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

Area of Science:

• Aging and Musculoskeletal Health
• Cellular Senescence and Regeneration
• Metabolic Pathways and NAD+ Metabolism

Background:

• Population aging necessitates strategies for maintaining musculoskeletal fitness.
• Musculoskeletal health relies on the integrated function of cartilage, bone, and muscle.
• Cellular senescence contributes to age-related musculoskeletal degeneration.

Purpose of the Study:

• To develop a combinatorial formulation to enhance nicotinamide adenine dinucleotide (NAD+) reserves for musculoskeletal regeneration.
• To investigate the efficacy of the N+A regimen (nicotinamide mononucleotide and apigenin) in combating age-related musculoskeletal decline.
• To elucidate the underlying mechanisms by which the N+A regimen promotes musculoskeletal health.

Main Methods:

• Formulation of a combinatorial regimen (N+A) using NMN and apigenin.
• Administration of the N+A formulation to aged mice.
• Assessment of musculoskeletal health markers, including cartilage integrity, bone density, and muscle mass.
• Analysis of NAD+ levels, cellular senescence markers, and key metabolic pathways.
• Investigation of the role of gut microbiota in mediating the effects of the N+A regimen.

Main Results:

• The N+A regimen significantly alleviated cellular senescence, promoting differentiation of skeletal precursor cells.
• Oral N+A administration improved cartilage degeneration, bone loss, and muscle atrophy in aged mice.
• The N+A strategy preserved NAD+ levels, supporting mitochondrial sirtuin 3 (SIRT3) activity and reducing senescence.
• N+A treatment enhanced the synthesis of phytosphingosine (PHS) via specific gut microbiota, mitigating age-related degeneration.
• Exercise capacity was improved in aged mice receiving the N+A formulation.

Conclusions:

• Enhancing NAD+ reservoirs through the N+A regimen is a promising strategy for musculoskeletal regeneration.
• The N+A formulation effectively combats age-related musculoskeletal decline by reducing senescence and promoting tissue repair.
• The study identified a novel combinatorial approach with potential for clinical translation in addressing aging-related musculoskeletal issues.