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NNMT Inhibitor Improves Muscle Function in Aged Mice

A recent paper has reported on improving muscle function in aged mice through combined treatment of exercise and the inhibition of NNMT, an enzyme involved in NAD+ metabolism [1].

Age-related muscle loss

Muscle loss is a common problem in the aging population. Studies estimate that “after age 50, adults lose approximately 1% of their muscle mass and strength each year.” After turning 60, the annual muscle strength loss is even higher [2, 3].

Great effort has been invested in identifying possible treatments for age-related muscle decline and the resulting loss of skeletal muscle and strength (sarcopenia), with over 100 clinical trials in the past decade [4]. The authors of this study investigated nicotinamide N-methyltransferase (NNMT), which is involved in NAD+ metabolism and plays a role in the methylation of nicotinamide and DNA [5].

The group that conducted this study recently reported that in aged mice, the inhibition of NNMT increased contractile muscle function following injury [6]. This made them hypothesize that inhibiting NNMT in sedentary mice should improve muscle function similarly to exercise. On the molecular level, if the mechanisms behind exercise and NNMT inhibition are different, combining the treatments should have an additive effect on muscle function.

Increasing strength and running capacity

The researchers used aged (22-month-old) mice and divided them into sedentary and exercise groups. The exercise group was engaged in progressive weighted wheel running (PoWeR). Each group was further divided into two subgroups. One subgroup received a daily NNMT inhibitor for eight weeks, and the second was a control.

For their indicator of muscle function, the researchers chose forelimb grip strength. According to this measurement, both exercise and NNMT inhibition positively affected strength. Compared to untreated sedentary mice, the mice treated with an NNMT inhibitor had ~40% higher grip strength and the PoWeR group had a 20% increase in grip strength. Combining the NNMT inhibitor with exercise gave an even bigger effect than single treatments, and the researchers observed approximately 60% greater grip strength than the sedentary, untreated control group. A similar effect was observed when grip strength was normalized to body weight.

The results of this research agree with the results from a different group, which observed that NNMT inhibition ameliorated the loss of grip strength in aged mice.

The researchers also measured average weekly running distances in week one of the experiment and analyzed how the treatments influenced it. The NNMT inhibitor-treated PoWeR group’s running capacity increased, and this was maintained throughout the eight weeks of the experiment. In contrast, the inhibitor-untreated PoWeR group’s running capacity first increased; however, it was not increased as much as in the NNMT inhibitor-treated PoWeR group, and at week seven, it went back to the week one level.

According to the authors, this suggests “that NNMTi treatment improved tolerance to, or recovery from, intensive exercise.” The authors also note that mice treated with an NNMT inhibitor had reduced susceptibility to fatigue compared to controls.

Additionally, the researchers observed changes in muscle mass and composition. They observed that the mass of a few muscles, including the heart, increased. NNMT inhibitor treatment didn’t have such an effect on muscle mass.

On the molecular level

To understand the molecular mechanisms behind the observed effects of NNMT inhibitor treatment and exercise, the authors analyzed the proteins and metabolites produced in one of the large leg muscles of the mice.

The bulk analysis of the protein profiles of different treatment groups showed that the sedentary and exercise groups’ protein profiles were distinct. However, the protein profile of the NNMT inhibitor-treated sedentary group overlapped with that of the exercise group. Over three-quarters of proteins differentially regulated in the NNMT inhibitor-treated and exercise groups were regulated in the same direction (either increased or decreased). This suggests the involvement of many similar cellular processes.

The protein profile of the NNMT inhibitor-treated exercising group overlapped partly with that of the untreated exercise group. The researchers noted that only 15% of those proteins were regulated in the same direction (either increased or decreased) in both groups, suggesting that treating the exercising mice with an NNMT inhibitor might have modulated additional molecular processes and pathways.

Metabolite analysis identified a similar pattern to the protein analysis of the sedentary and exercise groups. Metabolites from those two cohorts created separate clusters, indicating great differences between these cohorts and exercise’s great impact on muscle metabolism.

Further analysis suggested that treating the sedentary mice with an NNMT inhibitor might have shifted the metabolic profile of these mice closer to that of the exercising mice.

The researchers also noted differences between the metabolic and protein profiles of the NNMT inhibitor-treated exercising cohorts. Contrary to its protein profile, the metabolic profile of that group was separate from that of other groups, suggesting that the combination of an NNMT inhibitor and exercise has a profound impact.

On a more granular level, when comparing the sedentary group treated with an NNMT inhibitor and the exercise group to sedentary controls, the researchers noted an increase in proteins involved in the protein production process (protein translation), which can explain the increased muscle weight. AMP, a low-energy signal that activates AMPK, was also increased in the mice in the exercise and NNMT inhibitor-treated groups. AMPK is a protein known for its energy-sensing properties, muscle hypertrophy, and protein translation [7, 8], linking those two observations.

