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

Location: Jean Mayer Human Nutrition Research Center On Aging

2023 Annual Report

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.

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. A key focus of this research has been to identify micro ribonucleic acid (miR) molecules that have regulatory effects on skeletal muscle growth and their modification with advancing age. In previous experiments, we found that a particular miR (miR-19b) can negatively regulate the expression of Transforming growth factor-beta (TGF-beta) signaling (myostatin pathway), leading to a reduction of protein degradation pathways, and amplified anabolic capacity in human myocytes. Therefore, to determine the effect of the miR-17/92 cluster (a group of miRs that includes miR-19b) on the TGF-beta/myostatin pathway we used a technique to inhibit the expression of miR-17/92 cluster. When we used this technique it significantly decreased the expression of miR-17/92 after 72 h compared to control. MiR-17/92 inhibition significantly increased the expression of the TGF-beta family members Myostatin, SMAD2 and SMAD4 by ~40-50% while there was no effect on the expression of SMAD3 or Activin receptor 2B. We next measured the expression of key skeletal muscle E3 ubiquitin ligases (genes that induce skeletal muscle atrophy) and found that their expression was also upregulated. Our data shows that the inhibition of the miR-17/92 cluster is associated with the increased expression of the TGF-beta pathway and E3 ubiquitin ligases. These results provide additional evidence for the role of the miR-17/92 family members on age-related changes in skeletal protein turnover. Additionally, we continue to explore the impact of the aging gut microbiome on muscle structure and function. Prior evidence from our work in animal models suggested a role for the gut microbiome, and more specifically, on gut bacteria-derived metabolites (acetate, propionate, butyrate, which are short-chain fatty acids (SCFAs)) on the maintenance of muscle mass, muscle composition and physical function. Soluble fiber fermentation by gut bacteria results in the formation of SCFAs, and fecal SCFAs proportionally increase in response to high-soluble fiber diets. To date, studies aimed at positively impacting the gut-muscle axis in aged animals via an increased soluble fiber content are sparse. To fill this knowledge gap, we designed a custom, whole-food, high-soluble fiber diet (HSFD) for mice. The custom HSFD has 3x more soluble fiber than the control diet (LabDiet 5K52), with relatively similar levels of protein, carbohydrate and fat. These diets were then fed to aged (22 - 23-month-old) male and female mice (custom HSFD, n=8; control diet, n=9) for 6 weeks. Daily food intake (grams of food consumed/day) was not significantly different, but body weight was significantly decreased for mice fed the custom HSFD when compared with the control diet. Investigating further, although absolute whole body lean and fat mass were significantly reduced for mice fed the custom HSFD, relative body composition displayed favorable changes, including a higher percentage of lean mass in conjunction with a lower percentage of fat mass. After normalizing for body weight, grip strength and treadmill endurance capacity were not different between groups, but there were some gender-specific effects as female mice fed the custom HSFD had a significantly increased treadmill endurance capacity, when compared with control diet-fed mice. In addition, muscle mass, assessed as the sum of the gastrocnemius, tibialis anterior, soleus, quadriceps, and hamstrings was not different between groups. Contrary to our expectations, these data do not support the hypothesis that a HSFD can positively impact skeletal muscle-related measures in aged mice. However, there may be sex-specific differences with some positive effects observed in females. In contrast, a HSFD induced a reduction in adiposity and correspondingly, body weight. Further investigation will explore these relationships, including quantification of gut microbiome composition and circulating levels of SCFAs. Progress on Objective 2 is ongoing. We have interrogated an existing data set and biorepository samples to examine the impact of cellular senescence on muscle weakness, physical functioning and disability. Cellular senescence is a plausible mediator of age-associated declines in physical performance and development of disability. