Although the muscle function is exhausted

New research on the important role of nicotinamide adenine dinucleotide (NAD) in skeletal muscle health challenges long-standing beliefs, suggesting that our muscles may be more resilient to NAD deficiency than previously thought.

Scientists at the Novo Nordisk Center for Basal Metabolic Research show that mouse skeletal muscles can maintain normal function despite losing 85% of their NAD content – a finding that has raised questions about the role of NAD in aging and muscle aging.

“Skeletal muscles are significantly more elastic to NAD depletion,” the researchers reported in a study published this month in Cell Metabolism. Their comprehensive investigation found that despite significantly lower NAD levels, muscle structure, strength, motor ability and even aging trajectory remained very normal.

NAD acts as a crucial cofactor in energy metabolism, helping cells convert nutrients into available energy. It also plays an important role in various signaling pathways that affect metabolism, genomic stability, and aging. The decline in NAD levels is widely associated with aging and muscle dysfunction, which has led to great interest in NAD enhancement supplements.

To study the importance of NAD, the team developed a mouse model whose nicotinamide phosphate begosyltransferase (NAMPT) is a key enzyme responsible for NAD synthesis – especially in skeletal muscle cells. This intervention reduced muscle NAD levels by 85%, far exceeding the 10-30% reduction typically observed in aging.

Surprisingly, these stand-out muscles exhibit retained morphology, contractility and exercise tolerance. Mice maintain normal weight, ingredient and metabolic markers. Their ability to perform both voluntary wheel running and high-intensity treadmill tests remains intact.

“Although exhausted, the tolerance of exercise and muscle contraction remain intact,” the researchers noted in the publication.

Perhaps most importantly, the team found that even lifelong NAD exhaustion could not accelerate the aging process of skeletal muscle. After tracing mice for nearly two years, they observed no signs of premature muscle aging or worsening beyond normal age-related changes.

This study reveals some subtle metabolic adaptations in NAD-deficient muscles, including increased glycogen content and altered reactive oxygen production. However, these changes did not impair overall muscle function or systemic metabolism.

At the molecular level, mitochondria (cellular power station) maintain normal function despite 50% less NAD. Computer modeling shows that mitochondrial respiration remains stable even with significant dysfunction occurring only after a 99% decrease in NAD levels.

The researchers also examined DNA methylation patterns, commonly used as a “biological clock” for measuring aging. Even after nearly two years of NAD exhaustion, the epigenetic age of muscle tissue matches the age, further demonstrating that NAD exhaustion does not accelerate aging.

These findings contrast sharply with previous studies, suggesting that embryo loss of NAMPT leads to progressive muscle degeneration. The researchers believe that this difference may be caused by differences in time—in early research models, developing muscles may be more susceptible to NAD exhaustion than mature muscles.

“These findings challenge the presumption that NAD deficiency can lead to aging-related muscle dysfunction and call for a reevaluation of the role of NAD in energy metabolism,” the researchers concluded.

While the study did not directly address the efficacy of NAD enhancement supplements, it suggests that moderate NAD exhaustion may be less than previously thought, at least in healthy skeletal muscle. The researchers noted that different tissues may have different sensitivity to NAD depletion, highlighting the need for tissue-specific research.

This study opens new questions about when and how NAD levels affect health and aging, suggesting a more nuanced understanding that then attributes age-related decline to NAD deficiency.