NAD+

NAD+ — nicotinamide adenine dinucleotide — is not a peptide. It is a coenzyme, built from vitamin B3 and the same adenine found in DNA, and it appears in several hundred enzymatic reactions. Almost every pathway that releases energy from food passes electrons through it at some point.

Its primary job is carrying electrons. Breaking down glucose or fatty acids means stripping electrons from them, and those electrons have to be taken somewhere. NAD+ accepts them, becoming NADH, and delivers them to the mitochondrial machinery that uses their energy to make ATP. It then returns as NAD+ for the next reaction. Nothing is consumed; it is a shuttle in continuous circulation.

The reason it appears in ageing research is a second and quite different role. Several families of enzymes do not merely borrow NAD+ — they take it apart and consume it. Sirtuins, which remove chemical tags from proteins including those packaging DNA, are the best known. PARPs, which respond to DNA damage, are another. These enzymes spend NAD+ as a substrate, which means the supply is a limited resource that regulatory processes compete for.

• Two jobs, one molecule: It is both a recycled electron carrier and a consumed substrate. That dual role is what connects a cell's energy metabolism to its regulation of gene expression and DNA repair.

• Sirtuins depend on it: This family of enzymes cannot function without NAD+, and they modify the proteins that package DNA. Their dependence is the main reason NAD+ became a subject in ageing research.

• Measured decline with age: Tissue concentrations fall with age across several species, which is an observation rather than a hypothesis, and one of the firmer facts in this area.

• The salvage pathway: Cells recycle nicotinamide back into NAD+ continuously rather than building it from scratch. How efficiently that loop runs is what actually determines supply.

Burning fuel, chemically, means moving electrons from one molecule to another. Food molecules are electron-rich; the reactions that release their energy strip those electrons away in stages. They cannot be left loose, so the cell uses carriers, and NAD+ is the principal one. It collects electrons in the early stages of fuel breakdown and delivers them to the electron transport chain in the mitochondria, where their energy is captured as ATP.

This is a loop, and that matters for understanding the second role. A cell holds a limited amount of NAD+ at any moment, and it works only because the same molecules are used again and again. Anything that consumes NAD+ rather than cycling it reduces the pool available for everything else.

Which is precisely what sirtuins and PARPs do. Sirtuins remove acetyl tags from proteins — including histones, which control how tightly DNA is packed and therefore which genes can be read — and they destroy an NAD+ molecule with each removal. PARPs consume it in quantity while responding to DNA damage. The result is a direct competition: DNA repair, gene regulation and energy metabolism all draw on one pool, which is why the size of that pool is treated as a meaningful variable.

The biochemistry is settled and fundamental. NAD+'s structure, its role in energy metabolism, the salvage pathway, and its consumption by sirtuins and PARPs are established science. The decline in tissue concentrations with age has been measured in several species independently.

Work on raising it is less settled: human trials of precursors have shown that blood measures can be raised, with less clarity about tissue concentrations, and NAD+ itself is a large charged molecule that does not readily enter cells. It is supplied for laboratory research only. Its research value is that it sits at the junction of energy metabolism and gene regulation, which is what makes the size of the cellular pool a meaningful variable to study.

5-Amino-1MQ approaches the same pool from the other direction, inhibiting an enzyme that diverts nicotinamide away from recycling. Supplying more, or wasting less, are two genuinely different strategies for the same problem.

MOTS-c and SS-31 both concern mitochondrial function, where most NAD+ cycling happens, and Glutathione faces the same question about whether supplying a molecule from outside raises it inside cells.