NAD+ Therapy and Cellular Ageing: What the Research Shows

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme present in every living cell of the human body. It is essential for hundreds of metabolic reactions, including energy production, DNA repair, and the regulation of cellular ageing pathways. As we age, NAD+ levels decline significantly, a process that is now recognised as a key driver of biological ageing. This article examines the science of NAD+ therapy, its mechanisms of action, and what the current research evidence shows.

What Is NAD+ and Why Does It Matter?

NAD+ exists in two forms: NAD+ (the oxidised form) and NADH (the reduced form). Together, they participate in critical redox reactions that drive cellular metabolism. NAD+ is required for:

Energy metabolism: NAD+ is a central component of the mitochondrial electron transport chain, where it helps convert nutrients into adenosine triphosphate (ATP), the primary energy currency of cells. Without adequate NAD+, cellular energy production becomes impaired.

DNA repair: NAD+ is consumed by poly(ADP-ribose) polymerases (PARPs), a family of enzymes responsible for detecting and repairing DNA damage. As DNA damage accumulates with age, PARP activity increases, creating a growing demand for NAD+ that can outstrip supply.

Sirtuin activation: Sirtuins are a family of NAD+-dependent enzymes (SIRT1–SIRT7) that regulate numerous cellular processes including gene expression, inflammation, stress resistance, and mitochondrial biogenesis. Often referred to as “longevity genes,” sirtuins require NAD+ as a co-substrate and cannot function without it.

Circadian rhythm regulation: NAD+ levels fluctuate in a circadian pattern, and this oscillation plays a role in regulating the body’s internal clock. Disrupted NAD+ metabolism may contribute to the circadian dysregulation observed in ageing.

The NAD+ Decline with Age

Research has consistently demonstrated that NAD+ levels decline with age across multiple tissues and organ systems. Studies in both animal models and human subjects have documented reductions of 50% or more in NAD+ levels between young adulthood and older age.

This decline is driven by several converging factors:

Increased consumption of NAD+ by PARPs in response to accumulated DNA damage. Increased activity of CD38, an enzyme that degrades NAD+, particularly in the context of chronic inflammation. Reduced efficiency of NAD+ biosynthesis pathways. Mitochondrial dysfunction that creates a self-reinforcing cycle of NAD+ depletion and further mitochondrial impairment.

The consequences of NAD+ depletion are far-reaching. With insufficient NAD+, cells lose their capacity for efficient energy production, DNA repair slows, sirtuin activity declines, and the cell becomes increasingly vulnerable to stress and damage. This cascade is now understood to be a central mechanism of biological ageing.

How NAD+ Therapy Works

NAD+ therapy aims to restore cellular NAD+ levels to support the metabolic processes that decline with age. Several approaches are used:

Intravenous NAD+ Infusion

Intravenous (IV) administration delivers NAD+ directly into the bloodstream, bypassing the digestive system and achieving rapid elevation of circulating NAD+ levels. IV NAD+ infusions typically take two to four hours and are administered in a clinical setting under medical supervision.

The advantage of IV delivery is its ability to achieve supraphysiological NAD+ levels quickly. However, IV NAD+ must be metabolised and transported into cells, and the kinetics of cellular uptake are an area of ongoing research.

NAD+ Precursor Supplementation

An alternative approach uses NAD+ precursors, molecules that the body can convert into NAD+ through established biosynthetic pathways. The two most studied precursors are:

Nicotinamide riboside (NR): A form of vitamin B3 that is converted to NAD+ via the nicotinamide riboside kinase (NRK) pathway. Multiple clinical trials have demonstrated that NR supplementation effectively increases blood NAD+ levels in humans.

Nicotinamide mononucleotide (NMN): A direct precursor to NAD+ that is one enzymatic step closer to NAD+ than NR. NMN has shown robust NAD+-boosting effects in animal studies, and early human clinical trials have reported positive results on insulin sensitivity, muscle function, and aerobic capacity.

Combination Approaches

At Longevity Thailand, NAD+ therapy is typically integrated into a broader regenerative protocol rather than administered in isolation. Combining IV NAD+ with complementary therapies, such as peptide protocols, antioxidant support, and lifestyle optimisation, may enhance therapeutic outcomes by addressing multiple hallmarks of ageing simultaneously.

What Does the Research Show?

Animal Studies

The preclinical evidence for NAD+ repletion is compelling. Studies in aged mice have demonstrated that restoring NAD+ levels through NMN or NR supplementation can:

Reverse age-related muscle wasting and improve exercise endurance. Restore mitochondrial function to levels comparable to younger animals. Improve insulin sensitivity and metabolic function. Enhance cognitive performance and neuronal resilience. Extend healthy lifespan in certain experimental models.

A landmark 2013 study published in Cell by Gomes and colleagues showed that raising NAD+ levels in aged mice restored mitochondrial function within one week, a finding that generated significant excitement in the longevity research community.

Human Clinical Trials

Human research on NAD+ therapy is less mature but growing rapidly. Published clinical trials have demonstrated:

NR supplementation safely increases blood NAD+ levels by 40–90% in healthy middle-aged and older adults. NMN supplementation at 250mg daily for 10 weeks improved muscle insulin sensitivity and insulin signalling in premenopausal women with overweight or obesity (published in Science, 2021). NMN supplementation at 250mg daily improved aerobic capacity in recreational runners, as reported in the Journal of the International Society of Sports Nutrition (2022). IV NAD+ infusion protocols have been associated with self-reported improvements in energy, cognitive clarity, and overall well-being, though controlled trial data for IV administration is still emerging.

It is important to note that whilst the direction of evidence is encouraging, large-scale, long-term randomised controlled trials in humans are still needed to fully characterise the clinical benefits and optimal dosing of NAD+ therapy.

Safety and Tolerability

NAD+ therapy, whether administered intravenously or as oral precursors, has demonstrated a favourable safety profile in published studies. Common side effects of IV NAD+ infusion include temporary flushing, mild nausea, and a sensation of chest tightness during infusion, all of which are typically mild and resolve promptly.

Oral NR and NMN supplementation have been well tolerated in clinical trials at doses up to 1,000–2,000mg daily, with no serious adverse events reported.

Patients with certain medical conditions should discuss NAD+ therapy with their physician before commencing treatment. NAD+ therapy is not recommended as a substitute for conventional medical treatment of diagnosed conditions.

Practical Considerations for Patients

For patients considering NAD+ therapy, several factors are worth discussing with their physician:

Baseline assessment: Measuring baseline NAD+ levels and related biomarkers can help guide dosing and track response. At Longevity Thailand, NAD+ therapy is preceded by comprehensive biomarker testing to establish an individualised protocol.

Protocol duration: NAD+ infusion programmes typically involve a series of sessions over several days, often as part of a broader regenerative treatment plan. Ongoing maintenance strategies may include periodic IV top-ups and oral precursor supplementation.

Lifestyle integration: NAD+ therapy is most effective when combined with lifestyle factors known to support NAD+ metabolism, including regular exercise, caloric moderation, and adequate sleep. These factors independently influence NAD+ biosynthesis and should be considered part of any comprehensive longevity strategy.

The Broader Context

NAD+ therapy is one component of an evolving understanding of biological ageing. It addresses a real and measurable biochemical deficit that occurs with age, and the mechanistic rationale for supplementation is grounded in decades of biochemical research. However, as with all interventions in longevity medicine, it is important to maintain realistic expectations. NAD+ therapy is not a cure for ageing, but it is a scientifically supported approach to addressing one of the key molecular mechanisms underlying age-related decline.