1a. Objectives (from AD-416):
LAB NAME: Nutrition, Exercise Physiology, and Sarcopenia 1. Characterize the mechanisms associated with nutritional and contraction-related mediators of anabolic resistance associated with advancing age and/or obesity in animal models and humans. 2. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on physical functioning in older adults with chronic kidney disease or limited mobility. 3. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on cognitive functioning in older adults with chronic kidney disease or limited mobility.
1b. Approach (from AD-416):
LAB NAME: Nutrition, Exercise Physiology, and Sarcopenia Sarcopenia, the age-associated loss in skeletal muscle mass and function, is a contributing factor to the observed declines in physiological capacity and physical functioning with advancing age. The overall theme of this project will be to conduct basic and clinical studies focused on the identification, evaluation, and understanding of nutritional and physical activity interventions that possess anabolic properties in skeletal muscle and have the potential to prevent or reverse impaired motor and cognitive performance and/or physical dysfunction in older individuals. Our basic research program will focus on understanding the molecular mechanisms associated with age-related anabolic resistance in skeletal muscle. These basic studies will be uniquely synergized with our clinical/translational studies designed to evaluate the potential efficacy of nutritional and exercise interventions in older adults. Our proposed clinical studies will further seek to understand the role of structured physical activity and nutritional supplementation on changes in physical function and disability in older adults with mobility limitations as a consequence of anabolic resistance and/or sarcopenia. In addition, we will also examine the role of structured physical activity on changes in cognition and the role of physical activity on dementia risk. The pairing of clinical studies examining the influence of protein nutrition and physical activity on sarcopenia with basic approaches that identify the molecular landscape and potential targets in skeletal muscle for preventive interventions (nutritional, physical activity) may accelerate our ability to translate these findings to aging people.
3. Progress Report:
This is the final report for project 8050-51000-091-00D. The project has made progress on all objectives outlined in the project plan. Culminating in year 5, researchers in the Nutrition, Exercise, and Sarcopenia Lab met the majority of the approved milestones. Objective 1. Characterize the mechanisms associated with nutritional and contraction-related mediators of anabolic resistance associated with advancing age and/or obesity in animal models and humans. Researchers in the lab have completed studies aimed at the identification of mechanisms underlying age-related changes in physical functioning. Researchers used metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6-month change in amino acids, fatty acids, and acylcarnitines with baseline and the 6-month changes in muscle strength, lower extremity function (short physical performance battery), and mobility (400M gait speed) in response to 6 months of a combined resistance exercise and nutritional supplementation intervention in functionally-limited older adults. Metabolites related to gut bacterial metabolism and insulin sensitivity were associated with function at baseline and with the 6-month change in function. These data suggest that gut microbial metabolism and insulin sensitivity may be involved in mechanisms that underlie physical functioning in older adults. To better understand the molecular changes associated with the loss of skeletal muscle mass with aging, researchers examined the role of microRNA in the aging process. Researchers in the lab demonstrated marked alterations in miRNA expression profile in adipose tissue from C57BL/6 mice with advancing age. At 24 months, there was a substantial decrease in the expression of miRNA in both miR-17/92 and other adipose-specific miRNA compared to 6 and 18-month-old animals. In these animals, researchers found similar changes in the expression of miRNA in skeletal muscle with age and in response to high-fat feeding. Researchers in the NEPS lab have previously reported that miR-17/92 expression in circulation is highly predictive of age and the anabolic response to exercise in humans. Using adenoviral gene vectors to overexpress miR-19-3p in human myocytes, researchers found that protein synthesis and anabolic signaling were increased at 3h compared to control, but miR-19b-3p could not reverse rapamycin-induced inhibition of protein synthesis. These changes were likely due to a blunted expression of the phosphatase and tensin homolog transcript and protein after overexpression. However, miR-19b had no effect on mitochondrial genes suggesting a role for miR-19b in regulating muscle protein turnover exclusively. Objective 2. