The War Inside Every Cell – NAD+ Between PARPs and Sirtuins

The War Inside Every Cell, and NAD+ in the Crossfire

Inside the nucleus of every cell, two enzyme families wage a silent competition for the same resource. The winner determines whether the cell repairs itself, ages, or collapses.

Biological System: Mitochondrial Energy System | Compound: NAD+ (Nicotinamide Adenine Dinucleotide) | Focus of this article: the PARP vs. sirtuin axis, competition for NAD+ as a limited resource

Every system with limited resources faces the same problem: when demand exceeds supply, someone loses. In the case of NAD+ inside the cell, the dispute is between two systems you want to function, and that depend on the same fuel to survive.

On one side, the sirtuins, enzymes that regulate gene expression, repair DNA methodically, stimulate mitochondrial biogenesis, and control inflammation. On the other, the PARPs, emergency enzymes that respond to acute DNA damage with speed and voracity. Both need NAD+ to function. Both consume it in use.

The question at the center of one of the most active areas of aging biology is this: what happens when available NAD+ begins to fall, and both families need more and more of it?

“The NAD+ budget hypothesis suggests that, with aging, total demand for NAD+ exceeds replenishment capacity. And when the resource grows scarce, the cell must make choices it was not designed to make.

Two systems. One resource. One dispute.

Under normal conditions, this competition is manageable. The young organism produces NAD+ in sufficient quantity to supply both systems. The salvage pathway, led by the enzyme NAMPT, recycles the nicotinamide released by sirtuin and PARP reactions back into NAD+, maintaining the stock.

But aging changes this balance. Studies in animal models and human tissues document that the capacity to produce NAD+ declines with age. At the same time, the accumulated DNA damage, inevitable over time, keeps the PARPs chronically activated. The result is that demand for NAD+ rises exactly when supply is decreasing.

“It is like a city facing a blackout while electricity demand breaks records. The infrastructure was not built for this scenario, and the choices about what loses power have consequences.

The vicious cycle, and why it matters

Research on the PARP/NAD+/sirtuin axis gained an additional layer of complexity when studies began to document the role of CD38, an ectoenzyme that degrades NAD+ and whose levels rise significantly with aging and inflammatory states.

The cycle that emerges from this dynamic is the object of intense investigation: accumulated DNA damage activates PARPs → PARPs consume NAD+ → lower NAD+ reduces SIRT1 activity → less active SIRT1 means less activated PGC-1α → less mitochondrial biogenesis → more dysfunctional mitochondria → more reactive oxygen species → more DNA damage → more PARP activation.

Chini and colleagues of the Mayo Clinic and NIH, in an analysis published in Aging Cell in 2024, added another piece: senescent cells, those that have stopped dividing but have not died, secrete inflammatory factors (the SASP) that activate CD38 in neighboring cells. This means senescence in one part of the tissue may accelerate NAD+ decline in other parts, creating a propagation effect.

The role of CD38, the third player. CD38 is an ectoenzyme that degrades NAD+ and its precursors. In aging models, its expression rises progressively, making it one of the principal drivers of the NAD+ decline observed in senescence. Researchers speculate that CD38 inhibition represents an alternative route to maintain NAD+ homeostasis, distinct from precursor supplementation. The convergence of cellular senescence, SASP, CD38 activation, and NAD+ depletion represents one of the most promising directions of current research.

What this opens for research

The “NAD+ budget” hypothesis, that different enzymes compete for an increasingly scarce resource, opens at least three directions of investigation with high potential.

The first is the question of route of administration and bioavailability. If the problem is one of supply, how to restore stocks effectively? Clinical trials with oral precursors (NR and NMN) document consistent elevation of circulating NAD+ levels. Research with intravenous NAD+ as an isolated compound is at an earlier stage, with data limited to pilot studies, but it represents a distinct investigative direction.

The second is the target of intervention. Restoring NAD+ resolves the dispute, but does not eliminate the excessive demand. Researchers are investigating combined strategies: NAD+ replenishment together with selective CD38 inhibition or PARP modulation to reduce consumption. The review by Chini and colleagues explicitly proposes combining senolytics (which eliminate senescent cells) with NAD+ precursors.

The third is timing. If the vicious cycle begins decades before any visible symptom of aging, when to intervene? And on which link of the chain? These are questions science is actively trying to answer, and that make NAD+ one of the most relevant research compounds in current mitochondrial biology.

“The most interesting question is not restoring NAD+. It is understanding which link of the vicious cycle, when broken, has the greatest impact on the system as a whole. That question still has no definitive answer, and that is exactly why it is being investigated.

Context within the AXION portfolio. SS-31 protects the inner mitochondrial membrane, where NAD+ operates as an electron carrier. MOTS-c activates AMPK, which stimulates the expression of NAMPT, the key enzyme of the NAD+ salvage pathway. Epithalon connects via SIRT6 and telomere maintenance. The combined research of these Mitochondrial Energy System molecules represents an investigative approach with multiple points of entry into the same biological system.