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1,377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-meter walk time. Activin A, Intercellular adhesion molecule 1, Matrix metalloproteinase 7, Vascular endothelial growth factor A, and Eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score = 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified Pulmonary and activation-regulated chemokine, A disintegrin and metalloproteinase with thrombospondin motifs 13, and Regulated on Activation, Normal T Cell Expressed and Secreted as top candidates in females, and Matrix metalloproteinase 2, Sclerostin, and Monocyte chemotactic protein 1 in males. We further examined whether these biomarkers were associated with major mobility disability, and whether they were altered in participants randomized to a structured moderate intensity physical activity intervention (PA) compared to a healthy aging intervention (HA). We observed significant associations between multiple SASP proteins and the onset of incident and persistent mobility disability (development of the inability to walk 400 meters). There was no significant difference in any of the SASP proteins between PA and HA at 12 or 24 months. However, when accelerometry assessed physical activity was separated by quartiles from lowest to highest moderate intensity activity (>760 counts/min) at 12 and 24 months, we found a significantly lower concentrations of 10 SASP proteins (Eotaxin, Interleukin 15, Interleukin 6, Interleukin 7, Matrix metalloproteinase 1, Matrix metalloproteinase 7, Osteopontin, Tumor necrosis factor alpha, Tumor necrosis factor receptor 2, Vascular endothelial growth factor A) by quartile of physical activity achieved. These data highlight an association between senescence biomarkers and strength, physical performance, mobility disability and the potential for physical activity to attenuate these effects in older adults. In attempt to gain better insights into the trajectory of the decline in walking speed in older adults with sarcopenia and existing mobility limitations, we recently completed a longitudinal study of older men and women with sarcopenia and mobility limitations (N = 185). In this longitudinal cohort study we followed men and women aged = 65 years old with a Short Physical Performance Battery (SPPB) = 8 and low appendicular lean mass. During the 400 M walk test, we observed a change in gait speed of negative 0.027±0.171 m/sec (P < 0.064). Correspondingly the distance completed during the 6-minute walk test increased (poorer performance) by 16.6 + 76.8 M (P < 0.006). These declines in walking performance were associated baseline levels of systemic inflammation and provide a framework for the time course of functional decline in older adults with mobility limitations and sarcopenia.

1. Cellular senescence may be associated with mobility problems in older adults. Cellular senescence is a process related to the aging of many cells in our bodies and may be associated with the development of mobility disability and be modified by physical activity. ARS-funded researchers in Boston, Massachusetts, using samples and data obtained longitudinally from the Lifestyle Interventions for Elders Study measured circulating concentrations of proteins secreted by senescent cells. Among approximately 1400 older women and men assigned randomly to either a structured physical activity or a healthy aging program, there were associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and Serum matrix metalloproteinase 7 (MMP7), and the onset of mobility disability. In contrast, there was no difference in senescence biomarker levels between those who participated in the physical activity program compared to those in the health aging program. These data reinforce cellular senescence as a mediator of age-associated functional decline and the potential for physical activity to attenuate this hallmark of aging.

Review Publications
Weiner, D., Liu, C.K., Miao, S., Fielding, R.A., Katzel, L., Giffuni, J., Well, A., Selinger, S. 2023. Effect of long-term exercise training on physical performance and cardiorespiratory function in adults with CDK: a randomized controlled trial. American Journal of Kidney Diseases.
Guralnik, J., Cawthon, P., Bhasin, S., Fielding, R.A., Magaziner, J., Cruz-Jentoft, A.J., Vellas, B., Clarke, L., Lattimer, L., Evans, W. 2023. Limited physician knowledge of sarcopenia: a survey. Journal of American Geriatric Society.
Westbury, L., Beaudart, C., Bruyere, O., Cauley, J.A., Cawthon, P., Cruz-Jentoft, A.J., Curtis, E., Ensrud, K., Fielding, R., Johansson, H., Kanis, J.A., Karlsson, M.K., Lane, N., Lengele, L., Lorentzon, M., McCloskey, E., Mellstrom, D., Newman, A.B., Ohlsson, C., Orwoll, E., Reginster, J., Ribom, E., Rosengren, B., Schousboe, J.T., Shiroma, E.J., Harvey, N.C., Dennison, E.M., Cooper, C., Kwok, T. 2023. Recent sarcopenia definitions - prevalence, agreement and association with mortality among men: findings from five population-based cohorts. Journal of Cachexia, Sarcopenia and Muscle.
Shilpak, M.G., Sheshadri, A., Hsu, F., Chen, S., Jotwani, V., Tranah, G., Fielding, R.A., Liu, C., Ix, J., Coca, S. 2022. Effect of structured, moderate exercise on kidney function decline in sedentary older adults: An ancillary analysis of the LIFE study randomized clinical trial. JAMA Internal Medicine. 182(6):650-659.