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on physical functioning in older adults with chronic kidney disease or limited mobility. The Lifestyle Interventions and Independence for Elders (LIFE) Study was a large multicenter randomized controlled trial, designed to compare the effects of a moderate intensity physical activity program with a successful aging health education program on the incidence of major mobility disability in older adults who were at high risk for mobility disability (scoring < 9 on the Short Physical Performance Battery) at baseline (N = 1,635). Researchers performed secondary analysis of the LIFE study data to examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability. Physical activity dose was assessed at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery, assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and Short Physical Performance Battery from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability. Researchers in the lab also analyzed the impact of the LIFE study intervention on the risk of developing physical frailty. Frailty was defined using the Study of Osteoporotic Fractures (unexpected weight loss (> 5% or 4.55 kg, inability to rise from a chair, self-reported reduced energy). Over 24 months of follow-up, the risk for frailty (n = 1623) was not different in the physical activity versus the health education group. Among the 3 criteria of the Study of Osteoporotic Fractures index, the physical activity intervention was associated with improvement in the inability to rise from a chair. Baseline frailty status did not modify the effect of physical activity on reducing the development of major mobility disability. These results indicate that a structured, moderate-intensity physical activity program was not associated with a reduced risk for frailty over 2 years among sedentary, community-dwelling older adults. However, importantly, the beneficial effect of physical activity on the incidence of major mobility disability did not differ between frail and non-frail participants. The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity, muscle cross sectional area, and fat accumulation in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150 kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). Mobility-limited (Short Physical Performance Battery ==9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. Primary outcome was gait speed assessed by the 400M walk. Secondary outcomes were total lean mass, thigh muscle cross sectional area, and muscle strength, power, and quality before and after the 6-month intervention. 149 subjects were randomized into the study. Adherence across supplement and placebo groups was similar. After the intervention period both groups demonstrated exercise related improvements. Nutritional supplementation lead to further losses of intermuscular fat and increased normal muscle density cross sectional area. Furthermore, both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo. Similar effects in physical function were observed using the Short Physical Performance Battery. Six-months of structured physical activity resulted in improvements in gait speed, body composition, subcutaneous fat, intermuscular fat, and strength measures. These results suggest nutritional supplementation provides additional benefits to mobility-limited older adults undergoing exercise training. Objective 3. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on cognitive functioning in older adults with chronic kidney disease or limited mobility. Epidemiologic evidence has suggested that physical activity benefits cognition, but results from randomized trials are limited and mixed. Researchers examined whether multiple domains of baseline cognitive performance were associated with prospective physical activity adherence in the Lifestyle Interventions and Independence for Elders Pilot study (LIFE-P). The LIFE-P study was a single-blind, multicenter, randomized controlled trial of a physical activity intervention compared to a successful aging educational intervention in sedentary, mobility-limited older adults that was the pilot for the phase 3 LIFE study. LIFE-P was a 12-month structured, moderate-intensity, multi-modal physical activity program that included walking, resistance training, and flexibility exercises. Tests of executive and global cognitive functioning, working memory and psychomotor speed were administered at baseline. Median test scores were used to dichotomize participants into low or high cognitive performance groups. 52 mobility-limited older adults (age: 76.9 ±5 yrs) were randomized to the physical activity arm of LIFE-P. Compared to participants with high cognitive performance, participants with low performance had similar physical activity adherence rates. Furthermore, there was no association between measures of cognition and overall physical activity adherence levels. These data suggest that cognitive performance does not limit long-term physical activity adherence in mobility-limited older adults.
