Comprehensive Physiology Wiley Online Library

Physical Exercise in the Oldest Old

Full Article on Wiley Online Library



Abstract

Societies are progressively aging, with the oldest old (i.e., those aged >80–85 years) being the most rapidly expanding population segment. However, advanced aging comes at a price, as it is associated with an increased incidence of the so‐called age‐related conditions, including a greater risk for loss of functional independence. How to combat sarcopenia, frailty, and overall intrinsic capacity decline in the elderly is a major challenge for modern medicine, and exercise appears to be a potential solution. In this article, we first summarize the physiological mechanisms underlying the age‐related deterioration in intrinsic capacity, particularly regarding those phenotypes related to functional decline. The main methods available for the physical assessment of the oldest old are then described, and finally the multisystem benefits that exercise (or “exercise mimetics” in those situations in which volitional exercise is not feasible) can provide to this population segment are reviewed. In summary, lifetime physical exercise can help to attenuate the loss of many of the properties affected by aging, especially when the latter is accompanied by an inactive lifestyle and benefits can also be obtained in frail individuals who start exercising at an advanced age. Multicomponent programs combining mainly aerobic and resistance training should be included in the oldest old, particularly during disuse situations such as hospitalization. However, evidence is still needed to support the effectiveness of passive physical strategies including neuromuscular electrical stimulation or vibration for the prevention of disuse‐induced negative adaptations in those oldest old people who are unable to do physical exercise. © 2019 American Physiological Society. Compr Physiol 9:1281‐1304, 2019.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Expected demographic evolution of the different population segments from 2015 to 2050. Data source: U.S. Census Bureau, 2013; International Data Base.
Figure 2. Figure 2. Hallmarks of aging proposed by López‐Otín et al. 171. Abbreviations: AMPK, AMP‐activated protein kinase; DNA, deoxyribonucleic acid; GH, growth hormone; IGF‐1, insulin‐like growth factor 1; IL, interleukin; miRNA, micro ribonucleic acid; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; NK, natural killer; NLRP3, NOD‐like receptor protein 3; PGC‐1, peroxisome proliferator‐activated receptor gamma coactivator 1; PTMs, posttranslational modifications; ROS, reactive oxygen species; SIRT, sirtuin; Glut 4; glucose transporter type 4; TERT, human telomerase reverse transcriptase; TNF, tumor necrosis factor.
Figure 3. Figure 3. Main physiological changes leading to loss of muscle mass and functional decline in the oldest old. Abbreviations: CRP, C‐reactive protein; FSH, follicle stimulating hormone; GH, growth hormone; IGF‐1, insulin‐like growth factor; IL, interleukin; LH, luteinizing hormone; TFG‐β, transforming growth factor β; TNFα, tumor necrosis factor α.
Figure 4. Figure 4. Algorithm for the diagnosis of sarcopenia and for the quantification of its severity proposed by the European Working Group on Sarcopenia in Older People 70, and available tests for its assessment. SPPB, short physical performance battery.
Figure 5. Figure 5. Overview of the relationship between sarcopenia, frailty, and overall functional decline in the elderly.
Figure 6. Figure 6. Relationship between the risk of functional/physiological decline during aging and the levels of physical activity.
Figure 7. Figure 7. Representative example of the evolution of muscle mass during aging in a very active and a sedentary old man.
Figure 8. Figure 8. Overview of the multisystem exercise benefits in the oldest old.
Figure 9. Figure 9. Benefits of aerobic and resistance exercise in the elderly.
Figure 10. Figure 10. Relationship between muscle protein synthesis (MPS) and breakdown (MPB) in different conditions, and potential factors that influence this relationship.
Figure 11. Figure 11. Physical interventions to prevent disuse‐induced adaptations. Abbreviations: BFR, blood flow restriction; NMES, neuromuscular electrical stimulation; Vo2peak, peak oxygen consumption.


Figure 1. Expected demographic evolution of the different population segments from 2015 to 2050. Data source: U.S. Census Bureau, 2013; International Data Base.


Figure 2. Hallmarks of aging proposed by López‐Otín et al. 171. Abbreviations: AMPK, AMP‐activated protein kinase; DNA, deoxyribonucleic acid; GH, growth hormone; IGF‐1, insulin‐like growth factor 1; IL, interleukin; miRNA, micro ribonucleic acid; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; NK, natural killer; NLRP3, NOD‐like receptor protein 3; PGC‐1, peroxisome proliferator‐activated receptor gamma coactivator 1; PTMs, posttranslational modifications; ROS, reactive oxygen species; SIRT, sirtuin; Glut 4; glucose transporter type 4; TERT, human telomerase reverse transcriptase; TNF, tumor necrosis factor.


Figure 3. Main physiological changes leading to loss of muscle mass and functional decline in the oldest old. Abbreviations: CRP, C‐reactive protein; FSH, follicle stimulating hormone; GH, growth hormone; IGF‐1, insulin‐like growth factor; IL, interleukin; LH, luteinizing hormone; TFG‐β, transforming growth factor β; TNFα, tumor necrosis factor α.


Figure 4. Algorithm for the diagnosis of sarcopenia and for the quantification of its severity proposed by the European Working Group on Sarcopenia in Older People 70, and available tests for its assessment. SPPB, short physical performance battery.


Figure 5. Overview of the relationship between sarcopenia, frailty, and overall functional decline in the elderly.


Figure 6. Relationship between the risk of functional/physiological decline during aging and the levels of physical activity.


Figure 7. Representative example of the evolution of muscle mass during aging in a very active and a sedentary old man.


