The Wnt–NAD+ axis in cancer, aging, and tissue regeneration

The intricate interplay between Wnt signaling and nicotinamide adenine dinucleotide (NAD⁺⁾ biosynthesis has emerged as a crucial axis that influences aging and tissue regeneration. Wnt signaling, a key regulator of cellular proliferation, differentiation, and tissue homeostasis, intersects with NAD⁺ metabolism, a cornerstone of cellular energy balance and genomic stability. This relationship is mediated through shared regulatory pathways involving sirtuins, poly(ADP-ribose) polymerases (PARPs), and metabolic enzymes which are sensitive to cellular NAD⁺ levels. Dysregulation of either pathway is implicated in cancer, age-related decline, and impaired regenerative capacity. This review consolidates current knowledge of the Wnt-NAD⁺ axis and highlights its cooperative roles in maintaining tissue integrity and combating the effects of aging. Furthermore, it explores therapeutic approaches targeting this axis to restore tissue health and enhance the capacity for repair, thereby offering promising avenues for addressing age-associated pathologies.