Both interventions also reduced fat content in the muscle cells, which suggests improvements in muscle quality since high fat content in muscles “correlates with poorer muscle quality, functional performance, increased skeletal muscle insulin resistance.” [9, 10]

Possible treatment improvements

These researchers point out that using NNMT inhibitors could be an avenue for improving the current standard of care for age-associated loss of muscle mass and strength, which includes resistance or a combination of resistance and endurance exercise. However, bringing this to the clinic would require further testing in humans.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Dimet-Wiley, A. L., Latham, C. M., Brightwell, C. R., Neelakantan, H., Keeble, A. R., Thomas, N. T., Noehren, H., Fry, C. S., & Watowich, S. J. (2024). Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice. Scientific reports, 14(1), 15554.

[2] Beaudart, C., Locquet, M., Reginster, J. Y., Delandsheere, L., Petermans, J., & Bruyère, O. (2018). Quality of life in sarcopenia measured with the SarQoL®: impact of the use of different diagnosis definitions. Aging clinical and experimental research, 30(4), 307–313.

[3] von Haehling, S., Morley, J. E., & Anker, S. D. (2010). An overview of sarcopenia: facts and numbers on prevalence and clinical impact. Journal of cachexia, sarcopenia and muscle, 1(2), 129–133.

[4] Lo, J. H., U, K. P., Yiu, T., Ong, M. T., & Lee, W. Y. (2020). Sarcopenia: Current treatments and new regenerative therapeutic approaches. Journal of orthopaedic translation, 23, 38–52.

[5] Roberti, A., Fernández, A. F., & Fraga, M. F. (2021). Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation. Molecular metabolism, 45, 101165.

[6] Neelakantan, H., Brightwell, C. R., Graber, T. G., Maroto, R., Wang, H. L., McHardy, S. F., Papaconstantinou, J., Fry, C. S., & Watowich, S. J. (2019). Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochemical pharmacology, 163, 481–492.

[7] Kong, L., Zhang, H., Lu, C., Shi, K., Huang, H., Zheng, Y., Wang, Y., Wang, D., Wang, H., & Huang, W. (2021). AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation. Frontiers in pharmacology, 12, 724514.

[8] Attwaters, M., & Hughes, S. M. (2022). Cellular and molecular pathways controlling muscle size in response to exercise. The FEBS journal, 289(6), 1428–1456.

[9] Distefano, G., Standley, R. A., Zhang, X., Carnero, E. A., Yi, F., Cornnell, H. H., & Coen, P. M. (2018). Physical activity unveils the relationship between mitochondrial energetics, muscle quality, and physical function in older adults. Journal of cachexia, sarcopenia and muscle, 9(2), 279–294.

[10] Stefan, N., Kantartzis, K., Machann, J., Schick, F., Thamer, C., Rittig, K., Balletshofer, B., Machicao, F., Fritsche, A., & Häring, H. U. (2008). Identification and characterization of metabolically benign obesity in humans. Archives of internal medicine, 168(15), 1609–1616.

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Weekend-Oriented Physical Activity Superior for Brain Health

According to a new study, “weekend warriors”, people who have most of their physical activity over one or two days a week, enjoy the most robust risk reduction for several brain health-related conditions [1].

Couch potato, except on weekends

Exercise is universally necessary to stay healthy for longer. It is one of the three staples of healthy longevity, along with a good diet and sleep. However, for people who work standard 40-hour weeks at sedentary jobs, it can be difficult to maintain healthy levels of physical activity. Many people clock most of their exercise hours on weekends, which can be done more enjoyably than on a treadmill, such as by hiking or skiing.

However, it was questioned whether this kind of physical activity provides the same health benefits as exercising more regularly. Last year, a study showed that, when it comes to lowering the risk of cardiovascular diseases, the answer is mostly yes [2].

This time, a group of scientists decided to check the same hypothesis with regard to brain health. Their study, published in Nature Aging, uses the same data source: UK Biobank, a vast repository of health information on hundreds of thousands of British citizens.

Some of them wore professional-grade accelerometers for a week to record their physical activity, and this data engendered a trove of studies. A week might not seem long, but research has shown that in sufficiently large samples, it is representative enough of regular exercise patterns.

“Weekend warriors” are the largest group

The researchers divided their sample of 75,000 participants into three categories: inactive (less than 150 minutes of moderate-to-vigorous physical activity, or MVPA), “weekend warriors” (more than 150 minutes of MVPA, with more than 50% of it occurring over the course of 1-2 days a week), and regular exercisers (more than 150 minutes of MVPA spread more evenly).

