NAD+ turnover

Electron transfer

The plus sign is useful. NAD+ and NADH form a pair involved in cellular oxidation and reduction: the chemistry of passing electrons between reactions. In this role, the molecule cycles between forms. Calling all of that activity ‘consumption’ would muddle the account before it began.

I picture working material circulating through a system, and that less glamorous account suits the chemistry. The review of NAD+ production, cycling and cellular compartments makes that system more complicated than a single tank with a level marked on its side. A concentration is a useful measurement; an entire metabolic life has more moving parts.

PARP1 consumption

PARP1 brings a different sort of demand. The review of PARP1, DNA repair and cell death describes NAD+ as a shared substrate for PARP1 and sirtuins. PARP1 activity couples the repair of damaged DNA to the availability of cellular resources; excessive activation can deplete energy and contribute to cell death. This is a review of mammalian cell biology.

Repair has an appealing reputation, and rightly so. Unlimited enthusiasm for a resource seems premature when it follows only from a useful cellular job. The review describes a system with competing demands and consequences when activity becomes excessive. It gives the expenditure a context.

That context becomes very concrete in the mouse immune cells on the inflammation page, where DNA damage and PARP activity helped create a dependence on NAD+ recycling.

Age-related CD38 consumption

In a mouse study of CD38, this NAD+-consuming enzyme became more active with age. Mice lacking CD38 were protected against the age-related fall in NAD+, with preserved SIRT3 activity and improved mitochondrial function. The experiment changes an enzyme genetically in mice. It gives a mechanistic reason to examine the rate of consumption.

The strongest objection, for me, concerns the moving quantities: an incoming supply and an outgoing demand can both change. The ingenuity deserves my admiration; treating a genetically altered mouse as a preview of a human outcome would ask too much of it. The human-evidence review describes sparse tissue-specific data and limited clinical efficacy. That leaves plenty of accounting still to do.