New research challenges long-held beliefs about the essential role of nicotinamide adenine dinucleotide (NAD) in skeletal muscle health, suggesting our muscles may be far more resilient to NAD deficiency than previously thought.
Scientists at the Novo Nordisk Foundation Center for Basic Metabolic Research have demonstrated that mouse skeletal muscle can maintain normal function despite losing 85% of its NAD content – a finding that calls into question widely accepted theories about NAD’s role in aging and muscle deterioration.
“Skeletal muscle exhibits markedly greater resilience to NAD depletion than previously thought,” the researchers report in their study published in Cell Metabolism this month. Their comprehensive investigation found that muscle structure, strength, exercise capacity, and even aging trajectories remained remarkably normal despite drastically reduced NAD levels.
NAD serves as a crucial cofactor in energy metabolism, helping cells convert nutrients into usable energy. It also plays essential roles in various signaling pathways that influence metabolism, genomic stability, and aging. Declining NAD levels have been widely associated with aging and muscle dysfunction, leading to substantial interest in NAD-boosting supplements.
To investigate NAD’s importance, the research team developed a mouse model with an inducible knockout of nicotinamide phosphoribosyltransferase (NAMPT) – a key enzyme responsible for NAD synthesis – specifically in skeletal muscle cells. This intervention reduced muscle NAD levels by 85%, far exceeding the 10-30% decline typically observed in aging.
Surprisingly, these NAD-depleted muscles showed preserved morphology, contractility, and exercise tolerance. The mice maintained normal body weight, composition, and metabolic markers. Their ability to perform both voluntary wheel running and high-intensity treadmill tests remained intact.
“Exercise tolerance and muscle contractility are intact despite NAD depletion,” noted the researchers in their published highlights.
Perhaps most significantly, the team found that even lifelong NAD depletion failed to accelerate the aging process in skeletal muscle. After tracking mice for nearly two years, they observed no signs of premature muscle aging or deterioration beyond normal age-related changes.
The study revealed some subtle metabolic adaptations in NAD-depleted muscle, including increased glycogen content and altered reactive oxygen species production. However, these changes didn’t compromise overall muscle function or whole-body metabolism.
At the molecular level, mitochondria – the cellular powerhouses – maintained normal function despite having 50% less NAD. Computer modeling suggested that mitochondrial respiration remains robust even when NAD levels drop by 90%, with significant dysfunction occurring only after a 99% reduction.
The researchers also examined DNA methylation patterns, often used as a “biological clock” to measure aging. Even after nearly two years of NAD depletion, the epigenetic age of the muscle tissue matched the chronological age, providing further evidence that NAD depletion doesn’t accelerate aging.
These findings contrast sharply with previous studies showing that embryonic deletion of NAMPT leads to progressive muscle degeneration. The researchers suggest this discrepancy may arise from differences in timing – developing muscle may be more vulnerable to NAD depletion than mature muscle – or potential confounding factors in earlier research models.
“These findings challenge the presumption that NAD deficiency causes aging-associated muscle dysfunction and call for a re-evaluation of the role of NAD in energy metabolism,” the researchers conclude.
While the study doesn’t directly address the efficacy of NAD-boosting supplements, it suggests that moderate NAD depletion may be less detrimental than previously thought, at least in healthy skeletal muscle. The researchers note that different tissues likely have varying sensitivity to NAD depletion, highlighting the need for tissue-specific studies.
This research opens new questions about when and how NAD levels impact health and aging, suggesting a more nuanced understanding is needed before broadly attributing age-related decline to NAD deficiency.
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