1. Progressive resistance training improves muscle fatigue and strength in older adults. Progressive resistance/strength training is consistently shown to improve muscle strength in older adults, but its effect on muscle fatigue in older adults with limited mobility remains unclear. ARS-funded researchers in Boston, Massachusetts recruited 70 mobility-limited older adults (age 70–92 years) and randomized them to either progressive resistance training or home-based flexibility three times per week for 12 weeks. Muscle fatigue and strength outcomes were assessed at baseline and 12 weeks. At follow-up, the progressive resistance training group showed a significant improvement in muscle fatigue and strength compared with home-based flexibility group. These results show that progressive resistance/strength training improves muscle fatigue and strength in mobility-limited older adults. As older adults are often affected by muscle and strength loss, the discovery of effective strength training interventions could prolong independence and quality of life in older adults.
Wanigatunga, A.A., Gill, T.M., Marsh, A.P., Shu, F., Yaghjyan, L., Woods, A.J., Glynn, N.W., King, A.C., Newton, R.L., Fielding, R.A., Pahor, M., Manini, T.M. 2018. Effect of hospitalizations on physical activity patterns in mobility-limited older adults. Journal of the American Geriatrics Society. https://doi.org/10.1111/jgs.15631.
Liu, Z., Hsu, F., Trombetti, A., King, A.C., Liu, C.K., Manini, T.M., Fielding, R.A., Pahor, M., Newman, A.B., Kritchevsky, S., Gill, T.M. 2018. Effect of 24-month physical activity on cognitive frailty and the role of inflammation: the LIFE randomized clinical trial. BioMed Central (BMC) Medicine. https://doi.org/10.1186/s12916-018-1174-8.
Manini, T.M., Buford, T.W., Kairalla, J.A., McDermott, M.M., Vazfragoso, C.A., Fielding, R.A., Hsu, F., Johannsen, N., Kritchevsky, S., Harris, T.B., Newman, A.B., Cummings, S.R., King, A.C., Pahor, M., Santanasto, A.J., Tranah, G.C. 2018. Meta-analysis identifies mitochondrial DNA sequence variants associated with walking speed. GeroScience. https://doi.org/10.1007/s11357-018-0043-x.
Callahan, K.E., Lovato, L., Miller, M.E., Marsh, A.P., Fielding, R.A., Gill, T.M., Groessl, E.J., Guralnik, J., King, A.C., Kritchevsky, S.B., McDermott, M.M., Manini, T.M., Newman, A.B., Rejeski, W. 2018. Self-reported physical function as a predictor of hospitalization in the Lifestyle Interventions and Independence for Elders Study. Journal of the American Geriatrics Society. 66(10):1927-1933. https://doi.org/10.1111/jgs.15468.
Pahor, M., Anton, S.D., Beavers, D.P., Cauley, J.A., Fielding, R.A., Kritchevsky, S.B., Leeuwenburgh, C., Lewis, K.H., Liu, C.K., Lovato, L., Lu, J., Manini, T.M., McDermott, M.M., Miller, M.E., Newman, A.B., Radziszewska, B., Stowe, C.L., Tracy, R.P., Walkup, M.P., Wu, S., Ambrosius, W.T. 2018. Effect of losartan and fish oil on plasma IL-6 and mobility in older persons. The ENRGISE Pilot randomized clinical trial. Journal of Gerontology Medical Science. https://doi.org/10.1093/gerona/gly277.
Von Berens, A., Fielding, R.A., Gustafsson, T., Kirn, D., Laussen, J., Nydahl, M., Reid, K.F., Travison, T.G., Zhu, H., Cederholm, T., Koochek, A. 2018. Effect of exercise and nutritional supplementation on health-related quality of life and mood in older adults: VIVE2 randomized controlled trial. BMC Geriatrics. 18:286. https://doi.org/10.1186/s12877-018-0976-z.
Buford, T.W., Manini, T.M., Kairalla, J.A., McDermott, M.M., Vaz Fragoso, C.A., Chen, H., Fielding, R.A., King, A.C., Newman, A.B., Tranah, G.J. 2018. Mitochondrial DNA sequence variants associated with blood pressure among 2 cohorts of older adults. Journal of the American Heart Association. 7(18):e010009. https://doi.org/10.1161/JAHA.118.010009.
