Research Project: Nutrition, Sarcopenia, Physical Function, and Skeletal Muscle Capacity During Aging

Location: Jean Mayer Human Nutrition Research Center On Aging

2022 Annual Report

Objectives
Objective 1: Characterize the mechanisms associated with nutritional and exercise-related mediators of anabolic resistance associated with sarcopenia, advancing age, and/or reduced mobility in cell/animal models and humans. Sub-objective 1A: Characterize the role of plasticity-related micro-RNA (PR-miRNA) on the anabolic response to specific amino acids, growth factors, and mechanical stretch in skeletal muscle and to further understand the interaction of adipocyte-derived micro-RNA on skeletal muscle anabolic capacity. Sub-objective 1B: Characterize in an exploratory manner the association between gut microbiome composition and function with skeletal muscle composition and performance. Objective 2: Determine the mechanisms by which selected nutrients and/or varying modes of exercise/physical activity influence skeletal muscle performance, cognitive performance, physical functioning, and quality of life in older adults. Sub-objective 2A: Characterize the effects of exercise training on skeletal muscle alone or in combination with daily supplementation of '-3 fatty acids in older adults with mobility limitations and chronic low-grade inflammation. Sub-objective 2B: Characterize the safety, scalability and relative suitability of a low-cost physical activity interventions in older adults with motoric cognitive risk syndrome in a community setting.

Approach
Sarcopenia, the age-associated loss in skeletal muscle mass and function, is a contributing factor to the observed declines in physiological capacity, reduced functional performance, and increased disability and mortality observed with advancing age. The underlying causes of sarcopenia are multi-factorial but include poor nutritional status, reduced levels of physical activity, inflammation, chronic disease burden and other co-morbidities. This project will continue to use a translational science approach to examine the underlying mechanisms by which nutrition and exercise alter skeletal muscle function, and to identify and evaluate the impact of nutritional and exercise interventions on skeletal muscle performance capacity and their potential to prevent or reverse impaired motor/cognitive performance and/or physical dysfunction in older adults. Specifically, we will continue to interrogate skeletal muscle-derived microRNA and microRNA expressed from adipocytes to understand their role in age-related changes in skeletal muscle gene expression and resultant impact on muscle anabolic capacity. In addition, we will investigate the role of age-related alterations in the gut microbiome on skeletal muscle composition and function. We will evaluate the interactive effects of exercise and omega-3 fatty acids on skeletal muscle composition and function in older adults at risk for mobility disability. Finally, we will evaluate the safety and scalability of a community-based exercise intervention in older adults with cognitive and physical limitations. The pairing of basic approaches that identify the molecular landscape and skeletal muscle targets with clinical studies of nutrition and physical activity on sarcopenia will accelerate our ability to translate these findings to aging people.

Progress Report
Work continues on Objective 1. We have continued to interrogate members of the Mirc1 microRNA family. While it is well established that older adults can increase their muscle mass and strength in response to resistance (strength) exercise training (PRET), the response to PRET among older adults varies considerably. We examined the relationship between short non-coding RNA molecules called "microRNA" of the mirc1 family and the gains in lean mass and strength following 6 months of PRET in older adults. Participants were grouped by gain (Gainers; mean +561.4 g, n = 33) or loss (Losers; mean -589.8 g, n = 40) of leg lean mass after PRET. Gainers significantly increased fat-free mass 2.4% vs. -0.4% for Losers. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. Using an aging mouse model, we then assessed if miR-19b-3p expression was different in young mice with larger muscle mass compared with older mice. Circulating and skeletal muscle miR-19b-3p expression was higher in young compared with old mice and was positively associated with muscle mass and grip strength. These results confirm our previous results in vitro identifying miR-19b-3p as a negative regulator of myostatin signaling and stimulator of muscle protein synthesis. This work adds further validity to the role of miR-19b-3p as a potent regulator of muscle anabolism that may contribute to the variability in response to PRET in mobility-limited older adults. For Objective 2, the clinical trial designed to examine the safety and scalability of a low-cost physical activity intervention in older adults with Motoric Cognitive Risk syndrome was concluded at the onset of the COVID-19 pandemic. MCR is a recently defined pre-dementia syndrome characterized by slow walking speeds and subjective memory complaints. MCR avoids the need for complex neuro-psychological testing, and its assessment can identify older persons who have a substantially greater risk for the development of subsequent dementia. We conducted a translational randomized controlled trial (RCT) of 24-weeks of physical activity (PA) or a healthy aging education (HE) control intervention in an urban senior center in Greater Boston. Using baseline data from this completed trial, we examined Cognitive Motor Dual Task (CMDT) paradigms in these participants. Previous work has shown that CMDT (i.e., gait paired with a cognitive task) demonstrates greater impairments for older adults compared to younger adults. Differences on CMDT scores may be related to reduced grey matter in prefrontal areas important for dividing or switching attentional resources between cognition and physical tasks such as gait. Understanding this interplay between cognition and gait is especially important for certain aging populations, such as older adults with MCR who are at increased risk of pre-dementia and dementia and at an increased risk of falling. We found that participants with lower CMDT scores (better dual task performance) performed higher on the same composite measures: Working Memory (r = -0.36, p = 0.04), Processing Speed (r = -0.39, p = 0.03), Shifting (r = -0.39, p = 0.03), as well as Overall Cognition (r = -0.38, p = 0.03). Given the exceptionally low average 4-meter gait speed of the participants enrolled in this trial (i.e., 0.52 m/s), we also examined associations between single task gait speed and cognitive composite scores. We found that participants with faster gait speed performed higher on Working Memory (r = 0.48, p = 0.01), Processing Speed (r = 0.57, p = 0.001), and Overall Cognition (r = 0.46, p = 0.01). Our results with an older adult MCR sample build on prior, non-MCR research that has found that dual task gait speed was related to lower cognitive scores, which further emphasizes the potential for using cognitive motor dual task assessments in clinical and community settings.