Figure 8. Overview of the multisystem exercise benefits in the oldest old.


Figure 9. Benefits of aerobic and resistance exercise in the elderly.


Figure 10. Relationship between muscle protein synthesis (MPS) and breakdown (MPB) in different conditions, and potential factors that influence this relationship.


Figure 11. Physical interventions to prevent disuse‐induced adaptations. Abbreviations: BFR, blood flow restriction; NMES, neuromuscular electrical stimulation; Vo2peak, peak oxygen consumption.
References
 1.Aagaard P, Suetta C, Caserotti P, Magnusson SP, Kjær M. Role of the nervous system in sarcopenia and muscle atrophy with aging: Strength training as a countermeasure. Scand J Med Sci Sport 20: 49‐64, 2010.
 2.Aalami O, Fang T, Song H, Nacamuli R. Physiological features of aging persons. Arch Surg 138: 1068‐1076, 2003.
 3.Abe T, Sakamaki M, Fujita S, Ozaki H, Sugaya M, Sato Y, Nakajima T. Effects of low‐intensity walk training with restricted leg blood flow on muscle strength and aerobic capacity in older adults [Online]. J Geriatr Phys Ther 33: 34‐40, 2010.
 4.Abercromby AFJ, Amonette WE, Layne CS, Mcfarlin BK, Hinman MR, Paloski WH. Variation in neuromuscular responses during acute whole‐body vibration exercise. Med Sci Sports Exerc 39: 1642‐1650, 2007.
 5.Abrahamsen B, Bonnevie‐Nielsen V, Ebbesen EN, Gram J, Beck‐Nielsen H. Cytokines and bone loss in a 5‐year longitudinal study hormone replacement therapy suppresses serum soluble interleukin‐6 receptor and increases interleukin‐1‐receptor antagonist: The Danish Osteoporosis Prevention Study. J Bone Miner Res 15: 1545‐1554, 2000.
 6.Akima H, Kubo K, Imai M, Kanehisa H, Suzuki Y, Gunji A, Fukunaga T. Inactivity and muscle: Effect of resistance training during bed rest on muscle size in the lower limb. Acta Physiol Scand 172: 269‐278, 2001.
 7.Akima H, Kubo K, Kanehisa H, Suzuki Y, Gunji A, Fukunaga T. Leg‐press resistance training during 20 days of 6 degrees head‐down‐tilt bed rest prevents muscle deconditioning. Eur J Appl Physiol 82: 30‐38, 2000.
 8.Akima H, Ushiyama JI, Kubo J, Tonosaki SI, Itoh M, Kawakami Y, Fukuoka H, Kanehisa H, Fukunaga T. Resistance training during unweighting maintains muscle size and function in human calf. Med Sci Sports Exerc 35: 655‐662, 2003.
 9.Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi H, Tokimura F, Yoshida H, Suzuki T, Nakamura K, Yoshimura N. Incidence of certified need of care in the long‐term care insurance system and its risk factors in the elderly of Japanese population‐based cohorts: The ROAD study. Geriatr Gerontol 14: 695‐701, 2014.
 10.Artero E, Lee D, Lavie C, España‐Romero V, Church T, Blair S. Effects of muscular strength on cardiovascular risk factors and prognosis. J Cardiopulm Rehabil Prev 32: 351‐358, 2012.
 11.Astrand I, Astrand P, Hallback I, Kilbom A. Reduction in maximal oxygen uptake with age. J Appl Physiol 35: 649‐654, 1973.
 12.Atherton PJ, Babraj J, Smith K, Singh J, Rennie MJ, Wackerhage H. Selective activation of AMPK‐PGC‐1α or PKB‐TSC2‐mTOR signaling can explain specific adaptive responses to endurance or resistance training‐like electrical muscle stimulation. FASEB J 19: 786‐788, 2005.
 13.Atherton PJ, Greenhaff PL, Phillips SM, Bodine SC, Adams CM, Lang CH. Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence. Am J Physiol Endocrinol Metab 311: E594‐E604, 2016.
 14.Atherton PJ, Smith K. Muscle protein synthesis in response to nutrition and exercise. J Physiol 590: 1049‐1057, 2012.
 15.Bachmann S, Finger C, Huss A, Egger M, Stuck AE, Clough‐Gorr KM. Inpatient rehabilitation specifically designed for geriatric patients: Systematic review and meta‐analysis of randomised controlled trials. BMJ 340: 1230, 2010.
 16.Bahat G, Ilhan B. Sarcopenia and the cardiometabolic syndrome: A narrative review. Eur Geriatr Med 7: 220‐223, 2016.
 17.Bautmans I, Van Hees E, Lemper JC, Mets T. The feasibility of whole body vibration in institutionalised elderly persons and its influence on muscle performance, balance and mobility: A randomised controlled trial. BMC Geriatr 5: 1‐8, 2005.
 18.Bean JF, Kiely DK, LaRose S, Alian J, Frontera WR. Is stair climb power a clinically relevant measure of leg power impairments in at‐risk older adults? Arch Phys Med Rehabil 88: 604‐609, 2007.
 19.Beard JR, Officer A, De Carvalho IA, Sadana R, Pot AM, Michel JP, Lloyd‐Sherlock P, Epping‐Jordan JE, Peeters GMEE, Mahanani WR, Thiyagarajan JA, Chatterji S. The World report on ageing and health: A policy framework for healthy ageing. Lancet 387: 2145‐2154, 2016.
