Using genetic models of impaired cholesterol efflux, we demonstrate that intracellular cholesterol accumulation activates liver X receptor (LXR) signaling and induces expression of the NAD⁺ hydrolase CD38 in macrophages and microglia. Elevated CD38 activity drives NAD⁺ depletion, leading to metabolic dysfunction and the emergence of a senescence-associated inflammatory phenotype characterized by increased p16/p21 expression and production of pro-inflammatory mediators. In the retina, accumulation of these senescent lipid-laden macrophages promotes hallmark features of age-related macular degeneration, including subretinal lipid deposition, retinal pigment epithelium dysfunction, and photoreceptor degeneration.

Importantly, restoration of NAD⁺ levels or elimination of senescent cells mitigates neurodegenerative pathology and restores tissue homeostasis, identifying NAD⁺ metabolism as a key regulator of immune cell aging. Beyond retinal disease, these findings provide a broader conceptual framework for understanding how metabolic stress in myeloid cells drives pathological neuroimmune interactions. In particular, similar mechanisms of lipid accumulation, CD38-mediated NAD⁺ depletion, and macrophage senescence may contribute to persistent neuroinflammation and neuronal sensitization in neuropathic pain.

Together, this work reveals how dysregulated lipid metabolism programs maladaptive immune responses that accelerate tissue aging and neurodegeneration. Targeting the cholesterol–LXR–CD38–NAD⁺ pathway may therefore represent a promising strategy to treat a spectrum of age-associated neuroinflammatory disorders, including retinal degeneration and chronic neuropathic pain.