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.
Karim et al. (Wed,) studied this question.