 20.Beaudart C, McCloskey E, Bruyère O, Cesari M, Rolland Y, Rizzoli R, Araujo de Carvalho I, Amuthavalli Thiyagarajan J, Bautmans I, Bertière MC, Brandi ML, Al‐Daghri NM, Burlet N, Cavalier E, Cerreta F, Cherubini A, Fielding R, Gielen E, Landi F, Petermans J, Reginster JY, Visser M, Kanis J, Cooper C. Sarcopenia in daily practice: assessment and management. BMC Geriatr 16: 1‐10, 2016.
 21.Belavý DL, Beller G, Armbrecht G, Perschel FH, Fitzner R, Bock O, Börst H, Degner C, Gast U, Felsenberg D. Evidence for an additional effect of whole‐body vibration above resistive exercise alone in preventing bone loss during prolonged bed rest. Osteoporos Int 22: 1581‐1591, 2011.
 22.Bell KE, von Allmen MT, Devries MC, Phillips SM. Muscle disuse as a pivotal problem in sarcopenia‐related muscle loss and dysfunction. J Frailty Aging 5: 33‐41, 2016.
 23.Bergland A, Jørgensen L, Emaus N, Strand BH. Mobility as a predictor of all‐cause mortality in older men and women: 11.8 year follow‐up in the Tromsø study. BMC Health Serv Res 17: 1‐7, 2017.
 24.Bickel CS, Cross JM, Bamman M. Exercise dosing to retain resistance training adaptations in young and older adults. Med Sci Sports Exerc 43: 1177‐1188, 2011.
 25.Biensø RS, Ringholm S, Kiilerich K, Aachmann‐Andersen NJ, Krogh‐Madsen R, Guerra B, Plomgaard P, Van Hall G, Treebak JT, Saltin B, Lundby C, Calbet JAL, Pilegaard H, Wojtaszewski JFP. GLUT4 and glycogen synthase are key players in bed rest‐induced insulin resistance. Diabetes 61: 1090‐1099, 2012.
 26.Bischoff‐Ferrari HA, Orav JE, Kanis JA, Rizzoli R, Schlögl M, Staehelin HB, Willett WC, Dawson‐Hughes B. Comparative performance of current definitions of sarcopenia against the prospective incidence of falls among community‐dwelling seniors age 65 and older. Osteoporos Int 26: 2793‐2802, 2015.
 27.Bleeker MWP, de Groot PCE, Pawelczyk JA, Hopman MTE, Levine BD. Effects of 18 days of bed rest on leg and arm venous properties. J Appl Physiol 96: 840‐847, 2004.
 28.Blickenstorfer A, Kleiser R, Keller T, Keisker B, Meyer M, Riener R, Kollias S. Cortical and subcortical correlates of functional electrical stimulation of wrist extensor and flexor muscles revealed by fMRI. Hum Brain Mapp 30: 963‐975, 2009.
 29.Bo H, Jiang N, Ji LL, Zhang Y. Mitochondrial redox metabolism in aging: Effect of exercise interventions. J Sport Health Sci 2: 67‐74, 2013.
 30.Bodine S. Disuse‐induced muscle wasting. Int J Biochem Cell Biol 45: 2200‐2208, 2013.
 31.Bone AE, Hepgul N, Kon S, Maddocks M. Sarcopenia and frailty in chronic respiratory disease: Lessons from gerontology. Chron Respir Dis 14: 85‐99, 2017.
 32.Boyd C, Landefeld C, Counsell S, Palmer R, Fortinsky R, Kresevic D, Burant C, Covinsky K. Recovery in activities of daily living among older adults following hospitalization for acute medical illness. J Am Geriatr Soc 56: 2171‐2179, 2008.
 33.Breen L, Stokes KA, Churchward‐Venne TA, Moore DR, Baker SK, Smith K, Atherton PJ, Phillips SM. Two weeks of reduced activity decreases leg lean mass and induces “anabolic resistance” of myofibrillar protein synthesis in healthy elderly. J Clin Endocrinol Metab 98: 2604‐2612, 2013.
 34.Brooks NE, Schuenke MD, Hikida RS. Ageing influences myonuclear domain size differently in fast and slow skeletal muscle of rats. Acta Physiol 197: 55‐63, 2009.
 35.Brown BM, Peiffer JJ, Taddei K, Lui JK, Laws SM, Gupta VB, Taddei T, Ward VK, Rodrigues MA, Burnham S, Rainey‐Smith SR, Villemagne VL, Bush A, Ellis KA, Masters CL, Ames D, MacAulay SL, Szoeke C, Rowe CC, Martins RN. Physical activity and amyloid‐β plasma and brain levels: Results from the Australian imaging, biomarkers and lifestyle study of ageing. Mol Psychiat. 18: 875‐881, 2013.
 36.Brown CJ, Foley KT, Lowman JD, MacLennan PA, Razjouyan J, Najafi B, Locher J, Allman RM. Comparison of posthospitalization function and community mobility in hospital mobility program and usual care patients a randomized clinical trial. JAMA Intern Med 176: 921‐927, 2016.
 37.Brown CJ, Redden DT, Flood KL, Allman RM. The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc 57: 1660‐1665, 2009.
 38.Bruusgaard JC. Distribution of myonuclei and microtubules in live muscle fibers of young, middle‐aged, and old mice. J Appl Physiol 100: 2024‐2030, 2006.
 39.Bruusgaard JC, Gundersen K. In vivo time‐lapse microscopy reveals no loss of murine myonuclei during weeks of muscle atrophy. J Clin Invest 118: 1450‐1457, 2008.
 40.Bruyère O, Beaudart C, Reginster JY, Buckinx F, Schoene D, Hirani V, Cooper C, Kanis JA, Rizzoli R, McCloskey E, Cederholm T, Cruz‐Jentoft A, Freiberger E. Assessment of muscle mass, muscle strength and physical performance in clinical practice: An international survey. Eur Geriatr Med 7: 243‐246, 2016.
 41.Burd NA, Gorissen SH, Van Loon LJC. Anabolic resistance of muscle protein synthesis with aging. Exerc Sport Sci Rev 41: 169‐173, 2013.
