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Double‐Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration

Year: 2026

Type: article

Abstract: ABSTRACT In the context of population aging, musculoskeletal fitness has emerged as a cornerstone of overall well‐being and injury prevention, relying on the coordinated function of cartilage, bone, and muscle. Drawing on the principle of “increasing income and reducing expenditure,” we propose a combinatorial formulation consisting of the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide mononucleotide (NMN) and the NAD + ‐consuming enzyme inhibitor apigenin (API), hereafter referred to as the “N + A” regimen, to enhance NAD + reserves. Our results revealed that the N + A formulation alleviated cellular senescence, thereby promoting the differentiation of skeletal precursor cells into chondrocytes, osteoblasts, and myocytes for the reconstruction of the musculoskeletal system. Oral administration of the N + A formulation alleviated cartilage degeneration, bone loss, and muscle atrophy; additionally, it enhanced exercise capacity in aged mice. Mechanistically, the N + A strategy preserves NAD + levels, which are subsequently utilized by mitochondrial sirtuin 3 (SIRT3) to promote deacetylation modifications and alleviate the senescent phenotype. Moreover, oral administration of N + A indirectly enhanced the synthesis of the metabolite phytosphingosine (PHS) by the intestinal microbiota members Coriobacteriaceae_UCG‐002 and Ruminococcus , thereby alleviating age‐related degeneration. In summary, our findings demonstrate that enhancing the NAD + reservoir represents a promising strategy for promoting musculoskeletal regeneration, and we developed a rational combinatorial regimen with potential for clinical translation.

Source: Aging Cell

DOI: 10.1111/acel.70468