Zhang, X., Habiballa, L., Aversa, Z., Ng, Y., Sakamoto, A.E., England, D.A., Pearsall, V.M., White, T.A., Robinson, M.M., Rivas, D., Dasari, S., Hruby, A.J., Lagnado, A.B., Jachim, S.K., Granic, A., Sayer, A.A., Jurk, D., Lanza, I., Khosla, S., Fielding, R., Nair, K., Schafer, M., Passos, J.F., Lebrasseur, N.K. 2022. Characterization of cellular senescence in aging skeletal muscle. Nature Aging.
Batsis, J.A., Petersen, C.L., Cook, S.B., Al-Nimr, R.I., Driesse, T., Pidgeon, D., Fielding, R. 2021. Impact of whey protein supplementation in a weight-loss intervention in rural dwelling adults: A feasibility study. Clinical Nutrition. 45:426-432.
Cawthon, P.M., Patel, S.M., Kritchevsky, S.B., Newman, A.B., Santanasto, A., Kiel, D.P., Travison, T.G., Lane, N., Cummings, S.R., Orwoll, E.S., Duchowny, K.A., Kwok, T., Hirani, V., Schousboe, J., Karlsson, M.K., Mellstrom, D., Ohlsson, C., Ljunggren, O., Xue, Q., Shardell, M., Jordan, J.M., Pencina, K.M., Fielding, R., Magaziner, J., Correa-De-Araujo, R., Bashin, S., Manini, T.M. 2021. What cut-point in gait speed best discriminates community-dwelling older adults with mobility complaints from those without? A pooled analysis from the sarcopenia definitions and outcomes consortium. Journals of Gerontology.
Turunen, K.M., Tirkkonen, A., Savikangas, T., Hanninen, T., Alen, M., Fielding, R., Kivipelto, M., Neely, A.S., Tormakangas, T., Sipila, S. 2021. Effects of physical and cognitive training on falls and concern about falling in older adults: results from a randomized controlled trial. Journals of Gerontology. 77(7):1430-1437.
Pandey, A., Shah, S.J., Butler, J., Kellogg, Jr., D.L., Lewis, G.D., Forman, D., Mentz, R.J., Borlaug, B.A., Simon, M.A., Chirinos, J.A., Fielding, R.A., Volpi, E., Molina, A.J., Haykowsky, M.J., Sam, F., Goodpaster, B.H., Bertoni, A.G., Justice, J.N., White, J.P., Ding, J., Hummel, S.L., Lebrasseur, N.K., Taffet, G.E., Pipinos, I.I., Kitzman, D.W. 2021. Exercise intolerance in older adults with heart failure with preserved ejection fraction: JACC state-of-the-art review. Journal of the American College of Cardiology. 78(11):1166-1187.
Savikangas, T., Tormakangas, T., Tirkkonen, A., Alen, M., Fielding, R., Kivipelto, M., Rantalainen, T., Neely, A.S., Sipila, S. 2021. The effects of a physical and cognitive training intervention vs. physical training alone on older adults' physical activity: A randomized controlled trial with extended follow-up during COVID-19. PLOS ONE. 16(10):e0258559.
McGrath, R., Cawthon, P., Clark, B., Fielding, R., Lang, J., Tomkinson, G. 2022. Recommendations for reducing heterogeneity in handgrip strength protocols. The Journal of Frailty and Aging. 11:143-150.
Skoglund, E., Lundberg, T.R., Rullman, E., Fielding, R.A., Kirn, D.R., Englund, D.A., von Berens, A., Koochek, A., Cederholm, T., Berg, H.E., Gustafsson, T. 2021. Functional improvements to 6 months of physical activity are not related to changes in size or density of multiple lower-extremity muscles in mobility-limited older individuals. Experimental Gerontology. 157:111631.
Fielding, R.A., Atkinson, E.J., Aversa, Z., White, T.A., Heeren, A.A., Achenbach, S.J., Mielke, M.M., Cummings, S.R., Pahor, M., Leeuwenburgh, C., Lebrasseur, N.K. 2022. Associations between biomarkers of cellular senescence and physical function in humans: Observation from the lifestyle interventions for elders (life) study. Nature Aging.
Salekeen, R., Lustgarten, M., Didarul Islam, K. 2023. Model organism life extending therapeutics modulate diverse nodes in the drug-gene-microbe tripartite human longevity interactome. Journal of Biomolecular Structure and Dynamics.