 42.Butcher LR, Thomas A, Backx K, Roberts A, Webb R, Morris K. Low‐intensity exercise exerts beneficial effects on plasma lipids via pparγ. Med Sci Sports Exerc 40: 1263‐1270, 2008.
 43.Cadore EL, Casas‐Herrero A, Zambom‐Ferraresi F, Idoate F, Millor N, Gómez M, Rodriguez‐Mañas L, Izquierdo M. Multicomponent exercises including muscle power training enhance muscle mass, power output, and functional outcomes in institutionalized frail nonagenarians. Age (Omaha) 36: 773‐785, 2014.
 44.Cadore EL, Moneo ABB, Mensat MM, Muñoz AR, Casas‐Herrero A, Rodriguez‐Mañas L, Izquierdo M. Positive effects of resistance training in frail elderly patients with dementia after long‐term physical restraint. Age (Omaha) 36: 801‐811, 2014.
 45.Callen BL, Mahoney JE, Grieves CB, Wells TJ, Enloe M. Frequency of hallway ambulation by hospitalized older adults on medical units of an academic hospital. Geriatr Nurs (Minneap) 25: 212‐217, 2004.
 46.Canepari M, Pellegrino MA, D'Antona G, Bottinelli R. Single muscle fiber properties in aging and disuse. Scand J Med Sci Sport 20: 10‐19, 2010.
 47.Cannon RO. Role of nitric oxide in cardiovascular disease: Focus on the endothelium [Online]. Clin Chem 44: 1809‐1819, 1998. http://clinchem.aaccjnls.org/content/clinchem/44/8/1809.full.pdf
 48.Capelli C, Antonutto G, Kenfack MA, Cautero M, Lador F, Moia C, Tam E, Ferretti G. Factors determining the time course of V̇O2max decay during bedrest: Implications for V̇O2max limitation. Eur J Appl Physiol 98: 152‐160, 2006.
 49.Cardinale M, Soiza RL, Leiper JB, Gibson A, Primrose WR. Hormonal responses to a single session of wholebody vibration exercise in older individuals. Br J Sports Med 44: 284‐288, 2010.
 50.Cartee GD, Hepple RT, Bamman MM, Zierath JR. Exercise promotes healthy aging of skeletal muscle. Cell Metab 23: 1034‐1047, 2016.
 51.Celis‐Morales CA, Welsh P, Lyall DM, Steell L, Petermann F, Anderson J, Iliodromiti S, Sillars A, Graham N, MacKay DF, Pell JP, Gill JMR, Sattar N, Gray SR. Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all cause mortality: Prospective cohort study of half a million UK Biobank participants. BMJ 361: 1‐10, 2018.
 52.Cesari M, Kritchevsky SB, Newman AB, Eleanor M, Harris TB, Penninx BW, Brach JS, Tylavsky FA, Satterfield S, Bauer D, Rubin S, Visser M, Pahor M. Added value of physical performance measures in predicting adverse health‐related events: Results from the health, aging, and body composition study. J Am Geriatr Soc 57: 251‐259, 2009.
 53.Chang KV, Hsu TH, Wu WT, Huang KC, Han DS. Association between sarcopenia and cognitive impairment: A systematic review and meta‐analysis. J Am Med Dir Assoc 17: 1164.e7‐1164.e15, 2016.
 54.Cheang WS, Tian XY, Wong WT, Huang Y. The peroxisome proliferator-activated receptors in cardiovascular diseases: Experimental benefits and clinical challenges. Br J Pharmacol 172: 5512‐5522, 2015.
 55.Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV. Mitochondrial aging and age‐related dysfunction of mitochondria. Biomed Res Int 2014, 2014.
 56.Cho S‐I, An D‐H. Effects of a fall prevention exercise program on muscle strength and balance of the old–old elderly. J Phys Ther Sci 26: 1771‐1774, 2014.
 57.Chodzko‐Zajko W, Proctor D, Singh M, Minson C, Nigg C, Salem G, Skinner J. Exercise and physical activity for older adults. Med Sci Sports Exerc 11: 1510‐1530, 2009.
 58.Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model. Science (80‐) 361: eaan8821, 2018.
 59.Chou CH, Hwang CL, Wu YT. Effect of exercise on physical function, daily living activities, and quality of life in the frail older adults: A meta‐analysis. Arch Phys Med Rehabil 93: 237‐244, 2012.
 60.Clegg A, Young J, Iliffe S, Olde Rikkert M, Rockwood K. Frailty in elderly people. Lancet 381: 752‐762, 2013.
 61.Coelho FGDM, Vital TM, Stein AM, Arantes FJ, Rueda AV, Camarini R, Teodorov E, Santos‐Galduróz RF. Acute aerobic exercise increases brain‐derived neurotrophic factor levels in elderly with Alzheimer's disease. J Alzheimers Dis 39: 401‐408, 2014.
 62.Coker RH, Hays NP, Williams RH, Wolfe RR, Evans WJ. Bed rest promotes reductions in walking speed, functional parameters, and aerobic fitness in older, healthy adults. Journals Gerontol—Ser A Biol Sci Med Sci 70: 91‐96, 2015.
 63.Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence of frailty in community‐dwelling older persons: A systematic review. J Am Geriatr Soc 60: 1487‐1492, 2012.
 64.Cook SB, Brown KA, DeRuisseau K, Kanaley JA, Ploutz‐Snyder LL. Skeletal muscle adaptations following blood flow‐restricted training during 30 days of muscular unloading. J Appl Physiol 109: 341‐349, 2010.
