitochondrial NADH during acute, demanding endurance-type exercise fits with a ‘backing-up’ of the electron transport chain as the demand for NADH oxidation exceeds its capacity. This fits with observed reductions in the effect of acute exercise on NAD+ and NADH availability following a period of training, where the mitochondrial capacity for NADH oxidation would be expected to have increased (7). The lack of clarity in this area likely arises from mediating effects of exercise intensity, exercise duration, and training status on the acute effect of exercise on NAD+ and NADH, as well as the challenging biochemistry required for its analysis (8).
Ageing and NAD+
There is significant evidence that NAD+ availability decreases with ageing in multiple human tissues (6, 9). Given the myriad roles of NAD+ in physiological function, it is therefore quite plausible that the age-related reductions in NAD+ availability and physiological function are linked. For example, DNA damage increases with ageing, and NAD+ has important roles in anti-oxidative DNA repair. Similarly, inflammation and immune activation increase with ageing, which increases the burden on reducing NAD+ stores. Ageing also decreases sirtuin 3 (SIRT3) expression (5). This is interesting given sirtuin activity is dependent on NAD+, and sirtuin expression and activity have been linked to, amongst other things, mitochondrial remodelling (8). Therefore, maintaining adequate NAD+ availability with ageing is likely important for maintaining reducing DNA damage and maintaining mitochondrial health.
Exercise and NAD+
Some good news is that metabolic stresses such as exercise seem to promote chronic NAD+ availability (1, 4), as well as mitigate the age-related decline in capacity for endogenous NAD+ synthesis through the salvage pathway (2). Another disappointing effect of ageing is a decrease in sirtuin 3 (SIRT3) expression, but again this age-related decrease is ameliorated with regular endurance exercise (5). Therefore, whilst clear negative effects of ageing on NAD+ metabolism, and therefore health, seem to occur, we can at least partially offset these with regular exercise. Determining the optimal exercise modalities and prescriptions to best harness the positive effects on NAD+ metabolism is undoubtedly a worthy challenge for skilled teams of exercise physiologists and biochemists to be working on in the coming years.
Therefore, whilst the research in this space – particularly human research – is still emerging, I think it is fair to say that remaining active and engaging in regular endurance-type exercise is likely to be beneficial for NAD+ metabolism and help ward off the harmful physiological effects of ageing on NAD+ availability. I can recommend, to realise the benefits of exercise on NAD+ as well as many other facets of human health, engaging in a mixed endurance programme involving lower-intensity sessions eliciting smaller homeostatic disturbances, alongside high-intensity work designed to generate acute metabolic stress. This approach will help you to generate positive adaptations in your slow-twitch type I and fast-twitch type II fibres, as well as manage your exercise stress across each week and encourage long-term engagement.
Get after it!
1. Cantó C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11: 213–219, 2010. doi: 10.1016/j.cmet.2010.02.006.
2. de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, Larsen S, Brandauer J, Houmard JA, Treebak JT. Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiol Rep 7: 1–15, 2019. doi: 10.14814/phy2.14139.
3. Graham T, Sjøgaard G, Löllgen H, Saltin B. NAD in muscle of man at rest and during exercise. Pflugers Arch - Eur J Physiol 376: 35–39, 1978.
4. Koltai E, Szabo Z, Atalay M, Boldogh I, Naito H, Goto S, Nyakas C, Radak Z. Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats. Mech Ageing Dev 131: 21–28, 2010. doi: 10.1016/j.mad.2009.11.002.
5. Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, McConnell JP, Nair KS. Endurance exercise as a countermeasure for aging. Diabetes 57: 2933–2942, 2008. doi: 10.2337/db08-0349.
6. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7: 1–9, 2012. doi: 10.1371/journal.pone.0042357.
7. Phillips SM, Green HJ, Tarnopolsky MA, Heigenhauser GJF, Grant SM. Progressive effect of endurance training on metabolic adaptations in working skeletal muscle. Am J Physiol - Endocrinol Metab 270: E265–E272, 1996. doi: 10.1152/ajpendo.1996.270.2.e265.
8. White AT, Schenk S. NAD +/NADH and skeletal muscle mitochondrial adaptations to exercise. Am J Physiol - Endocrinol Metab 303: E308–E321, 2012. doi: 10.1152/ajpendo.00054.2012.
9. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A 112: 2876–2881, 2015. doi: 10.1073/pnas.1417921112.
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