Cesari, M., Calvani, R., Canevelli, M., Aprahamian, I., de Souto Barreto, P., Azzolino, D., Fielding, R., Vanacore, N., Inzitari, M., Marzetti, E. 2021. On Schrodinger's cat and evaluation of trials disrupted by the Covid19 pandemic: A critical appraisal. The Journal of Frailty and Aging. 10(4)310-312.
Desouto-Barreto, P., Cesari, M., Morley, J.E., Gonzalez-Bautista, E., Rolland, Y., Azzolino, D., Vellas, B., Fielding, R. 2022. Assessment and management of appetite loss in older adults: an ICFSR task force report. The Journal of Frailty and Aging.
Sahni, S., Dufour, A., Wang, N., Kiel, D.P., Hannan, M., Jacques, P.F., Benjamin, E., Vasan, R.S., Murabito, J.M., Newman, A.B., Fielding, R.A., Mitchell, G.F., Hamburg, N. 2023. Association of vascular health measures and physical function: a prospective analysis in the Framingham Heart Study. Journal of Gerontology Medical Science.
Groarke, J., Tarasenko, L., Smoyer, K., Fielding, R., Francesco, L. 2023. Association of anorexia/appetite loss with malnutrition and mortality in older populations: a systematic literature review. Journal of Cachexia, Sarcopenia and Muscle.
Dagenais, S., Fielding, R.A., Clark, S., Cantu, C., Prasad, S., Groarke, J. 2023. Anorexia in medicare fee-for-service beneficiaries: A claims-based analysis of epidemiology and mortality. Journal of Nutrition Health and Aging.
Dioh, W., Narkar, V., Singh, A., Malik, A., Ferrucci, L., Tourette, C., Mariani, J., Vanmaanen, R., Fielding, R.A. 2023. Novel potential targets for function-promoting therapies: orphan nuclear receptors, anti-inflammatory drugs, troponin activators, mas receptor agonists, and urolithin A. Journal of Gerontology Medical Science.
Cesari, M., Azzolino, D., Lebrasseur, N.K., Whitson, H., Rooks, D., Sourdet, S., Angioni, D., Fielding, R., Vellas, B., Rolland, Y. 2022. Resilience: biological basis and clinical significance - A perspective from the International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force. The Journal of Frailty and Aging.
Bhasin, S., Cawthon, P., Correa-De-Arauju, R., Storer, T.W., Volpi, E., Newman, A.B., Evans, W.J., Fielding, R. 2023. Optimizing the design of clinical trials to evaluate the efficacy of function promoting therapies. Journal of Gerontology Medical Science.
Correa-De-Araujo, R., Evans, W.J., Fielding, R.A., Krishnan, V., Carter, R., Appleby, J., Guralnik, J., Klickstein, L.B., Marks, P., Moore, A., Peschin, S., Shalender, B. 2023. Synergistic strategies to accelerate the development of function promoting therapies: Lessons from operation warp speed and oncology drug development. Journal of Gerontology Medical Science.
Storer, T.W., Pahor, M., Woodhouse, L., Lachman, M.E., Fielding, R.A. 2023. Exercise and behavior: adjuncts to pro-myogenic compounds for enhancing mobility in older adults. Journal of Gerontology Medical Science.
Pahor, M., Guralnik, J.M., Anton, S.D., Ambrosius, W.T., Blair, S.N., Church, T.S., Espeland, M.A., Fielding, R.A., Gil, T.M., Glynn, N.W., Groessl, E.J., King, A.C., Kritchevsky, S.B., Manini, T.M., McDermott, M.M., Miller, M.E., Newman, A.B., Williamson, J.D. 2020. Impact and lessons learned from the Lifestyle Intervention and Independence for Elders (LIFE) clinical trails of physical activity to prevent mobility disability. Journal of the American Geriatrics Society. 00:1-10, 2020.
Cawthon, P.M., Visser, M., Arai, H., Cruz-Jentoft, A.J., Kiel, D.P., Kirk, B., Rocco, B., Avan, S., Cooper, C., Binder, E., Landi, F., Duque, G., Woo, J., Avila-Funes, J.A., Chen, L., Bruyere, O., Fielding, R., Bhasin, S., Haehling, S.V., Cederholm, T. 2022. Defining terms commonly used in sarcopenia research: a glossary proposed by the global leadership in sarcopenia (glis) steering committee. European Geriatric Medicine.