Senolytic therapy for age-related neurodegeneration

# Novel Therapeutic Hypotheses for Age-Related Neurodegeneration ## 1. Senescence-Activated NAD+ Depletion Rescue **Description:** Senescent glial cells upregulate CD38 NADase, creating local NAD+ depletion zones that impair neuronal energy metabolism and synaptic function. Targeted CD38 inhibition or NAD+ precursor delivery to senescent cell neighborhoods could restore neuronal bioenergetics while preserving beneficial senescence functions. **Target:** CD38 NADase/NAMPT pathway **Supporting ...

# Critical Evaluation of Age-Related Neurodegeneration Hypotheses ## 1. Senescence-Activated NAD+ Depletion Rescue ### Specific Weaknesses: - **Spatial specificity unclear**: No evidence that CD38 upregulation in senescent cells creates discrete "depletion zones" rather than global NAD+ reduction - **Causality assumption**: Correlation between CD38 expression and NAD+ decline doesn't establish that senescent cell CD38 is the primary driver - **Selective targeting challenge**: Mechanism for del...

# Druggability Assessment of Age-Related Neurodegeneration Hypotheses ## 1. Senescence-Activated NAD+ Depletion Rescue **Revised Confidence: 0.45** ### Druggability: HIGH **CD38 Inhibitors:** - **78c**: Potent, selective CD38 inhibitor (IC50 = 40 nM), brain-penetrant - **Kuromanin**: Natural flavonoid CD38 inhibitor, oral bioavailability - **Apigenin**: Dual CD38/CD157 inhibitor, clinical safety data available **NAD+ Precursors:** - **Nicotinamide riboside (NR)**: ChromaDex's NIAGEN®, FDA GRA...