How nicotinamide and pyridoxine offer a groundbreaking, safe solution to counter muscle loss and strengthen recovery in aging populations.

Study: Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging. Image Credit: michaelheim / Shutterstock

A recent study published in The Journal of Clinical Investigation identified oral combination therapy comprising nicotinamide (NAM) and pyridoxine (PN) as a safe and natural means of supporting muscle stem cells (MuSCs). These cells are instrumental in muscle repair and regeneration, but their function and effectiveness decline with increasing age. The study revealed that NAM activates CK1-mediated β-catenin signaling, while PN stimulates the AKT pathway, both of which are critical for MuSC proliferation and differentiation. Custom high-throughput imaging of in vitro, in vivo (mouse models), and preclinical trials revealed that NAM and PN, natural food-derived nutrients, can enhance MuSC growth, effectively reversing age-associated declines.

The natural aging process was found to reduce circulating NAM and PN levels, highlighting these FDA-approved nutrients as promising solutions for addressing age-related muscle degeneration. Interestingly, NAM and PN levels were directly associated with muscle mass and gait speed in a cohort of older adults, emphasizing their potential clinical significance.

Graphical Abstract

Background

Skeletal muscles display a surprising amount of plasticity, dynamically adapting to exercise, injury, and disuse. These muscles rely on muscle stem cells (MuSCs) for growth, repair (following injury), and maintenance. Under normal conditions, excess MuSCs are dormant, only activating to replenish circulating MuSC pool declines or repair injury. Unfortunately, previous research has identified that aging impairs MuSC function due to enhanced inflammation, altered cellular signals, or oxidative stress. Collectively, these factors retard muscle mass and enhance strength loss, a condition medically termed ‘sarcopenia.’

The last few years have produced a handful of preclinical studies aimed at identifying methods to reverse age-related MuSC declines. Unfortunately, these studies have failed to account for intervention safety, making even successful reversals of MuSC degeneration unfit for human use. The current study stands out by focusing on nutrients classified as GRAS (Generally Recognized As Safe), ensuring physiological safety alongside therapeutic efficacy. Identifying natural nutrients that display physiological safety, low cost, and high therapeutic efficacy would provide an ideal solution to the loss of age-related quality of life (QoL) in today’s aging society.

About the Study

In the present study, researchers devised a high-throughput custom imaging pipeline (phenotypic assay) to screen 50,000 food-derived nutrients and plant extracts to identify safe bioactives that could enhance MuSC growth and efficacy. Of the numerous nutrients identified, downstream analyses were restricted to nutrients classified by the United States (US) Food and Drug Administration (FDA) as ‘Generally Recognized As Safe (GRAS).’

Their assay highlighted nicotinamide (NAM) and pyridoxine (PN) as effective in stimulating MuSCs via their ability to enhance cellular signaling in the AKT and CK1/β-catenin pathways. These pathways regulate proliferation and differentiation and are critical to maintaining healthy muscle repair mechanisms. Declines in the former result in slower muscle recovery (following routine use), reduced strength, and poorer repair efficacy (following injury).

The study subsequently tested the value of NAM/PN supplementation in in vitro human myogenic progenitors (hMPs) assays, in vivo murine models (male C57BL/6JRj mice of different ages), and a preclinical human epidemiology study (the Bushehr Elderly Health [BEH] program). Additionally, the difference in natural NAM and PN content and efficacy was evaluated in murine models (young versus old mice) and human fibroblast cell assays.

The study methodology included imaging (for nutrient identification), screening (to restrict identified nutrients to only those considered safe for human consumption), and molecular and biochemical assays to evaluate identified supplement performance under differing ages and concentrations. Statistical analyses included 2-tailed Student’s t-tests and Analysis of Variance for between-group computations. Since males and females are historically known to differ in their age-related muscle function decline rate, hMP assays were carried out on both male and female donor cells. This ensured that findings accounted for potential sex-based biological differences.

Study Findings

Of the thousands of nutrients screened, NAM and PN were selected for downstream investigations due to their observed efficacy and FDA-approved safety. The study demonstrated that NAM promotes MuSC proliferation via CK1-mediated β-catenin signaling, while PN enhances differentiation through the AKT pathway and energy metabolism. Notably, these nutrients display independent yet synergistic modes of MuSC-enhancing function.

Since both differentiation and proliferation are required to achieve desired results, these assays suggest that combination therapies comprising both NAM and PN are required for optimal outcomes. Comparisons between old and young mice revealed that the circulating levels of NAM and PN declined with age, corresponding almost perfectly with observed declines in MuSC function. This was further corroborated by human epidemiological data, which linked low levels of these nutrients to reduced muscle mass and slower gait speed. Together, these findings suggest that NAM/PN combination supplements can help stabilize circulating levels of these nutrients, effectively maintaining MuSC function and, in turn, preventing age-related muscle degeneration.

Encouragingly, orally administered NAM/PN combination supplements were found to reverse age-associated muscle declines in both murine and human subjects. Participants consuming these nutrients displayed significantly improved muscle regeneration and strength and reduced healing periods compared to those provided equivalent quantities of placebos. However, the authors noted that NAM and PN supplements should ideally complement exercise and dietary protein for holistic muscle health.

Conclusion

The present study presents a comprehensive evaluation of the efficacy and safety of food-derived nutrients in addressing the persistent and growing problem of age-related muscle degeneration. It screened 50,000 nutrients and identified just two – NAM and PN – as safe and effective in reversing natural muscle degeneration, especially when administered as a combination therapy. While the impacts of healthy lifestyles (dietary patterns) and physical activity (exercise) cannot be understated, orally administered NAM/PN combinations improved muscle regeneration, enhanced muscle repair, and increased muscle strength in older individuals.

This study, therefore, highlights NAM and PN as clinically ready solutions to address QoL losses accompanying aging and forms the first step towards a stronger and more independent tomorrow in today’s increasingly elderly society. Future research could explore how these nutrients interact with other cells in the muscle niche and evaluate their long-term impacts in clinical settings.