150 minutes of MVPA per week is an amount that lies somewhere in the middle of the current WHO recommendations for physical activity: “All adults should undertake 150–300 min of moderate-intensity, or 75–150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vigorous-intensity aerobic physical activity, per week.” [3]

One example of moderate activity is brisk walking that still allows you to maintain a conversation, while running is already considered a vigorous activity. A more technical definition is 3-6 metabolic equivalents of task (METs) or more than 6 METs, respectively.

The study population was relatively old, with an average age of 62. Interestingly, the proportion of “weekend warriors” was the highest (40%), followed by physically inactive (32%) and regular exercisers (28%). The researchers controlled for a variety of confounding variables, including age, sex, diet, smoking, alcohol consumption, and relevant health conditions: diabetes, hypertension, and cancer. The median follow-up period was 8.4 years.

Weekend warriors reign supreme

The results were somewhat surprising: not only “weekend warriors” did much better than the inactive participants, but they also beat regular exercisers. Compared to the inactive group, weekend warriors enjoyed a 26% risk reduction for dementia, 21% for stroke, 45% for Parkinson’s disease, 40% for depression, and 37% for anxiety disorder. For regular exercisers, the reduction in dementia risk was only 9% and did not reach statistical significance. For other conditions, the results of weekend warriors and regular exercisers were closer, although in the fully adjusted model, risk reduction for stroke in regular exercisers landed below the statistical significance threshold.

This picture generally held true for all ages and both sexes. However, risk reductions for dementia, stroke, and Parkinson’s disease were slightly more pronounced in people over 65.

This study had several limitations, including a rather coarse-grained division into groups. Despite that, its results are intriguing and warrant further investigation. If the superiority of the “weekend warrior” pattern is confirmed, it would be interesting to understand the reasons behind it. One such reason might conceivably be that weekend activities provide increased stimulation for the brain compared to going to the gym.

In this large population-based cohort study, we found that adhering to the weekend warrior pattern was similarly associated with a lower risk of both neurological diseases and psychiatric disorders in regularly active individuals. The findings were almost consistent after adjusting for various covariates, including sociodemographical factors, lifestyles and health conditions.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Min, J., Cao, Z., Duan, T., Wang, Y., & Xu, C. (2024). Accelerometer-derived ‘weekend warrior’ physical activity pattern and brain health. Nature Aging, 1-9.

[2] Khurshid, S., Al-Alusi, M. A., Churchill, T. W., Guseh, J. S., & Ellinor, P. T. (2023). Accelerometer-Derived “Weekend Warrior” Physical Activity and Incident Cardiovascular Disease. JAMA, 330(3), 247-252.

[3] Bull, F. C., Al-Ansari, S. S., Biddle, S., Borodulin, K., Buman, M. P., Cardon, G., … & Willumsen, J. F. (2020). World Health Organization 2020 guidelines on physical activity and sedentary behaviour. British journal of sports medicine, 54(24), 1451-1462.

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Young Longevity Talent from the 2024 Xplore Program

LongX, an initiative dedicated to providing global early-career avenues into longevity, has concluded Cohort 1 of its first fully remote educational venture, the Xplore Program.

The longevity community is welcome to attend the Xplore Program showcase event on Sep 7, 2024 to support the next generation of longevity talent. The virtual event will feature pitch presentations by Xplore Program fellows and will document the progress made by fellows over the past few months.

Register for the Xplore Program Showcase: https://lu.ma/xs648ekv

The Xplore Program

From June to August, 9 fellows were guided through the longevity field in a 1 month primer course, an incubator, and an educational experience with a longevity biotechnology company. The 2024 longevity biotechnology partners were AgeRate (Canada), AuroraFit (Germany), Tomorrow Biostasis/Oxford Cryotechnology (United Kingdom) and Senexell (Germany), a division of Longaevus Technologies.

Fellows also had the opportunity to develop LongX projects internally and engage with experts such as Dr. Courtney Hudson-Paz (TIME Initiative), Dr. Stijn Heesen (Alder Tx), Dylan Wenzlau (Guava Health), Dr. Matthew Scholz (Oisin Biotechnology), Dr. Mitchell Lee (Ora Biomedical), Dr. Andrea Maier (Chi Longevity, NUS), and Dr. Amelia Anderson (Cyclarity Tx), through fireside events. A collaborative program was established with SENS Research Foundation (SRF) for fellows to learn about aging biology research from scientists at SRF.

Those interested in facilitating Cohort 2 of the Xplore Program in 2025 are encouraged to visit the LongX website. Applications for Cohort 2 will open in early 2025. Interested students may also contact LongX to be involved in other educational efforts.

About LongX

LongX was launched in 2023 as a platform for youth interested in longevity. We prioritize fostering innovation and interdisciplinary collaboration, aiming for both short-term impact and long-term progress. We encourage exploration beyond traditional roles and aim to equip future experts with the skills to drive progress. Our Substack provides regular articles on our thoughts, experiences, and interviews.

Contact

Marvin Yan, Co-Founder

longevityxplorer@gmail.com