Reid, K.F., Walkup, M.P., Katula, J.A., Sink, K.M., Anton, S., Axtell, R., Kerwin, D.R., King, A.C., Kramer, A.F., Miller, M.E., Myers, V., Rosano, C., Studenski, S.A., Lopez, O.L., Verghese, J., Fielding, R.A., Williamson, J. 2016. Cognitive performance does not limit physical activity participation in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P). The Journal of Prevention of Alzheimer's Disease. 4(1):44-50. https://doi.org/10.14283/jpad.2016.107.
Layne, A.S., Hsu, F., Blair, S.N., Chen, S., Dungan, J., Fielding, R.A., Glynn, N.W., Hajduk, A.M., King, A.C., Manini, T., Marsh, A.P., Pahor, M., Pellegrini, C.A., Buford, T.W. 2016. Predictors of change in physical function in older adults in response to long-term, structured physical activity: the LIFE study. Physical Medicine and Rehabilitation Archives. 98(1):11-24. https://doi.org/10.1016/j.apmr.2016.07.019.
Wang, C., McAlindon, T., Fielding, R.A., Harvey, W.F., Driban, J., Price, L., Kalish, R., Schmid, A., Scott, T., Schmid, C.H. 2015. A novel comparative effectiveness study of Tai Chi versus aerobic exercise for fibromyalgia: study protocol for a randomized controlled trial. Trials. 16:34. https://doi.org/10.1186/s13063-015-0548-x.
Cauley, J.A., Manini, T.M., Lovato, L., Talton, J., Anton, S.D., Domanchuk, K., Kennedy, K., Stowe, C.L., Walkup, M., Fielding, R.A., Kritchevesky, S., McDermott, M.M., Newman, A.B., Ambrosius, W.T., Pahor, M. 2018. The Enabling Reduction of low-grade inflammation in seniors (ENRGISE) pilot study: screening methods and recruitment results. Journal of Gerontology Medical Science. https://doi.org/10.1093/gerona/gly204.
Von Berens, A., Cederholm, T., Fielding, R.A., Gustafsson, T., Kirn, D., Laussen, J., Nydahl, M., Travison, T.G., Reid, K.F., Koochek, A. 2018. Physical performance and serum 25(OH)vitamin D status in community dwelling old mobility limited adults: a cross-sectional study. Journal of Nutrition Health and Aging. 22(1):1-7. https://doi.org/10.1007/s12603-016-0849-0.
Mirsa, D., Fielding, R.A., Felson, D.T., Niu, J., Brown, C., Nevitt, M., Lewis, C.E., Torner, J., Neogi, T. 2018. Risk of knee osteoarthritis with obesity, sarcopenic obesity and sarcopenia. Arthritis and Rheumatology. https://doi.org/10.1002/art.40692.
Englund, D., Price, L.L., Grosicki, G., Iwai, M., Kashiwa, M., Liu, C., Reid, K.F., Fielding, R.A. 2018. Progressive resistance training improves torque capacity and strength in mobility-limited older adults. The Journals of Gerontology: Medical Sciences. https://doi.org/10.1093/gerona/gly199.
Sipila, S., Tirkkonen, A., Hanninen, T., Laukkanen, P., Alen, M., Fielding, R.A., Kivipelto, M., Kokko, K., Kulmala, J., Rantanen, T., Sihvonen, S.E., Sillanpaa, E., Stigsdotter-Neely, A., Tormakangas, T. 2018. Promoting safe walking among older people: the effects of a physical and cognitive training intervention vs. physical training alone on mobility and falls among older community-dwelling men and women (the PASSWORD study): design and methods of a randomized controlled study. BMC Geriatrics. 18:215. https://doi.org/10.1186/s12877-018-0906-0.
Lustgarten, M.S., Fielding, R.A. 2017. Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults. Experimental Gerontology. 100:1-10. https://doi.org/10.1016/j.exger.2017.10.003.
