Age-related transcriptional drift and physiological adaptation in long-living Ames dwarf skeletal muscle

Abstract Skeletal muscle aging is accompanied by deterioration in metabolic flexibility, neuromuscular connectivity, and structural integrity, all of which contribute to frailty and the loss of functional independence. Ames dwarf mice exhibit postnatal growth hormone deficiency and an exceptionally long lifespan, providing a unique model for revealing transcriptional programs that support healthy aging. Here, we present the first comprehensive transcriptomic and functional profile of hindlimb skeletal muscle in middle-aged and old-aged Ames dwarf mice. We show that Ames dwarf muscle maintains a transcriptional profile enriched for vascular remodeling, synaptic communication, extracellular matrix organization, and structural resilience while suppressing lipid metabolic pathways and age-associated transcriptional drift. Advanced age in Ames mice is marked by a substantial shift in transcription factors associated with downregulated genes and a temporally coordinated activation of senescence-associated and inflammatory-response signatures that appear to support, rather than impair, tissue maintenance. Functionally, Ames dwarf mice maintain neuromuscular coordination, grip strength, and endurance with age. Collectively, these findings indicate a distinct transcriptional drift in Ames dwarf skeletal muscle that integrates vascular, neuronal, and senescence-related signals to preserve structural and functional resilience. This work implicates molecular mediators including Apelin, Klotho, and Notch1 that may underline exceptional healthspan and modulate resistance to frailty.