The natural nutrients nicotinamide and pyridoxine counteract muscle aging

The natural nutrients nicotinamide and pyridoxine counteract muscle aging

How nicotinamide and pyridoxine offer a groundbreaking, safe solution to counteract muscle loss and enhance regeneration in aging populations.

A recent study published inThe Journal of Clinical Investigationidentified an oral combination therapy consisting of nicotinamide (NAM) and pyridoxine (PN) as a safe and natural agent to support muscle stem cells (MuSCs). These cells are instrumental in muscle repair and regeneration, but their function and effectiveness declines with age. The study found that NAM activates CK1-mediated β-catenin signaling, while PN stimulates the AKT signaling pathway, both of which are crucial for MuSC proliferation and differentiation. Custom high-throughput imaging in vitro, in vivo (mouse models), and preclinical studies revealed that NAM and PN, natural nutrients from food, can enhance MuSC growth and effectively reverse age-related declines.

The natural aging process has been found to decrease circulating levels of NAM and PN, highlighting these FDA-approved nutrients as promising solutions to combat age-related muscle degeneration. Interestingly, NAM and PN levels were directly related to muscle mass and gait speed in a cohort of older adults, highlighting their potential clinical significance.

Graphical summary

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Skeletal muscles exhibit a surprisingly high degree of plasticity and adapt dynamically to stress, injury, and disuse. These muscles rely on muscle stem cells (MuSCs) for growth, repair (after injury), and maintenance. Under normal conditions, excess MuSCs are dormant and are activated only to compensate for declines in the circulating MuSC pool or to repair injury. Unfortunately, previous research has shown that aging impairs MuSC function due to increased inflammation, altered cell signaling, or oxidative stress. Taken together, these factors slow muscle mass and increase strength loss, a condition medically referred to as “sarcopenia.”

In recent years, a handful of preclinical studies have been conducted aimed at finding methods to reverse age-related MuSC declines. Unfortunately, these studies failed to address intervention safety, so even successful reversals of MuSC degeneration are not suitable for human use. The current study is characterized by the fact that it focuses on nutrients that are classified as GRAS (Generally Recognized As Safe), thus ensuring physiological safety in addition to therapeutic effectiveness. Identification of natural nutrients that exhibit physiological safety, low cost, and high therapeutic efficacy would be an ideal solution to the age-related loss of quality of life (QoL) in today's aging society.

About the study

In the present study, researchers developed a customized high-throughput 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 analyzes were limited to nutrients classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration (FDA).

Pathway-Specific Benefits: Nicotinamide (NAM) enhances β-catenin signaling, while pyridoxine (PN) activates the AKT pathway and energy metabolism, providing complementary mechanisms to optimize muscle stem cell (MuSC) function.

Their assay showed that nicotinamide (NAM) and pyridoxine (PN) effectively stimulate 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 for maintaining healthy muscle repair mechanisms. A decline in the former results in slower muscle recovery (after routine use), reduced strength and poorer repair effectiveness (after injury).

The study then tested the value of NAM/PN supplementationin vitroTesting for human myogenic progenitors (hMPs), in vivo mouse models (male C57BL/6JRj mice of different ages) and a preclinical human epidemiology study (Bushehr Elderly Health). [BEH] program). In addition, the difference in natural NAM and PN content and potency was evaluated in mouse models (young versus old mice) and in human fibroblast cell assays.

The study methodology included imaging (for nutrient identification), screening (to limit the identified nutrients to those considered safe for human consumption), and molecular and biochemical testing to evaluate the performance of the identified dietary supplements at different ages and concentrations. Statistical analyzes included two-tailed Student's t tests and analysis of variance for between-group calculations. Since it has always been known that age-related decline in muscle function differs between men and women, hMP tests were performed on both male and female donor cells. This ensured that the results took into account potential gender-specific biological differences.

Study results

Age-Related Nutrient Decline: NAM and PN levels naturally decline with age, by up to 37% in muscle tissue and plasma, indicating a systemic nutrient deficiency that can be corrected with nutritional supplementation.

Of the thousands of nutrients studied, NAM and PN were selected for downstream studies based on their observed efficacy and FDA-approved safety. The study showed that NAM promotes MuSC proliferation via CK1-mediated β-catenin signaling, while PN promotes differentiation via the AKT pathway and energy metabolism. Notably, these nutrients exhibit independent yet synergistic modes of MuSC-enhancing function.

Because both differentiation and proliferation are required to achieve desired results, these tests suggest that combination therapies that include both NAM and PN are required for optimal results. Comparisons between old and young mice revealed that circulating NAM and PN levels decreased with age, which matched almost perfectly with the observed declines in MuSC function. This was further confirmed by human epidemiological data, which linked low levels of these nutrients to reduced muscle mass and slower gait speed. Taken together, these results suggest that NAM/PN combination preparations may help stabilize circulating levels of these nutrients, effectively maintain MuSC function, and thereby prevent age-related muscle degeneration.

Encouragingly, it was found that orally administered NAM/PN combination preparations were able to reverse age-related muscle loss in both mice and humans. Participants who consumed these nutrients showed significantly improved muscle recovery and strength, as well as shorter healing times, compared to participants who were given equal amounts of placebos. However, the authors noted that NAM and PN supplements should ideally complement exercise and dietary protein to achieve holistic muscle health.

Diploma

The present study presents a comprehensive assessment of the effectiveness and safety of food-derived nutrients in addressing the ongoing and growing problem of age-related muscle degeneration. It examined 50,000 nutrients and identified just two - NAM and PN - as safe and effective in reversing natural muscle degeneration, particularly when given as combination therapy. While the effects of a healthy lifestyle (dietary habits) and physical activity (exercise) cannot be underestimated, orally administered NAM/PN combinations improved muscle regeneration, improved muscle repair, and increased muscle strength in the elderly.

This study therefore highlights NAM and PN as clinically viable solutions to address quality of life declines associated with aging and represents the first step toward a stronger and more independent future in today's increasingly aging society. Future research could examine how these nutrients interact with other cells in the muscle niche and evaluate their long-term effects in clinical settings.

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