 65.Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev 14: 20‐39, 1993.
 66.Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: Key roles of growth factor cascades and inflammation. Trends Neurosci 30: 464‐472, 2007.
 67.Coudert J, Van Praagh E. Endurance exercise training in the elderly: Effects on cardiovascular function. Curr Opin Clin Nutr Metab Care 3: 479‐483, 2000.
 68.Covinsky KE, Palmer RM, Fortinsky RH, Counsell SR, Stewart AL, Kresevic D. Loss of independence in activities of daily living in older adults hospitalized with medical illnesses: Increased vulnerability with age. J Am Geriatr Soc 51: 451‐458, 2003.
 69.Covinsky KE, Pierluissi E, Story THEPS. Hospitalization‐associated disability “she was probably able to ambulate, but I'm not sure”. JAMA 306: 1782‐1793, 2011.
 70.Cruz‐Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M, Bautmans I, Baeyens J‐P, Cesari M, Cherubini A, Kanis J, Maggio M, Martin F, Michel J‐P, Pitkala K, Reginster J‐Y, Rizzoli R, Sánchez‐Rodríguez D, Schols J. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 1‐16, 48: 16‐31, 2019.
 71.Cuthbertson D. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 19: 422‐424, 2005.
 72.Dalle S, Rossmeislova L, Koppo K. The role of inflammation in age‐related sarcopenia. Front Physiol 8: 1045, 2017.
 73.Damas F, Phillips S, Vechin FC, Ugrinowitsch C. A review of resistance training‐induced changes in skeletal muscle protein synthesis and their contribution to hypertrophy. Sports Med 45: 801‐807, 2015.
 74.Daskalopoulou C, Stubbs B, Kralj C, Koukounari A, Prince M, Prina AM. Physical activity and healthy ageing: A systematic review and meta‐analysis of longitudinal cohort studies. Ageing Res Rev 38: 6‐17, 2017.
 75.Dayhoff‐Brannigan M, Ferrucci L, Sun K, Fried LP, Walston J, Varadhan R, Guralnik JM, Semba RD. Oxidative protein damage is associated with elevated serum interleukin‐6 levels among older moderately to severely disabled women living in the community. Journals Gerontol—Ser A Biol Sci Med Sci 63: 179‐183, 2008.
 76.Delezie J, Handschin C. Endocrine crosstalk between skeletal muscle and the brain. Front Neurol 9, 2018.
 77.Deschenes MR. Effects of aging on muscle fibre type and size. Sports Med 34: 809‐824, 2004.
 78.Després JP. Body fat distribution and risk of cardiovascular disease: An update. Circulation 126: 1301‐1313, 2012.
 79.Dirks ML, Wall BT, Nilwik R, Weerts DHJM, Verdijk LB, van Loon LJC. Skeletal muscle disuse atrophy is not attenuated by dietary protein supplementation in healthy older men. J Nutr 144: 1196‐1203, 2014.
 80.Dirks ML, Wall BT, Snijders T, Ottenbros CLP, Verdijk LB, Van Loon LJC. Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans. Acta Physiol 210: 628‐641, 2014.
 81.Dirks ML, Wall BT, Van De Valk B, Holloway TM, Holloway GP, Chabowski A, Goossens GH, Van Loon LJ. One week of bed rest leads to substantial muscle atrophy and induces whole‐body insulin resistance in the absence of skeletal muscle lipid accumulation. Diabetes 65: 2862‐2875, 2016.
 82.Dodds RM, Granic A, Davies K, Kirkwood TBL, Jagger C, Sayer AA. Prevalence and incidence of sarcopenia in the very old: Findings from the Newcastle 85+ Study. J Cachexia Sarcopenia Muscle 8: 229‐237, 2017.
 83.Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17, 2018.
 84.Duvoisin MR, Convertino VA, Buchanan P, Gollnick PD, Dudley GA. Characteristics and preliminary observations of the influence of electromyostimulation on the size and function of human skeletal muscle during 30 days of simulated microgravity. Aviat Sp Env Med 60: 671‐678, 1989.
 85.Ehlenbach WJ, Crane PK, Haneuse SJPA, Carson SS, Curtis JR, Larson EB. Association between acute care and critical illness hospitalization. JAMA 303: 763‐770, 2010.
 86.Ehsani AA, Ogawa T, Miller TR, Spina RJ, Jilka SM. Exercise training improves left ventricular systolic function in older men. Circulation 83: 96‐103, 1991.
 87.Falempin M, In‐Albon SF. Influence of brief daily tendon vibration on rat soleus muscle in non‐weight‐bearing situation [Online]. J Appl Physiol 87: 3‐9, 1999. http://www.ncbi.nlm.nih.gov/pubmed/10409551
 88.Fan H, Li X, Zheng L, Chen X, Lan Q, Wu H, Ding X, Qian D, Shen Y, Yu Z, Fan L, Chen M, Tomlinson B, Chan P, Zhang Y, Liu Z. Abdominal obesity is strongly associated with cardiovascular disease and its risk factors in elderly and very elderly community‐dwelling Chinese. Sci Rep 6: 1‐9, 2016.
 89.Feder ME, Hofmann GE. Heat‐shock proteins, molecular chaperones, and the stress response: Evolutionary and ecological physiology. Annu Rev Physiol 61: 243‐282, 1999.