Accomplishments
1. Biomarkers of cellular senescence are associated with reduced physical functioning and muscle strength in older adults. Cellular senescence is a process related to the aging of many cells in our bodies and may be associated with the decline in walking speed and other measures of physical functioning and strength. ARS-funded researchers in Boston, Massachusetts, examined associations between markers of cellular senescence in the blood and measures of physical function and muscle strength in 1377 older adults from the Lifestyle Interventions and Independence for Elders Study (LIFE). They observed significant associations between many of the blood markers and a person’s walking speed, balance, chair rise time and 400m walk time. A panel of 10 of these blood markers effectively identified participants at the greatest risk for mobility loss. These findings highlight the association between senescence factors, physical performance, and muscle strength and future studies should examine whether cellular senescence can be modulated through diet and physical activity interventions.

Review Publications
Fielding, R.A., Rivas, D.A., Grosicki, G.J., Ezzyat, Y., Ceglia, L., Price, L., Orhan, C., Sahin, K., Fowler, K., White, T., Durkee, S., Kritsch, K., Bellamine, A. 2021. Effects of low doses of L-carnitine tartrate and lipid multi-particulate formulated creatine monohydrate on muscle protein synthesis in myoblasts and bioavailability in humans and rodents. Nutrients. 13(11):3985. https://doi.org/10.3390/nu13113985.
Mey, J.T., Godin, J., Scelsi, A.R., Kullman, E.L., Malin, S.K., Yang, S., Floyd, Z.E., Poulev, A., Fielding, R.A., Ross, A.B., Kirwan, J.P. 2021. A whole-grain diet increases whole-body protein balance compared to a macronutrient-matched refined-grain diet. Current Developments in Nutrition. 5:nzab121. https://doi.org/10.1093/cdn/nzab121.
Aziz, J.J., Reid, K.F., Batsis, J.A., Fielding, R.A. 2021. Urban-rural differences in the prevalence of muscle weakness and slow gait speed: A cross-sectional analysis from the NHANES (2001-2002 and 2011-2014). Journal of Aging Research & Lifestyle. 10:19-25. https://doi.org/10.14283/jarlife.2021.4.
Manini, T.M., Patel, S., Newman, A.B., Travison, T.G., Kiel, D.P., Shardell, M., Pencina, K., Wilson, K.E., Kelly, T.L., Masaro, J.M., Fielding, R.A., Magaziner, J., Correa-de-Araujo, R., Kwok, T.C., Hirani, V., Karlsson, M.K., D'Agostino, R., Mellstrom, D., Ohlsson, C., Ribom, E., Jordan, J.M., Bhasin, S., Cawthon, P.M. 2020. Identification of sarcopenia components that discriminate slow walking speed: a pooled data analysis. Journal of the American Geriatrics Society. 68(7):1419-1428. https://doi.org/10.1111/jgs.16524.
Sipila, S., Tirkkonnen, A., Savikangas, T., Hanninen, T., Laukkanen, P., Alen, M., Fielding, R.A., Kivipelto, M., Kulmala, J., Rantanen, T., Sihvonen, S.E., Sillanpaa, E., Stigsdotter-Neely, A., Tormakangas, T. 2021. Effects of physical and cognitive training on gait speed and cognition in older adults: A randomized controlled trial. Scandinavian Journal of Medicine & Science in Sports. 31(7):1518-1533. https://doi.org/10.1111/sms.13960.
Guralnik, J.M., Feige, J.N., Singh, A., Fielding, R.A. 2021. Nutritional mediators of cellular decline and mitochondrial dysfunction in older adults. Geriatrics. 6(2):37. https://doi.org/10.3390/geriatrics6020037.
Lebrasseur, N.K., De Cabo, R., Fielding, R.A., Ferrucci, L., Rodriguez-Manas, L., Vina, J., Vellas, B. 2021. Identifying biomarkers for biological age: geroscience and the ICFSR task force. The Journal of Frailty and Aging. 10:196-201. https://doi.org/10.14283/jfa.2021.5.
Rivas, D.A., Peng, F., Benard, T., Sanchez Ramos da Silva , A., Fielding, R.A., Margolis, L. 2021. miR-19b-3p is associated with a diametric response to resistance exercise in older adults and regulates skeletal muscle anabolism via PTEN inhibition. American Journal of Physiology - Cell Physiology. 321(6):C977-C991. https://doi.org/10.1152/ajpcell.00190.2021.
Barger, K., Langsetmo, L., Orwoll, E.S., Lustgarten, M.S. 2020. Investigation of the diet-gut-muscle axis in the Osteoporotic Fractures in Men study. Journal of Nutrition Health and Aging. https://doi.org/10.1007/s12603-020-1344-1.