Reid, K.F., Laussen, J., Bhatia, K., Englund, D., Kirn, D.R., Price, L., Manini, T., Liu, C., Kowaleski, C., Fielding, R.A. 2018. Translating the lifestyle interventions and independence for elders clinical trial to older adults in a real-world community-based setting. Journal of Gerontology Medical Science. https://doi.org/10.1093/gerona/gly152.
Liu, C.K., Milton, J., Hsu, F., Beavers, K.M., Yank, V., Church, T., Shegog, J., Kashaf, S., Nayfield, S., Newman, A.B., Stafford, R.S., Nicklas, B.J., Weiner, D.E., Fielding, R.A. 2017. The effect of chronic kidney disease on a physical activity intervention: impact on physical function, adherence, and safety. Journal of Clinical Nephrology and Renal Care. 3:021. https://doi.org/10.23937/2572-3286.1510021.
Corcoran, M.P., Chui, K.K., White, D.K., Reid, K.F., Kirn, D., Nelson, M., Sacheck, J., Folta, S., Fielding, R.A. 2015. Accelerometer assessment of physical activity and its association with physical function in older adults residing at assisted care facilities. Journal of Nutrition Health and Aging. 20(7):752-758.
Miller, M.E., Magaziner, J., Marsh, A.P., Fielding, R.A., Gill, T.M., King, A.C., Kritchevsky, S., Manini, T., McDermott, M.M., Neiberg, R., Orwig, D., Santanasto, A.J., Pahor, M., Guralnik, J., Rejeski, W. 2018. Gait speed and mobility disability: revisiting meaningful levels in diverse clinical populations. Journal of the American Geriatrics Society. 66(5):954-961. https://doi.org/10.1111/jgs.15331.
Margolis, L.M., Ceglia, L., Rivas, D.A., Dawson-Hughes, B., Fielding, R.A. 2018. Pilot study examining the influence of potassium bicarbonate supplementation on nitrogen balance and whole-body ammonia and urea turnover following short-term energy restriction in older men. Nutrients. 10(5):624. https://doi.org/10.3390/nu10050624.
Wanigatunga, A.A., Manini, T.M., Cook, D.R., Katula, J., Fielding, R.A., Kramer, A.F., Verghese, J., Rapp, S.R., Sink, K.M., King, A.C., Buford, T.W., Anton, S., Nadkarni, N., Jennings, J.M., Reid, K.F., Espeland, M.A., Gill, T.M., Pahor, M., Nocera, J.R. 2018. Community-based activity and sedentary patterns are associated with cognitive performance in mobility-limited older adults. Frontiers in Aging Neuroscience. 10:341. https://doi.org/10.3389/fnagi.2018.00341.
Fanning, J., Rejeski, W., Chen, S., Nicklas, B.J., Walkup, M.P., Axtell, R.S., Fielding, R.A., Glynn, N.W., King, A.C., Manini, T.M., McDermott, M.M., Newman, A.B., Pahor, M., Tudor-Locke, C., Miller, M.E. 2019. A case for promoting movement medicine: preventing disability in the LIFE Randomized Controlled Trial. Journal of Gerontology Medical Science. https://doi.org/10.1093/gerona/glz050.
Cawthon, P., Travison, T.G., Manini, T.M., Patel, S., Pencina, K.M., Fielding, R.A., Magaziner, J.M., Newman, A.B., Brown, T., Kiel, D.P., Cummings, S.R., Shardell, M., Guralnik, J.M., Woodhouse, L.J., Pahor, M., Binder, E., D'Agostino, Sr., R.B., Quian-Li, X., Orwoll, E., Landi, F., Orwig, D., Schaap, L., Latham, N.K., Hirani, V., Kwok, T., Pereira, S.L., Rooks, D., Kashiwa, M., Torres-Gonzalez, M., Menetski, J.P., Correa-De-Araujo, R., Bhasin, S. 2019. Establishing the link between lean mass and grip strength cut points with mobility disability and other health outcomes: proceedings of the Sarcopenia Definitions and Outcomes Consortium Conference. Journal of Gerontology Medical Science. https://doi.org/10.1093/gerona/glz081.
