Location: Jean Mayer Human Nutrition Research Center On Aging
2024 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
A. MicroRNA (miRNA) are non-coding RNA molecules that can modulate gene expression,and can have effects on muscle cells. While the majority of miRNAs in the circulation originate from fat cells (adipocytes), it was unknown whether our previous observations of decreases in circulating Mirc1 (a family of related miRNAs) with age were due to decreases within adipocytes. Decreased adipose Mirc1 expression was associated with reduced grip strength, and a blunted anabolic response to muscle contraction in old mice compared to young mice and may be attributed to age-associated changes in adipose tissue expression. We then examined the relationship between microRNA of the Mirc1 family and the gains in lean mass and strength following 6 months of progressive resistance exercise training (PRT) 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 PRT. 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. 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 PRT in mobility-limited older adults.
B. We further examined exercise response heterogeneity (ERH) to PRT in older adults. To demonstrate the heterogeneity in response to a closely supervised PRT intervention, we examined data collected from 80 older adults (age 70-85 years, 58 percent female). The active intervention included high intensity whole body strengthening exercises for 24 weeks. Despite high adherence to the intervention (>70% of scheduled visits), changes in mid-thigh muscle cross sectional area (CSA) measured by computed tomography scans varied from a -10.5% loss to a + 17.0% gain in both males and females. Change in measures of muscle strength also demonstrated large ERH ranging from -14.9% loss to a + 94.1% gain in leg strength and suggest greater response variability in males compared to females. Measures of physical function revealed a strikingly similar ERH. Factors associated with ERH assessed by linear regression included baseline CSA, strength and SPPB, inflammatory markers (Il-6 and C reactive protein), and insulin resistance (insulin area under the curve during oral glucose tolerance test). These data clearly demonstrate substantial variability in important patient-centered and clinical outcomes of PRT in older adults and suggest a role for inflammation and insulin resistance as modifiers of these responses.
C. We also explored 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. We designed a custom, whole-food, high-soluble fiber diet (HSFD). The custom HSFD has 3x more soluble fiber than the control diet, with relatively similar levels of protein, carbohydrate and fat. Aged (22 - 23-month-old) male and female mice were fed HSFD (N=8) or control diet (N=9) for 6 weeks. Food intake (grams of food consumed/day) was not different, but body weight was decreased for mice fed the HSFD compared to control. Interestingly, 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 was not different between groups, but there were some sex-specific effects as female mice fed HSFD had a significantly increased treadmill endurance capacity, when compared with control diet-fed mice. In addition, muscle mass 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, HSFD induced a reduction in adiposity and correspondingly, body weight. We also observed that the HSFD altered gut bacterial structure and function with significantly increased fecal bacteria beta-diversity. Interestingly, serum short chain fatty acid concentrations were only increased in female mice in response to the HSFD suggesting potentially important sex differences.
D. Cellular senescence is a plausible mediator of age-associated declines in physical performance and disability onset. We examined associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function in 1,377 older adults. We showed significant associations between 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, and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score = 7). We further examined whether these biomarkers were associated with 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 mobility disability but no significant difference between PA and HA. 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 by quartile of physical activity achieved. These data highlight the association between senescence biomarkers and physical performance, mobility disability and the potential for physical activity to attenuate these effects.
Accomplishments
1. Physical activity may reduce cellular senescence. Cellular senescence, a process related to the aging of many cells in the body, may be a key regulator of multiple age-related syndromes and conditions. ARS-funded researchers in Boston, Massachusetts, in collaboration with colleagues at the Mayo Clinic in Rochester Minnesota, demonstrated that elevated blood-based markers of cellular senescence in older, overweight, and obese adults are related to mortality and are reduced with increasing levels of physical activity. Using data obtained from the Lifestyle Interventions for Elders Study (LIFE) and the Rochester Epidemiology Project (REP), researchers observed significant increases in seven biomarkers of senescence, and a significant decrease in one biomarker with an increase in BMI categories. Additionally, five biomarkers were associated with increased mortality in participants. In LIFE participants who demonstrated higher levels of physical activity measured using a waist-worn accelerometer, researchers found significantly lower concentrations of 10 biomarkers of senescence. These data highlight the role that cellular senescence plays on mortality risk of overweight and obesity, and how this process may be modifiable by lifestyle interventions such as increased physical activity.
Review Publications
St. Sauver, J.L., Weston, S.A., Atkinson, E.J., Mc Gree, M.M., Mielke, M.M., White, T.A., Heeren, A.A., Olson, J.E., Rocca, W.A., Palmer, A.K., Cummings, S.R., Fielding, R., Bielinski, S.J., Lebrasseur, N.K. 2023. Biomarkers of cellular senescence and risk of death in humans. Aging Cell. https://doi.org/10.1111/acel.14006.
Fielding, R.A., Alhmly, H. 2023. A critical review of current worldwide definitions of sarcopenia. Calcified Tissue International. https://doi.org/10.1007/s00223-023-01163-3.
Fielding, R. 2024. Sarcopenia: an emerging syndrome of advancing age. Calcified Tissues International. https://doi.org/10.1007/s00223-023-01175-z.
Liu, C.K., Miao, S., Giffuni, J., Katzel, L., Fielding, R.A., Selinger, S.I., Weiner, D.E. 2023. Geriatric syndromes and health-related quality of life in older adults with chronic kidney disease: Ancillary analysis of the award randomized clinical trial. Kidney360. https://doi.org/10.34067/KID.0000000000000078.
Sheshandri, A., Lai, M., Hsu, F., Bauer, S., Chen, S., Tse, W., Jotwani, V., Tranah, G.J., Lai, J.C., Hallan, S., Fielding, R., Liu, C.K., Li, J.H., Coca, S.G., Shlipak, M.G. 2023. Structured moderate exercise and biomarkers of kidney health in sedentary older adults: The lifestyle interventions and independence for elders randomized clinical trial. Kidney Medicine. https://doi.org/10.1016/j.xkme.2023.100721.
