What Is NAD+ and Why Does It Decline With Age?

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme found in every living cell. It shuttles electrons in the reactions that turn food into ATP — the energy currency your cells run on — and it is a required substrate for sirtuins and PARPs, the enzyme families involved in DNA maintenance and cellular stress responses.

What NAD+ actually does

Think of NAD+ as a molecular battery that cycles between a charged (NAD+) and discharged (NADH) state hundreds of times per day. Mitochondria use it to produce energy. Sirtuin enzymes consume it to regulate metabolism and circadian rhythm. PARP enzymes burn through it when repairing DNA. Because so many processes draw on the same pool, the amount of NAD+ available in a cell matters.

Why NAD+ levels fall

Multiple studies in human tissue have measured lower NAD+ in older adults than in younger ones. Massudi and colleagues (PLoS One, 2012) found that NAD+ in human skin declined with age while oxidative-damage markers rose. Zhu et al. (PNAS, 2015) used magnetic resonance to measure NAD+ in the living human brain and reported lower levels in older subjects. Work in skeletal muscle and liver points the same direction.

The likely drivers are a combination of higher consumption — chronic low-grade inflammation raises the activity of CD38, an enzyme that degrades NAD+ — and lower production, as the enzymes that recycle nicotinamide back into NAD+ become less efficient.

You can't just eat NAD+

NAD+ itself is a large, charged molecule that is broken down in the digestive tract. That is why supplements use precursors: smaller molecules your cells convert into NAD+. The most studied oral precursor is nicotinamide riboside (NR). In a randomized, placebo-controlled trial, Trammell et al. (Nature Communications, 2016) showed that a single oral dose of NR raised blood NAD+ in healthy adults, and Martens et al. (Nature Communications, 2018) found that six weeks of daily NR raised NAD+ in blood cells by about 60% in middle-aged and older adults.

What that means in practice

Raising NAD+ is not a magic switch — the human studies so far measure NAD+ levels and safety, not dramatic outcomes. What they do establish is that a daily oral precursor reliably moves the number. From there, the practical question is which form you will actually take every day. That is the reason simplyNAD+ is a liquid: one berry packet, no capsules to swallow, no powder to mix.

Frequently asked

Is NAD+ the same as niacin? No. Niacin (vitamin B3) is one of several precursors, but at effective doses it causes flushing. NR is a different form of vitamin B3 that does not.

How long does it take? In Trammell's study, blood NAD+ rose within hours of a single dose; Martens measured a sustained increase after six weeks of daily use.

How your body makes NAD+

Cells build NAD+ through three routes. The de novo pathway starts from the amino acid tryptophan and takes eight enzymatic steps — it is slow and contributes little in most tissues. The Preiss–Handler pathway starts from nicotinic acid (niacin). The salvage pathway recycles nicotinamide, the fragment left behind every time a sirtuin or PARP consumes NAD+, back into NAD+ via the enzyme NAMPT. The salvage pathway supplies the large majority of NAD+ in adult tissue, which is why NAMPT is often called the rate-limiting enzyme of NAD+ production. Nicotinamide riboside enters this system one step downstream of NAMPT: NR is phosphorylated by the NRK1/NRK2 kinases into NMN, and NMN is then joined to ATP to form NAD+.

What draws the pool down

Three enzyme families consume NAD+ in large amounts. Sirtuins (SIRT1–7) use it to remove acetyl groups from proteins, a mechanism that regulates metabolism, mitochondrial biogenesis and the circadian clock. PARPs, especially PARP1, burn NAD+ when they respond to DNA damage — under heavy damage they can consume it fast enough to deplete a cell. CD38, a membrane enzyme on immune cells, degrades NAD+ to make calcium-signalling messengers; Camacho-Pereira et al. (Cell Metabolism, 2016) reported that CD38 expression rises with age in mouse tissue and that CD38-deficient mice were protected from the age-related NAD+ decline. Together these consumers explain why the NAD+ pool is a balance rather than a fixed stock: production has to keep pace with consumption, and with age it increasingly does not.

Lifestyle factors linked to NAD+

Precursors are not the only lever. Endurance exercise raises NAMPT in skeletal muscle — Costford et al. (American Journal of Physiology, 2010) found that athletes had roughly twice the muscle NAMPT of sedentary adults, and that a training programme increased it in previously untrained people. Alcohol works in the opposite direction: metabolising ethanol converts NAD+ to NADH in the liver, temporarily shifting the ratio. Chronic inflammation raises CD38 activity. Sleep and the circadian clock matter because NAMPT is itself under clock control (Nakahata et al., Science 2009). A precursor supplement sits on top of these, not instead of them.

How much do precursors move the number?

In Trammell et al. (2016), a single 1,000mg oral dose of NR raised NAD+ in blood cells within hours, with the largest increases seen around eight hours after dosing. In Martens et al. (2018), 1,000mg per day for six weeks raised NAD+ in peripheral blood mononuclear cells by about 60% versus placebo and was well tolerated. Elhassan et al. (Cell Reports, 2019) gave 1,000mg per day to adults aged 70–80 for three weeks and measured an expanded NAD+ metabolome in skeletal muscle along with lower levels of circulating inflammatory markers. These are level and safety studies — they show the dose moves the biomarker reliably. Larger outcome trials are still being run.

Glossary

• NAD+ / NADH — the oxidised and reduced forms of the same coenzyme; cells cycle between them.
• NR — nicotinamide riboside, a form of vitamin B3 and the most-studied oral NAD+ precursor.
• NMN — nicotinamide mononucleotide, NR with a phosphate attached; the step between NR and NAD+.
• NAMPT — the enzyme that recycles nicotinamide into NAD+; the rate-limiting step of the salvage pathway.
• Sirtuins — NAD+-dependent enzymes involved in metabolism, stress response and circadian rhythm.
• CD38 — the main NAD+-degrading enzyme; its activity rises with age and inflammation.
• PGC-1α — the regulator that tells cells to build new mitochondria.

Read next: Nicotinamide riboside vs NMN · Liquid NAD+ vs capsules

References

Massudi H et al. PLoS One 2012;7:e42357 · Zhu XH et al. PNAS 2015;112:2876–2881 · Trammell SAJ et al. Nat Commun 2016;7:12948 · Martens CR et al. Nat Commun 2018;9:1286 · Camacho-Pereira J et al. Cell Metab 2016;23:1127–1139 · Costford SR et al. Am J Physiol Endocrinol Metab 2010;298:E117–E126 · Elhassan YS et al. Cell Rep 2019;28:1717–1728 · Nakahata Y et al. Science 2009;324:654–657

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. This article is educational and is not medical advice — talk to your doctor before starting any supplement.