Research Found an Association Between Muscle Health and NAD+ Abundance in Humans
Why This Matters
Aging results in a gradual loss of skeletal muscle function over time. Sarcopenia, the progressive loss of skeletal muscle mass, strength, and performance with age, is one of the critical causes of functional decline in aged adults [1]. Essential for supporting breathing, as well as moving and maintaining posture and balance, skeletal muscle makes up nearly 40% of a young, healthy individual’s total body mass and decreases between 3 to 8% each decade after 30 years of age [2]. While the development of sarcopenia is commonly associated with aging, other key contributors are physical inactivity, mitochondrial dysfunction, and a decrease in mitochondrial metabolism [3]. As muscles rely on a constant supply of cellular energy to function, skeletal muscle health is dependent on healthy mitochondria [4] as well as an essential molecule called nicotinamide adenine dinucleotide (NAD+). While studies have demonstrated an age-associated decline in NAD+, whether this decline occurs in skeletal muscle tissue with age and whether this may be associated with skeletal muscle health is unclear. Researchers of this study set out to investigate the association between NAD+ levels and human aging by comparing young and aged individuals and identifying whether metabolomic differences in aged individuals are associated with muscle and mitochondrial function.
Results Demonstrated a Clear Association Between NAD+ and the Health Status of an Aging Individual
The study consisted of 52 participants, who were divided into four groups of 12 young individuals (aged 20-30), 17 older adults (aged 65-80) who had normal levels of physical activity, 17 “trained” older adults who were “exercise-trained” or had above-average levels of physical activity, and 12 older adults categorized as physically impaired with low physical activity levels (more or less sedentary) [5].
The study found that there were clear differences in metabolite levels between young vs. older adults, suggesting that aging causes large changes in the muscle metabolome. One of the metabolites that was most significantly depleted in older adults was NAD+, indicating NAD+ declines with age, despite older adults maintaining sufficient physical activity. Exercise-trained older adults had NAD+ levels that were similar to those of young individuals, suggesting a lifestyle that includes exercise may be beneficial for maintaining NAD+ levels during aging. NAD+ was also positively associated with an average number of steps per day, as well as mitochondrial respiration and muscle functioning. More specifically, the more steps an individual took per day, the higher their muscle NAD+.
While NAD+ levels were negatively correlated with age and positively correlated with physical activity, other metabolites exhibited opposite behavior, including markers of oxidative stress. More specifically, older adults had higher levels of ophthalmic acid, a marker of oxidative stress, and dihydroxyacetone-phosphate and 3-methoxytyramine, two metabolite families that are negatively associated with mitochondrial respiration [5].
The Significance of The Study
This is the first study to demonstrate age-related changes in the muscle metabolome of humans. NAD+ was found to be one of the most depleted metabolites with age, building on existing preclinical and clinical data showing age-associated NAD+ decline in tissues. The study also highlights the relationship between NAD+ and muscle health—a relationship well-demonstrated in preclinical models. More specifically, individuals’ average daily step count strongly correlated with muscle NAD+ levels, suggesting there is a clear association between NAD+ and the health status of an aging individual. Overall, these results suggest that there is a clear association between human skeletal muscle health and NAD+ in human aging and NAD+ is an indicator of muscle health status in aging individuals.