NAD+

What NAD+ does in your cells

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in every living cell. It participates in more than 500 enzymatic reactions, working as an electron carrier in mitochondrial energy production and as a substrate consumed by three enzyme families tied to cellular maintenance: sirtuins, PARPs (poly-ADP-ribose polymerases), and CD38. Without adequate NAD+, cells can't efficiently produce ATP, repair damaged DNA, or regulate inflammatory responses.

NAD+ levels drop by roughly 50% between ages 40 and 60 ^[1]. This decline is now considered a hallmark of biological aging, linked to mitochondrial dysfunction, genomic instability, and weakened cellular repair.

Why NAD+ declines with age

Several factors converge to drain NAD+ as we get older. CD38, an enzyme expressed on immune cells, ramps up activity during chronic low-grade inflammation (sometimes called inflammaging) and is the single largest consumer of NAD+ in aging tissues ^[1][2]. PARP enzymes, which patch up accumulated DNA damage, also consume more NAD+ over time. Meanwhile, expression of NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway, decreases with age, reducing the body's capacity to recycle NAD+ from nicotinamide. The result is a progressive energy deficit at the cellular level.

NAD+ biosynthesis: three pathways

Your body produces NAD+ through three distinct routes. The de novo pathway converts the amino acid tryptophan into NAD+ via the kynurenine pathway. The Preiss-Handler pathway uses dietary niacin (vitamin B3). And the salvage pathway recycles nicotinamide back into NAD+ through NAMPT. The salvage pathway handles the majority of daily NAD+ turnover and is the one most affected by aging.

NMN vs. NR as precursors

The two most studied NAD+ precursors are nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). NMN sits one enzymatic step closer to NAD+ in the biosynthesis chain, while NR must first be phosphorylated to NMN by NR kinases. Both effectively raise blood NAD+ levels in human trials. NMN at 250 to 1,000 mg daily has shown improvements in muscle insulin sensitivity, aerobic capacity, and walking speed in older adults ^[3][5]. NR at 300 to 1,000 mg daily has raised NAD+ by 40 to 90% in clinical studies, with safety data at doses up to 2,000 mg ^[4]. A 2025 meta-analysis found that despite clear NAD+ elevation, most clinically relevant endpoints in muscle mass and function did not reach statistical significance across pooled trials ^[6].

Sirtuins and the NAD+ connection

The sirtuin family (SIRT1 through SIRT7) are NAD+-dependent deacetylases that regulate DNA repair, mitochondrial biogenesis, inflammation, and circadian rhythm. SIRT1 mimics caloric restriction benefits by deacetylating PGC-1 alpha and FOXO transcription factors, while SIRT3 protects mitochondrial proteins from oxidative damage. NAD+ availability is the rate-limiting factor for sirtuin activity, which is why NAD+ decline and accelerated aging track so closely together.

Safety and emerging concerns

NAD+ precursors are generally well tolerated. The most common side effects reported in trials are mild: nausea, flushing, and headaches ^[8]. However, a 2024 Cleveland Clinic study raised a new concern: elevated levels of 4PY (N1-methyl-4-pyridone-3-carboxamide), a terminal breakdown product of excess niacin, were associated with increased cardiovascular inflammation and higher risk of heart attack and stroke ^[9]. This doesn't apply equally to all precursors (NMN and NR are metabolized differently from free niacin), but it warrants caution with high-dose, long-term supplementation. People with active cancer should also exercise caution, since NAD+ fuels rapidly dividing cells regardless of whether they're healthy or malignant. Long-term safety data beyond 12 weeks remains limited for most precursors.

Practical strategies to maintain NAD+

• Exercise regularly: HIIT and endurance training upregulate NAMPT and naturally boost NAD+ through the salvage pathway ^[5]
• Practice time-restricted eating: fasting activates AMPK and increases NAMPT expression, synergizing with any precursor supplementation
• Consider TMG (trimethylglycine, 500 to 1,000 mg): NAD+ synthesis consumes methyl groups, and TMG supports methylation balance
• Include CD38-inhibiting foods: apigenin (parsley, chamomile) and quercetin (onions, apples) are natural CD38 inhibitors that may slow NAD+ degradation ^[1]
• Take precursors in the morning to align with circadian NAD+ peaks and avoid possible sleep disruption from evening dosing
• Start low (250 mg NMN or 300 mg NR) and increase gradually based on tolerance