Critical findings on NAD+
NAD+ is an essential molecule for life that primarily acts as a “coenzyme”: a cofactor for enzymes in oxidation-reduction (redox) reactions, facilitating the transfer of hydrogen atoms. This transfer is crucial in enabling cells to adapt to changes such as DNA damage, daily rhythm disruptions, infections, inflammation, exposure to foreign chemicals and one of the most important: nutrient availability and the production of ATP, the cell's main energy currency, essential for proper functioning of all cells in the body.
Interestingly, NAD+ has been identified as a key link connecting oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity, and overall health span (1). Maintaining optimal NAD+ levels is thus vital for supporting metabolic health. This is highly relevant in modern societies, where lifestyle factors such as poor dietary habits, chronic stress, sedentarism, lack of sunlight or high exposure to chemicals contribute to an increasing prevalence of impaired metabolic health (2, 3).
Metabolic dysfunction is a root cause of chronic inflammation, which over time can lead to the development of autoimmune diseases—conditions that are increasing at an alarming rate each year (4, 5).
Why is NAD+ considered a hallmark of aging?
Although NAD+ research is dated since the early 1900s, NAD+ has gained a lot of interest in the recent years as it has been identified as a hallmark of aging.
NAD+ levels consistently decline with age due to decreased NAD+ synthesis and increased consumption, driven by NAD+’s increasing demand in essential cellular oxidation-reduction reactions (6). Importantly, NAD+ levels have also been shown to be decreased through overnutrition, alcohol consumption, viral infection and a sedentary lifestyle in clinical and preclinical studies (6,7). Decreased NAD+ levels lead to metabolic alterations and increased disease susceptibility, such as cardiovascular disease, neurodegenerative diseases, and cancer.
Interestingly, studies showed that restoring NAD+ levels in old or diseased animals promoted health and extended lifespan (1). The discovery of NAD+’s crucial role in aging and metabolic health has prompted further research in humans and uncovered its therapeutic potential, driving the growth of a substantial market for NAD-boosting molecules, which have clinically shown promising results in slowing down age-related processes and increasing the body’s resilience to many autoimmune diseases such as Parkinson’s or multiple sclerosis, thereby extending healthy human lifespan (6).
What are NAD+’s main functions in the body?
NAD+ acts in many critical processes in our body (6, 8, 9), including:
Cellular energy production: NAD+ collects hydrogen atoms during glycolysis (breakdown of sugar), fatty acid breakdown, and the subsequent tricarboxylic acid (TCA) cycle - occurring in the mitochondria – which forms NADH. NADH then donates these hydrogens to produce ATP (the cell's main energy currency) through mitochondrial oxidative phosphorylation (OXPHOS). Additionally, NAD+ supports mitochondrial biogenesis, the process of forming new mitochondria, which is critical for energy production and metabolism.
Sirtuin activity and 24-hour daily rhythm cycle (circadian rhythm): NAD+ plays a crucial role in regulating the body's circadian rhythm by directly affecting the transcription of clock genes via enzymes, such as sirtuins (SIRT1/6). Sirtuins act as intracellular NAD+ sensors and have been described to help modulate the circadian clock, influencing metabolism, sleep, and overall health.
DNA repair: NAD+ is essential for activating enzymes known as PARPs (poly(ADP-ribose) polymerases), which are involved in repairing damaged DNA. This function helps maintain genomic stability and prevents the accumulation of DNA damage that contributes to aging and disease development.
How is NAD+ synthesised and regulated?
NAD+ is one of the most common metabolites in the human body and it is in a homeostatic status of biosynthesis, consumption, recycling and degradation at both cellular and systemic levels (Figure 1) (6).
(In agreed, similar figure with information below pending to be generated)
Figure 1. Mammalian cells can synthesize NAD+ de novo from tryptophan by the kynurenine pathway or from NA by the Preiss‐Handler pathway, while most NAD+ is recycled via salvage pathways from nicotinamide (NAM), NA, NR and NMN to maintain the cellular NAD+ levels. NAD+ can be reduced into NADH in the metabolic processes, including glycolysis, fatty acid oxidation and the TCA cycle. As a co-substrate important to various post-synthesis modifications of fundamental macromolecules, NAD+ can be cleaved (“degraded”) by NAD+-consuming enzymes including: PARPs, sirtuins, CD38 and SARM1, to generate NAM and ADP-ribose. The precursor NR is imported by ENTs and transformed to NMN by NRK (6).
Non-pharmacologic strategies to increase NAD+ bioavailability
Intracellular NAD+ levels can be increased naturally by adopting a series of lifestyle habits, which serve as effective preventive measures to slow the aging process. Thus far, research has shown that NAD+ can be increased by energy stress, including caloric and glucose restriction, as well as exercise (6, 10).
Caloric restriction: Caloric restriction has been shown to help counteract age-related declines in circadian rhythm – the body’s 24-hour cycle – by improving circadian control of NAD+ metabolism and enhancing NAD+/SIRT1-related epigenetic changes. Both long-term and short-term caloric restriction have been shown to reduce artery stiffness and improve endothelial function. Additionally, another study reported that caloric restriction raised NAD+ levels and protected the brain against aging and disease by reducing oxidative stress and cellular damage.
Exercise: Exercise has gained attention for its ability to potentially boost NAD+ levels and SIRT1 activity, by increasing NAMPT. Regular training significantly raises NAMPT protein in the muscles as a way to respond to energy stress, as seen in a study with non-obese sedentary adults.
Boosting NAD+ as a Therapeutic Strategy
NAD+ depletion is a key feature of aging and age-related disorders. Increasing NAD+ levels can slow aging and combat diseases, promoting a longer, healthier life. Therapeutically, NAD+ can be boosted through dietary supplementation of NAD+ precursors such as Trp, NA, NMN and NR, or by inhibition NAD+-consuming enzymes (e.g., PARP1, CD38) (6).
NAD+ precursors, especially the soluble and orally bioavailable molecules NR, NAM, and Niacin, have shown therapeutic potential in human clinical trials. In particular, NR has become one of the most popular options given the high amount of beneficial clinical results in many different NAD+ related diseases (see our article about NR for more detail).
MNM has also been shown to be rapidly absorbed and converted to NAD+ in organs like muscle, liver, and kidney, but its cellular transport mechanisms remain unclear. In addition, MNM has significantly less clinical studies than NR and the other NAD+ precursors and has shown some risks. A study showed that NMN-induced inflammation promoted the development of pancreatic cancer, highlighting the need for long-term safety studies of NMN NAD+ boosters (6, 11, 12).
Conclusions
NAD+ levels regulate many critical processes, including cellular energy balance, genomic stability, metabolism, stress responses, circadian rhythm, inflammation, redox homeostasis and mitochondrial balance. NAD+ levels consistently decline with age, as well as through modern lifestyle poor habits such as overnutrition, alcohol consumption, viral infection and a sedentary lifestyle. Decreased NAD+ levels lead to metabolic alterations and increased prevalence of chronic inflammation leading to autoimmune diseases.
Boosting NAD+ through lifestyle changes such as exercise or caloric restriction can offer a non-pharmacological way to promote healthy aging by improving resilience and extending healthy lifespan. Clinically approved NAD+ pharmacological boosters, NR being the most studied, are uncovering a broad spectrum of health benefits in both healthy and diseased humans, particularly in NAD+ deficiency related pathologies such as aging-related neurodegenerative disorders, cancer, metabolic diseases, acute injury, infection and overall aging.