Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain.

See https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1

(Chaubey et al., Cell Reports Medicine, 2025)

Your body has a built-in "NAD+ thermostat." In your youth, this system keeps NAD+ levels perfectly tuned. As we age (and especially in Alzheimer’s), the machinery doesn't just run out of fuel; it breaks down and begins to "leak" or "over-consume," leading to an energy crisis.

Here is the breakdown of the problem and the "machine-fixing" solutions.

1. The Problem: The "Drain" vs. The "Refill"

The paper highlights that in Alzheimer's and aging, NAD+ levels decline because the homeostatic balance is lost.

• The "Leak" (Consumption): Enzymes like CD38 and PARPs act like open drains. As inflammation increases (inflammaging), CD38 becomes hyperactive and starts "eating" NAD+ faster than your body can make it.
• The "Broken Pump" (Recycling): Your body is designed to recycle 99% of its NAD+ through the Salvage Pathway. The key engine here is an enzyme called NAMPT. In aging, this pump slows down.
• The "Waste Management" (NNMT): When the system is stressed, an enzyme called NNMT starts tagging the broken-down NAD+ (nicotinamide) to be thrown out in your urine rather than recycled.

The Study’s Insight: Simply dumping more NMN/NR (precursors) into the system is like trying to fill a bathtub without plugging the drain. The study used a compound (P7C3-A20) that helps the cell maintain its own balance.

2. Fixing the Machinery: Supplement Solutions

If you want to fix the "thermostat" rather than just "crank the heat" with NMN/NR, you look at supplements that target the enzymes responsible for the drain and the pump.

A. Plug the Drain: CD38 Inhibitors

CD38 is the primary "sink" that wastes NAD+ as we age.

• Supplement: Apigenin (found in chamomile and parsley) or Luteolin.
• The Fix: These are potent natural inhibitors of CD38. By slowing down CD38, you "plug the drain," allowing your body's natural NAD+ levels to rise and stabilize without external precursors.

B. Repair the Recycling Pump: NAMPT Activators

NAMPT is the rate-limiting "recycling engine." If this isn't working, no amount of NMN will help long-term.

• Solution: Aerobic & Resistance Exercise.
• The Fix: Exercise is the most powerful known activator of NAMPT. It literally upgrades the machinery so your cells become better at recycling the NAD+ they already have.

C. Stop the Waste: NNMT Inhibition

If your body is throwing away too much of the "spent" NAD+ (nicotinamide), you lose your raw materials.

• Supplement: Methyl Donors (TMG / Betaine).
• The Fix: While not a direct inhibitor, TMG helps manage the methylation process. High-dose NAD+ boosting can "drain" your methyl groups as the body tries to excrete excess nicotinamide. Taking TMG ensures that the "garbage disposal" (methylation) doesn't steal resources from other vital processes like DNA repair.

The "Paper" Conclusion

The Cell Reports Medicine study suggests that P7C3-A20 (a small molecule) could reverse Alzheimer’s because it didn't just "boost" NAD+; it stabilized the energy balance. For someone looking to follow this "machinery" philosophy today, the strategy would be:

• Inhibit the Drain: Apigenin (to stop CD38 from wasting NAD+).
• Activate the Pump: Exercise (to upregulate the NAMPT recycling enzyme).
• Protect the System: Quercetin or Fisetin (to clear out "senescent cells" which are the main source of the inflammation that triggers the NAD+ drain).

In the context of longevity and NAD+ optimization for the 50+ age group.

For CD38 inhibition—plugging the "leak" that drains your NAD+ levels—the following dosages are typically observed in clinical research and advanced longevity protocols.

Note on Bioavailability: Apigenin and Quercetin are notoriously difficult to absorb. Recent 2025 data suggests that liposomal or nano-emulsified versions can be up to 5–10x more effective, potentially allowing for lower dosages (e.g., 50–100mg of liposomal apigenin) to achieve the same CD38-blocking effect.

The "Machinery" Problem: Leak vs. Pump

The 2025 research you're referencing (likely the Cell Reports Medicine paper on P7C3-A20) highlights a fundamental flaw in traditional NAD+ supplementation. For an adult over 50, the cellular energy system isn't just "low on gas"—the engine itself is failing.

1. The Leak (The CD38 Problem)

Think of your cellular NAD+ pool as a water tank. As we age, an enzyme called CD38 becomes hyper-activated (driven by low-grade inflammation, or "inflammaging").

• The Problem: CD38 is like a massive hole in the bottom of the tank. You can pour in as much "fuel" (NMN/NR) as you want, but the CD38 "leak" will consume it faster than you can use it.
• The Supplement Solution: Apigenin and Quercetin act as the "plugs." They inhibit CD38 activity, slowing the degradation of NAD+ so your baseline levels can naturally recover.

2. The Pump (The NAMPT Problem)

The other side of the coin is NAMPT, the rate-limiting enzyme that recycles used NAD+ (Nicotinamide) back into fresh NAD+.

• The Problem: In your 50s, this "recycling pump" slows down. If the pump is broken, the cell becomes littered with metabolic waste (NAM) that it can’t process, eventually signaling the cell to enter senescence.
• The Supplement Solution: This is where P7C3-A20 (currently in clinical development) differs from NMN. It doesn't provide fuel; it activates the pump (NAMPT). It fixes the machinery so the cell can recycle its own NAD+ supply indefinitely, maintaining "homeostasis" rather than a temporary spike.

The 50+ Strategy: Clinical consensus is moving toward a triad approach:

• Plug the Leak (250mg Apigenin)
• Prime the Pump (Exercise and/or NAMPT activators)
• Top off the Fuel (Vitamin B3)