Nicotinamide adenine dinucleotide (NAD+) is a bodily substance critical to several essential physiological processes. Its widespread and complex mechanisms make it a key contributor to functions involving muscle recovery, energy metabolism, anti-aging, and weight loss. Thus, supplementation of NAD+ and its precursors can play a role in improving related parameters, and several studies have evaluated these effects in animal. This article will discuss the evidence supporting NAD+ and how repletion has the potential to improve certain conditions.
What is NAD+?
NAD+ is a coenzyme critical to redox reactions, a type of chemical reaction that occurs in the body. It also contributes as a cofactor for non-redox NAD+-dependent enzymes such as poly(ADP-ribose) polymerases (PARPs). Due to these mechanisms, NAD+ plays a key role in energy metabolism.
In chemical reactions, NAD+ can accept a hydride ion to create its reduced form NADH. This process is essential to several metabolic pathways such as fatty acid oxidation, glycolysis, and glutaminolysis1. When NAD+ accepts electrons, these electrons are donated to the electron transport chain (ETC), forming ATP. NAD+ can also be phosphorylated, creating NADP+, which can accept a hydride ion to form NADPH. NADPH can prevent oxidative stress.
NAD+ also serves several functions outside of energy metabolism. NAD+ can acts as a cofactor for many enzymes, contributing to several cellular functions and processes. Likewise, NAD+ is implicated in several conditions and diseases. One example is the disease pellagra, in which niacin deficiency causes diarrhea, dermatitis, and dementia. Low niacin caused reduced NAD+ levels. NAD+ is also related to certain neurodegenerative and metabolic diseases1.
In addition to its apparent role in preventing disease, NAD+ shows promise in improving certain bodily functions and conditions. This article will discuss the specifics with regard to energy, muscle recovery, anti-aging, and weight loss.
Mouse models demonstrate a significant decrease in in skeletal muscle NAD+ with age. This causes damage, leading to progressive muscle myopathy. Studies have examined how administering nicotinic riboside (NR), an NAD+ precursor, affects Deletor mice muscle. Results indicated that treatment delayed disease progression via mitochondrial biogenesis in skeletal muscle and adipose tissue, suggesting the role of NAD+ in treating mitochondrial myopathy2. Another study demonstrated similar effects when administering nicotinamide mononucleotide (NMN), an NAD+ precursor, to older mice. Treatment for one week improved markers of mitochondrial function in skeletal muscle. It did not, however, restore muscle strength3. Overall, evidence suggest that NAD+ and its precursors play a prominent role in improving mitochondrial metabolism and function in muscle.
NAD+ is central to energy metabolism, improving energy utilization and minimizing energy waste1. The mechanisms underlying this phenomenon relate to its aforementioned role in chemical reactions. NAD+ can accept a hydride ion to form NADH, a chemical reaction implicated in energy metabolism in eukaryotic cells.
NAD+ precursors can also play a role in energy. NR treatment, for example, increases NAD+ levels and enhance SIRT1 and SIRT3 activities. Activating SIRT1 and SIRT3 consequently increase mitochondrial content in adipose tissue and skeletal muscle, elevating the use of lipids as energy substrates and energy expenditure2.
As individuals age, cellular and tissue NAD+ levels gradually decrease in both human and animal models. This reduction in NAD+ correlates with several age-related diseases, including cancer, cognitive decline, sarcopenia, metabolic disease, and frailty. This is because NAD+ levels regulate several biological processes related to aging, including metabolism, neurodegeneration, DNA repair, and genomic stability. By supplementing with NAD+, several of these conditions may be prevented or reversed, prolonging an individual’s lifespan and maintaining their health. This section will discuss the molecular mechanisms underlying the anti-aging phenomenon of NAD+. There are several ways to replete NAD+, including lifestyle changes and certain therapeutics.
Inflammation and immune function
Inflammageing is an age-related condition in which blood inflammatory markers are elevated, causing sickness, disability, and ultimately death. Low NAD+ levels during aging correlates with increased concentration of pro-inflammatory entities such as M1-like resident macrophages. These macrophages can increase pro-inflammatory cytokines in aging tissues, causing age-related disease. Thus, researchers hypothesize that changing NAD+ levels could reverse age-associated immunologic dysfunction.
Another common symptom of aging is cognitive decline, and many older individuals experience more serious neurodegenerative diseases such as Alzheimer’s, amyotrophic lateral sclerosis (ALS), and Parkinson disease. Evidence exists that NAD+ can play a neuroprotective role with regards to aging, and experts hypothesize several reasons for this.
One example of NAD+’s neuroprotective effects involve axonal degeneration, which occurs prior to multiple age-related neuronal conditions. Axonal degeneration correlates with low NAD+ levels, implicating NAD+ in associated cognitive disorders. Repleting NAD+ and overexpressing related enzymes NAMPT and NMNAT1 helped to avoid axon degeneration.
Other entities, such as NAD+ precursors NR and NMN, have demonstrated effects in bettering memory, cognitive function, and neuronal cell health in animal Alzheimer’s models. Several studies are also ongoing assessing the cognitive effects of NAD+. One study, for example, is evaluating how NAD+ affects cognitive performance in those with cognitive decline and impairment due to aging1. Because of the involvement of NAD+ in these processes, researchers hypothesize that NAD+ may improve related disorders.
Obesity accelerates the process of aging, and thus maintaining a healthy weight should be a goal for those looking to maintain their youth. NAD+ can prevent metabolic dysfunction, specifically with regards to obesity. Rodent models indicate that repleting low NAD+ levels provide protective effects against obesity. Additionally, supplementing NR via diet prevent diet-induced obesity. NMN has also shown promise in preventing age-associated weight gain in mice models4. These findings suggest that restoring NAD+ and its precursor concentrations can optimize metabolic health. However, other studies demonstrate that increased NAD+ level do not influence weight loss or insulin. Thus, the utility of NAD+ in human metabolic disorders is unclear1.
Varied evidence suggests that leveraging NAD+ can affect several bodily processes related to energy, aging, muscle recovery, and weight loss. There is potential to target biological pathways associated with NAD+, including utilizing its precursors NMN and NR. Thus, targeting NAD+ mechanisms may provide a possible therapeutic approach to treating related diseases and conditions.
- Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews. Molecular Cell Biology, 22(2), 119–141. https://doi.org/10.1038/s41580-020-00313-x
- Cantó, C., Menzies, K., & Auwerx, J. (2015). NAD+ metabolism and the control of energy homeostasis—A balancing act between mitochondria and the nucleus. Cell Metabolism, 22(1), 31–53. https://doi.org/10.1016/j.cmet.2015.05.023
- Mendelsohn, A. R., & Larrick, J. W. (2014). Partial reversal of skeletal muscle aging by restoration of normal NAD+Rejuvenation Research, 17(1), 62–69. https://doi.org/10.1089/rej.2014.1546
- Shade, C. (2020). The science behind nmn–a stable, reliable nad+activator and anti-aging molecule. Integrative Medicine: A Clinician’s Journal, 19(1), 12–14.