 90.Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, Kinlay JBMC. Age trends in the level of serum testosterone and other hormones in middle‐aged men: Longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87: 589‐598, 2002.
 91.Ferri A, Scaglioni G, Pousson M, Capodaglio P, Van Hoecke J, Narici MV. Strength and power changes of the human plantar flexors and knee extensors in response to resistance training in old age. Acta Physiol Scand 177: 69‐78, 2003.
 92.Firth J, Stubbs B, Vancampfort D, Schuch F, Lagopoulos J, Rosenbaum S, Ward PB. Effect of aerobic exercise on hippocampal volume in humans: A systematic review and meta‐analysis. Neuroimage 166: 230‐238, 2018.
 93.Fisher S, Ottenbacher KJ, Goodwin JS, Graham JE, Ostir GV. Short physical performance battery in hospitalized older adults. Aging Clin Exp Res 21: 445‐452, 2009.
 94.Fiuza‐Luces C, Santos‐Lozano A, Joyner M, Carrera‐Bastos P, Picazo O, Zugaza J, Izquierdo M, Ruilope L, Lucia A. Exercise benefits in cardiovascular disease: Beyond attenuating traditional risk factors. Nat Rev Cardiol 15: 731‐743, 2018.
 95.Flach A, Jaegers L, Krieger M, Bixler E, Kelly P, Weiss EP, Ahmad SO. Endurance exercise improves function in individuals with Parkinson's disease: A meta‐analysis. Neurosci Lett 659: 115‐119, 2017.
 96.Fortinsky RH, Covinsky KE, Palmer RM, Landefeld CS. Effects of functional status changes before and during hospitalization on nursing home admission of older adults. J Gerontol – Ser A Biol Sci Med Sci 54: 521‐526, 1999.
 97.Francis P, Toomey C, Mc Cormack W, Lyons M, Jakeman P. Measurement of maximal isometric torque and muscle quality of the knee extensors and flexors in healthy 50‐ to 70‐year‐old women. Clin Physiol Funct Imag 37: 448‐455, 2017.
 98.Francis S, Lin X, Aboushoushah S, White TP, Phillips M, Bowtell R, Constantinescu CS. fMRI analysis of active, passive and electrically stimulated ankle dorsiflexion. Neuroimage 44: 469‐479, 2009.
 99.Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA. Frailty in older adults: Evidence for a phenotype. Journals Gerontol Ser A Biol Sci Med Sci 56: M146‐M157, 2001.
 100.Fry CS, Glynn EL, Drummond MJ, Timmerman KL, Fujita S, Abe T, Dhanani S, Volpi E, Rasmussen BB. Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men. J Appl Physiol 108: 1199‐1209, 2010.
 101.Fujita S, Abe T, Drummond MJ, Cadenas JG, Dreyer HC, Sato Y, Volpi E, Rasmussen BB. Blood flow restriction during low‐intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis. J Appl Physiol 103: 903‐910, 2007.
 102.Gale CR, Cooper C, Sayer AA. Prevalence of frailty and disability: findings from the English Longitudinal Study of Ageing. Age Ageing 44: 162‐165, 2015.
 103.García‐Hermoso A, Cavero‐Redondo I, Ramírez‐Vélez R, Ruiz JR, Ortega FB, Lee DC, Martínez‐Vizcaíno V. Muscular strength as a predictor of all‐cause mortality in an apparently healthy population: A systematic review and meta‐analysis of data from approximately 2 million men and women. Arch Phys Med Rehabil 99: 2100‐, 2018.
 104.Gavin TP, Ruster RS, Carrithers JA, Zwetsloot KA, Kraus RM, Evans CA, Knapp DJ, Drew JL, McCartney JS, Garry JP, Hickner RC, No difference in the skeletal muscle angiogenic response to aerobic exercise training between young and aged men. J Physiol 585: 231‐239, 2007.
 105.Gill JF, Santos G, Schnyder S, Handschin C. PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice. Aging Cell 17: 1‐13, 2018.
 106.Gill TM, Allore HG, Gahbauer E, Murphy T. Change in disability after hospitalization or restricted activity in older persons. JAMA 304: 1919‐1928, 2010.
 107.Gill TM, Allore HG, Holford TR, Guo Z. Hospitalization, restricted activity, and the development of disability among older persons. JAMA 292: 2115‐2124, 2004.
 108.Giné‐Garriga M, Roqué‐Fíguls M, Coll‐Planas L, Sitjà‐Rabert M, Salvà A. Physical exercise interventions for improving performance‐based measures of physical function in community‐dwelling, frail older adults: A systematic review and meta‐analysis. Arch Phys Med Rehabil 95, 2014.
 109.Gonzalez MC, Barbosa‐Silva TG, Heymsfield SB. Bioelectrical impedance analysis in the assessment of sarcopenia. Curr Opin Clin Nutr Metab Care 21: 1, 2018.
 110.Gonzalez MC, Heymsfield SB. Bioelectrical impedance analysis for diagnosing sarcopenia and cachexia: What are we really estimating? J Cachexia Sarcopenia Muscle 8: 187‐189, 2017.
 111.Greenhaff PL, Karagounis LG, Peirce N, Simpson EJ, Hazell M, Layfield R, Wackerhage H, Smith K, Atherton P, Selby A, Rennie MJ. Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab 295: E595‐E604, 2008.
 112.Gries KJ, Raue U, Perkins RK, Lavin KM, Overstreet BS, D'Acquisto LJ, Graham B, Finch WH, Kaminsky LA, Trappe TA, Trappe S. Cardiovascular and skeletal muscle health with lifelong exercise. J Appl Physiol 125: 1636‐1645, 2018.
