Early-life NAD⁺ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood

Nicotinamide adenine dinucleotide (NAD⁺) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD⁺ levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD⁺ biosynthesis pathway, drastically reduced NAD⁺ levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD⁺ levels were restored to normal in middle-aged NADS-knockout mice, whereas muscle function remained compromised. Gene expression analysis showed that hyaluronic acid synthase 2 (Has2) was downregulated in both young NADS-knockout mice and aged wild-type mice. We also found that the α-ketoglutarate-JMJD3 axis downregulates Has2 expression. Then, impaired hyaluronic acid signaling dampened muscle stem cells, leading to decreased locomotor activity. These results suggest that maintaining NAD⁺ levels during early life is important for promoting healthy aging in skeletal muscle.