Hypothesis: In aging liver, elevated primary bile acids activate the hepatocyte‑expressed receptor TGR5, initiating a cAMP‑PKA cascade that phosphorylates NAMPT and diminishes its catalytic activity, thereby reducing NAD+ salvage synthesis. This suppression is not a passive consequence of damage but an adaptive feedback loop designed to limit PARP‑driven NAD+ consumption that is amplified by bile‑acid‑induced oxidative stress. By lowering NAD+ availability, the cell attenuates hyperactive PARP, conserving ATP and reducing necrotic signaling, even though this comes at the cost of diminished sirtuin activity and impaired DNA repair over time.

Mechanistic rationale: Primary bile acids such as cholic acid act as agonists for TGR5, raising intracellular cAMP and activating protein kinase A (PKA). PKA can phosphorylate NAMPT at conserved serine residues (e.g., Ser¹⁰⁰ in mouse NAMPT), a modification shown in vitro to decrease its V_max for NMN production (1). Phosphorylated NAMPT exhibits reduced affinity for its substrate NAMPT, leading to lower intracellular NAD+ pools. The resulting NAD+ decline limits the substrate for PARP1/2, which are hyperactivated by bile‑acid‑induced ROS and DNA damage (3). Simultaneously, reduced NAD+ diminishes SIRT1 deacetylase activity, favoring a more glycolytic, stress‑resistant metabolic state that short‑term protects hepatocytes from apoptosis.

Testable predictions: 1) Pharmacological inhibition of TGR5 (e.g., with antagonistic compound SBI‑115) in aged mice will increase hepatic NAMPT protein activity, raise NAD+ levels, and decrease PARP‑mediated NAD+ consumption without altering DNA damage markers. 2) Hepatocyte‑specific overexpression of a phospho‑deficient NAMPT mutant (Ser→Ala) will rescue NAD+ levels in aged livers despite high bile acid concentrations. 3) Conversely, activation of TGR5 in young mice using agonist INT‑777 will recapitulate the aged phenotype: reduced NAMPT activity, lowered NAD+, elevated PARP activity, and increased markers of oxidative stress. 4) Microbiota restoration via co‑housing or fecal transplant that lowers primary bile acids will diminish TGR5 signaling, increase NAMPT activity, and partially restore NAD+ pools, linking the microbiome‑bile‑acid axis directly to NAD+ biosynthesis regulation.

Falsifiability: If blocking TGR5 fails to elevate NAMPT activity or NAD+ in aged hepatocytes, or if phospho‑deficient NAMPT does not rescue NAD+ levels despite TGR5 activation, the hypothesis would be refuted, supporting the view that NAD+ decline is solely a damage‑driven consequence rather than a regulated adaptive response. This framework shifts the interpretation of NAD+ loss from passive deterioration to a bile‑acid‑mediated rheostat that balances immediate cytoprotection against long‑term genomic maintenance.