Full mechanism, in text

What uses up NAD⁺

1 · Pool + three consumers

Around the pools in the cytoplasm and mitochondria, three enzyme families wait to cut NAD⁺, and every cut uses one up.The cytoplasm and mitochondria each hold an pool. Human skin samples and several mouse tissues show it falling with age; how far it falls in people varies widely with the tissue and the method, and there is no single figure.

Around the pool, three enzyme families wait to cut NAD⁺ — every cut turns NAD⁺ into nicotinamide plus another product, and that NAD⁺ is used up:

· (SIRT1-7) — deacetylases, often called longevity genes
· PARP1/2 — emergency repair enzymes for DNA damage
· CD38 — an enzyme that specifically cuts NAD⁺ (an NADase), which grows with age

The three consume at different speeds, are regulated differently, and switch on to different degrees in different states. The next three steps look at what each is doing — and why the age-related fall in NAD⁺ does not look like a shortage of raw material.

2 · Sirtuin — restrained drip

use 1 for each acetyl group they strip off a protein, a slow and frugal drain that slows further when the pool drops. (SIRT1-7) are -dependent histone / protein deacetylases — they strip acetyl groups (-COCH₃) off proteins and in doing so tune gene expression, metabolism and stress responses.

Reaction:

Acetylated protein + NAD⁺ → protein + nicotinamide + 2'-O-acetyl-ADP-ribose

Each acetyl group removed uses 1 NAD⁺ — a frugal kind of consumption:

· Activity is sensitive to NAD⁺ concentration, so it slows when the pool drops
· It consumes far more slowly than PARP does during DNA damage

This is the basis of the boost NAD⁺ → activate SIRT → longer life hypothesis: raise the pool → sirtuin activity recovers → longevity pathways switch on.

But: the early finding that overexpressing SIR2 extends lifespan in yeast, worms and flies disappeared in worms and flies once Burnett 2011 (Nature) standardized the genetic background and used proper controls. The sirtuin hypothesis has been downgraded in science while it is still in use in marketing.

3 · PARP — emergency burst

When DNA breaks, PARP1/2 is recruited to the damage, and a single repair uses up a large handful of to build poly(ADP-ribose) chains.When DNA suffers single- or double-strand breaks (UV, oxidative stress, replication errors, chronic inflammation), PARP1/2 is recruited to the site at once and takes big bites of :

NAD⁺ → ADP-ribose → poly(ADP-ribose) chains (attached to proteins at the damage site)

One chain can carry dozens to a hundred or more ADP-ribose units, so a single repair uses up a large handful of NAD⁺.

· This is the emergency consumer, using far more per event than the
· Acute oxidative stress, chemotherapy and radiotherapy can keep PARP working until supplies run out
· PARP overactivation → NAD⁺ depletion → cell death (parthanatos) — conversely, PARP inhibitors such as olaparib work as cancer drugs by exploiting cancer cells' dependence on PARP for DNA repair

In old age: DNA damage accumulates and chronic inflammation becomes the norm → PARP keeps working at a low level → a steady drain on NAD⁺.

But in the mouse data PARP1 expression did not rise with age — what clearly grows with age is the next step's CD38.

4 · CD38 — the drain that widens with age

CD38 is a membrane-bound glycohydrolase: one cut splits NAD⁺ into nicotinamide + cyclic ADP-ribose (cADPR, a small calcium-signalling molecule).Key facts (Camacho-Pereira 2016, Cell Metab):

· In old mice, CD38 rose to at least 2-3 times its young level in liver, fat, muscle and spleen, while PARP1 and SIRT1 expression did not rise with age
· In human fat samples, CD38 mRNA in older people was up to about 2.5 times that in younger people
· Mice with CD38 knocked out no longer lose with age
· Chronic inflammation also turns CD38 up

So: in mice, CD38 is treated as the main explanation for the age-related NAD⁺ fall, rather than a shortage of raw material. Read the limit carefully: the causal chain was shown in mice; in people, only half of it — the rise in CD38 — has been seen so far.

Then what can / do?

· Can: open the tap and raise the pool — Martens 2018 gave middle-aged and older adults 1000 mg of NR a day (500 mg twice), and after 6 weeks NAD⁺ in peripheral blood mononuclear cells was about 60% higher than in the placebo period
· Cannot: make the CD38 drain smaller

The two approaches compared:

· Precursor only: the pool rises and the leak stays; the mechanism predicts a return to the old balance after stopping — a step not yet properly measured in people
· Precursor + patching the leak (CD38 inhibition): a hypothesis; no CD38 inhibitor is approved for human use, and candidate molecules (such as 78c and apigenin) are still preclinical

Core message: what the market sells is all tap. More water in the tank does not mean a healthier person — that is a separate question only outcome trials can answer. This does not make NMN / NR useless; it means the promise to reverse ageing does not yet stand on its mechanism.

Full mechanism, in text

1 · Pool + three consumers

2 · Sirtuin — restrained drip

3 · PARP — emergency burst

4 · CD38 — the drain that widens with age

Who drains the NAD⁺ pool

Full mechanism, in text

1 · Pool + three consumers

2 · Sirtuin — restrained drip

3 · PARP — emergency burst

4 · CD38 — the drain that widens with age

Who drains the NAD⁺ pool