The Three Competing Demands for NAD+

1. Energy metabolism: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate dehydrogenase, and the TCA cycle all require NAD+. Without NAD+, glycolysis stalls and ATP production collapses.

2. Redox homeostasis: The NAD+/NADH ratio reflects cellular redox state. A high ratio indicates oxidizing conditions (energy replete); low ratio indicates reducing conditions (energy depletion or hypoxia).

3. Signaling: Sirtuins consume NAD+ to deacetylate proteins, regulating metabolism, DNA repair, and stress responses. PARPs consume NAD+ for DNA repair. CD38 consumes NAD+ to produce cADPR, regulating calcium signaling.

The Aging Crisis

With age:

• Consumption increases: PARPs become hyperactive due to accumulated DNA damage. CD38 expression increases (especially in immune cells), degrading NAD+.
• Synthesis decreases: NAMPT (the rate-limiting enzyme in NAD+ salvage) declines with age.
• Result: NAD+ depletion creates a competition between essential functions.

The Competition Model

Under NAD+ repletion (youth):

• All three functions are fully funded
• High sirtuin activity maintains mitochondrial function and genome stability
• PARPs can respond to DNA damage without depleting reserves

Under NAD+ depletion (aging):

• Cells must prioritize
• PARPs consume NAD+ for DNA repair, leaving less for sirtuins
• Sirtuin activity drops → mitochondrial dysfunction → more ROS → more DNA damage → more PARP activation
• Vicious cycle ensues

Testable Predictions

1. In aged tissues, the NAD+/NADH ratio should correlate better with functional decline than absolute NAD+ levels. The ratio reflects the balance between consumption and production.

2. Cells with high PARP activity (genome instability) should show reduced sirtuin activity even if total NAD+ is normal. The competition for NAD+ creates a tradeoff.

3. Inhibiting CD38 (a major NAD+ consumer in aging) should rescue sirtuin activity and improve mitochondrial function without increasing NAD+ synthesis.

4. Combining NAD+ precursors with PARP or CD38 inhibition should show synergistic benefits—addressing both supply (precursors) and demand (consumption).

Therapeutic Implications

Current approaches focus on increasing NAD+ supply (NMN, NR). But if the problem is competition, strategies should also address demand:

• CD38 inhibitors: Reduce NAD+ consumption, freeing more for sirtuins
• PARP modulators: Fine-tune DNA repair without excessive NAD+ depletion
• Sirtuin activators: Bypass NAD+ requirement (though this is chemically challenging)

The Systems Perspective

NAD+ is a shared resource. Like any currency, its value depends on both supply and demand. Aging increases demand (more DNA damage, more inflammation) while decreasing supply (lower NAMPT). The resulting shortage forces cells into suboptimal tradeoffs.

NAD+ boosting is not just about adding more currency—it's about restoring the balance between competing essential functions.