 113.Groen B, Hamer HM, Snijders T, van Kranenburg J, Frijns D, Vink H, van Loon LJC. Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes. J Appl Physiol 116: 998‐1005, 2014.
 114.Groot C, Hooghiemstra AM, Raijmakers PGHM, van Berckel BNM, Scheltens P, Scherder EJA, van der Flier WM, Ossenkoppele R. The effect of physical activity on cognitive function in patients with dementia: A meta‐analysis of randomized control trials. Ageing Res Rev 25: 13‐23, 2016.
 115.Guerreiro AC, Tonelli AC, Orzechowski R, Dalla Corte RR, Moriguchi EH, de Mello RB. Bedside ultrasound of quadriceps to predict rehospitalization and functional decline in hospitalized elders. Front Med 4, 2017.
 116.Gundersen K, Bruusgaard JC. Nuclear domains during muscle atrophy: Nuclei lost or paradigm lost? J Physiol 586: 2675‐2681, 2008.
 117.Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, Scherr PA, Wallace RB. A short physical performance battery assessing lower extremity function: Assocation with self‐reported disability and prediction of mortality and nursing home admission. J Gerontol Med Sci 49: M85‐M94, 1994.
 118.Gusi N, Raimundo A, Leal A. Low‐frequency vibratory exercise reduces the risk of bone fracture more than walking: A randomized controlled trial. BMC Musculoskelet Disord 7: 1‐8, 2006.
 119.von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: Facts and numbers on prevalence and clinical impact. J Cachexia Sarcopenia Muscle 1: 129‐133, 2010.
 120.Hall ZW, Ralston E. Nuclear domains in muscle cells. Cell 59: 771‐772, 1989.
 121.Hameed M, Harridge SDR, Goldspink G. Sarcopenia and hypertrophy: A role for insulin‐like growth factor‐1 in aged muscle? Exerc Sport Sci Rev 30: 15‐19, 2002.
 122.Hartigan I. A comparative review of the Katz ADL and the Barthel Index in assessing the activities of daily living of older people. Int J Older People Nurs 2: 204‐212, 2007.
 123.He W, Goodkind D, Kowal P. U.S. Census Bureau, International Population Reports. Washington, DC: U.S. Government Publishing Office, 2016.
 124.Hennessy S, Kurichi JE, Pan Q, Streim JE, Bogner HR, Xie D, Stineman MG. Disability stage is an independent risk factor for mortality in medicare beneficiaries aged 65 years and older. PM R 7: 1215‐1225, 2015.
 125.Howard C, Ferrucci L, Sun K, Freied L, Walston J, Varadhan R, Guralnik JM, Semba RD. Oxidative protein damage is associated with poor grip strength among older women living in the community. J Appl Physiol 103: 17‐20, 2007.
 126.Huang T, Larsen KT, Ried‐Larsen M, Møller NC, Andersen LB. The effects of physical activity and exercise on brain‐derived neurotrophic factor in healthy humans: A review. Scand J Med Sci Sport 24: 1‐10, 2014.
 127.Hughes L, Paton B, Rosenblatt B, Gissane C, Patterson SD. Blood flow restriction training in clinical musculoskeletal rehabilitation: A systematic review and meta‐analysis. Br J Sports Med 51: 1003‐1011, 2017.
 128.Hunter GR, Treuth MS, Weinsier RL, Kekes‐Szabo T, Kell SH, Roth DL, Nicholson C. The effects of strength conditioning on older women's ability to perform daily tasks. J Am Geriatr Soc 43: 756‐760, 1995.
 129.Iida H, Nakajima T, Kurano M, Yasuda T, Sakamaki M, Sato Y, Yamasoba T, Abe T. Effects of walking with blood flow restriction on limb venous compliance in elderly subjects. Clin Physiol Funct Imaging 31: 472‐476, 2011.
 130.Inagaki Y, Madarame H, Neya M, Ishii N. Increase in serum growth hormone induced by electrical stimulation of muscle combined with blood flow restriction. Eur J Appl Physiol 111: 2715‐2721, 2011.
 131.Inouye SK, Peduzzi PN, Robison JT, Hughes JS, Horwitz RI, Concato J. Importance of functional measures in predicting mortality among older hospitalized patients. JAMA 279: 1187‐1198, 1998.
 132.Irrcher I, Adhihetty PJ, Joseph AM, Ljubicic V, Hood DA. Regulation of mitochondrial biogenesis in muscle by endurance exercise. Sports Med 33: 783‐793, 2003.
 133.Izquierdo M, Ibañez J, Häkkinen K, Kraemer WJ, Larrión JL, Gorostiaga EM. Once weekly combined resistance and cardiovascular training in healthy older men. Med Sci Sports Exerc 36: 435‐443, 2004.
 134.Jones DM, Song X, Rockwood K. Operationalizing a frailty index from a standardized comprehensive geriatric assessment. J Am Geriatr Soc 52: 1929‐1933, 2004.
 135.Jones S, Man William DC, Gao W, Higginson Irene J, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev 10: CD009419, 2016.
 136.Kadi F, Charifi N, Denis C, Lexell J. Satellite cells and myonuclei in young and elderly women and men. Muscle Nerve 29: 120‐127, 2004.
 137.Kamel HK, Maas D, Duthie EH. Role of hormones in the pathogenesis and management of sarcopenia. Drugs Aging 19: 865‐877, 2002.