Lessard, S.J., MacDonald, T.L., Pathak, P., Han, M., Coffey, V.G., Edge, J., Rivas, D.A., Hirshman, M.F., Davis, R.J., Goodyear, L.J. 2018. JNK regulates muscle remodeling via myostatin/SMAD inhibition. Nature Communications. 9:3030. https://doi.org/10.1038/s41467-018-05439-3.
Grosicki, G.J., Fielding, R.A., Lustgarten, M.S. 2018. Gut microbiota contribute to age-related changes in skeletal muscle size, composition, and function: biological basis for a gut-muscle axis. Calcified Tissue International. 102(4):433-442. https://doi.org/10.1007/s00223-017-0345-5.
Rizzoli, R., Branco, J., Brandi, M., Boonen, S., Bruyere, O., Cacoub, P., Cooper, C., Diez-Perez, A., Duder, J., Fielding, R.A., Harvey, N.C., Hiligsmann, M., Kanis, J.A., Petermans, J., Ringe, J.D., Tsourderos, Y., Weinman, J., Reginster, J. 2014. Management of osteoporosis of the oldest old. Osteoporosis International. 25(11):2507-2529.
Landi, F., Sieber, C., Fielding, R.A., Rolland, Y., Guralnik, J. 2018. Nutritional intervention in sarcopenia: report from the International Conference on Frailty and Sarcopenia Research Task Force. The Journal of Frailty and Aging. 7(4):247-252. https://doi.org/10.14283/jfa.2017.26.
Buckinx, F., Landi, F., Matteo, C., Fielding, R.A., Visser, M., Engelke, K., Maggi, S., Dennison, E., Al-Daghri, N.M., Allepaerts, S., Bauer, J., Bautmans, I., Brandi, M.L., Bruyere, O., Cederholm, T., Cerreta, F., Cherubini, A., Cooper, C., Cruz-Jentoft, A., Mccloskey, E., Dawson-Hughes, B., Kaufman, J., Laslop, A., Petermans, J., Reginster, J., Rizzoli, R., Robinson, S., Rolland, Y., Rueda, R., Vellas, B., Kanis, J. 2018. Pitfalls in the measurement of muscle mass: a need for a reference standard. Journal of Cachexia, Sarcopenia and Muscle. 9(2):269-278. https://doi.org/10.1002/jcsm.12268.
Vellas, B., Fielding, R.A., Bens, C., Bernabei, R., Cawthon, P.M., Cederholm, T., Cruz-Jentoft, A.J., Del Signore, S., Donahue, S., Morley, J., Pahor, M., Reginster, J., Rodriguez Manas, L., Rolland, Y., Roubenoff, R., Sinclair, A., Cesari, M. 2017. Implications of ICD-10 for sarcopenia clinical practice and clinical trials: report by the International Conference on Frailty and Sarcopenia Research Task Force. The Journal of Frailty and Aging. 7(1):2-9. https://doi.org/10.14283/jfa.2017.30.
Custodero, C., Mankowski, R.T., Lee, S.A., Chen, Z., Wu, S., Manini, T.M., Hincapie Echeverri, J., Sabba, C., Beavers, D.P., Cauley, J.A., Espeland, M.A., Fielding, R.A., Kritchevsky, S.B., Liu, C.K., Mcdermott, M.M., Miller, M.E., Tracy, R.P., Newman, A.B., Ambrosius, W.T., Pahor, M., Anton, S.D. 2018. Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: a systematic review and meta-analysis. Ageing Research Reviews. 46:42-59. https://doi.org/10.1016/j.arr.2018.05.004.