 138.Kan GAVAN, Rolland Y, Andrieu S, Bauer J, Beauchet O, Bonnefoy M, Cesari M, Donini LM, Inzitari M, Nourhashemi F, Onder G, Ritz P, Salva A, Visser M, Vellas B. Gait speed at usual pace as a predictor of adverse outcomes in community‐dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 13: 881‐889, 2009.
 139.Kang C, Ji LL. Role of PGC‐1α in muscle function and aging. J Sport Health Sci 2: 81‐86, 2013.
 140.Katz S, Ford A, Moskowitz R, Jackson B, Jaffe M. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychological function. JAMA 185: 914‐918, 1963.
 141.Kawakami Y, Akima H, Kubo K, Muraoka Y, Hasegawa H, Kouzaki M, Imai M, Suzuki Y, Gunji A, Kanehisa H, Fukunaga T. Changes in muscle size, architecture, and neural activation after 20 days of bed rest with and without resistance exercise. Eur J Appl Physiol 84: 7‐12, 2001.
 142.Kelijman M. Age‐related alterations of the growth hormone/insulin‐like‐growth‐factor I axis. J Am Geriatr Soc 39: 295‐307, 1991.
 143.Kent‐Braun JA, Ng AV, Young K. Skeletal muscle contractile and noncontractile components in young and older women and men. J Appl Physiol 88: 662‐668, 2000.
 144.Kern H, Barberi L, Löfler S, Sbardella S, Burggraf S, Fruhmann H, Carraro U, Mosole S, Sarabon N, Vogelauer M, Mayer W, Krenn M, Cvecka J, Romanello V, Pietrangelo L, Protasi F, Sandri M, Zampieri S, Musaro A. Electrical stimulation (ES) counteracts muscle decline in seniors. Front Aging Neurosci 6: 1‐11, 2014.
 145.Kido A, Tanaka N, Stein RB. Spinal excitation and inhibition decrease as humans age. Can J Physiol Pharmacol 82: 238‐248, 2004.
 146.Klass M, Baudry S, Duchateau J. Voluntary activation during maximal contraction with advancing age: A brief review. Eur J Appl Physiol 100: 543‐551, 2007.
 147.Knudson R, Lebowitz M, Holberg C, Burrows B. Changes in the normal maximal expiratory flow‐volume curve with growth and aging. Am Rev Respir Dis 127: 725‐734, 1983.
 148.Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, Yamada N, Sone H, Satoru Kodama MD, PhD Kazumi Saito MD, PhD Shiro Tanaka, PhD Miho Maki, MS Yoko Yachi, RD, MS Mihoko Asumi, MS Ayumi Sugawara, RD Kumiko Totsuka, RD Hitoshi Shimano, MD, PhD Yasuo Ohashi, PhD Nobuhiro Yamada, MD, PhD Hirohito Sone MD P. Cardiorespiratory fitness as a quantitative predictor of all‐cause mortality and cardiovascular events. JAMA 301: 2024‐2035, 2009.
 149.Koh JM, Khang YH, Jung CH, Bae S, Kim DJ, Chung YE, Kim GS. Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre‐ and postmenopausal women: Evidence for a link between systemic inflammation and osteoporosis. Osteoporos Int 16: 1263‐1271, 2005.
 150.Kubicki A. Functional assessment in older adults: Should we use timed up and go or gait speed test? Neurosci Lett 577: 89‐94, 2014.
 151.Kubo K, Kanehisa H, Azuma K, Ishizu M, Kuno S, Okada M, Funugaka T. Muscle architectural characteristics in women aged 20–79 years. Med Sci Sports Exerc 35: 39‐44, 2003.
 152.Kubo K, Kanehisa H, Azuma K, Ishizu M, Kuno SY, Okada M, Fukunaga T. Muscle architectural characteristics in young and elderly men and women. Int J Sports Med 24: 125‐130, 2003.
 153.Kumar V, Selby A, Rankin D, Patel R, Atherton P, Hildebrandt W, Williams J, Smith K, Seynnes O, Hiscock N, Rennie MJ. Age‐related differences in the dose‐response relationship of muscle protein synthesis to resistance exercise in young and old men. J Physiol 587: 211‐217, 2009.
 154.Lamberts S, van den Beld A, van der Lely A. The endocrinology of aging. Science (80‐) 278: 419‐424, 1997.
 155.Landi F, Cruz‐Jentoft AJ, Liperoti R, Russo A, Giovannini S, Tosato M, Capoluongo E, Bernabei R, Onder G. Sarcopenia and mortality risk in frail older persons aged 80 years and older: Results from iLSIRENTE study. Age Ageing 42: 203‐209, 2013.
 156.Landi F, Onder G, Russo A, Liperoti R, Tosato M, Martone AM, Capoluongo E, Bernabei R. Calf circumference, frailty and physical performance among older adults living in the community. Clin Nutr 33: 539‐544, 2014.
 157.Larsson L, Degens H, Li M, Salviati L, Lee Y il, Thompson W, Kirkland JL, Sandri M. Sarcopenia. Aging‐related loss of muscle mass and function. Physiol Rev 99: 427‐511, 2019.
 158.Lau RWK, Liao LR, Yu F, Teo T, Chung RCK, Pang MYC. The effects of whole body vibration therapy on bone mineral density and leg muscle strength in older adults: A systematic review and meta‐analysis. Clin Rehabil 25: 975‐988, 2011.
 159.Lavin KM, Roberts BM, Fry CS, Moro T, Rasmussen BB, Bamman MM. The importance of resistance exercise training to combat neuromuscular aging. Physiology 34: 112‐122, 2019.
 160.Lawton M, Brody E. Assessment of older people: Selfmaintaining and instrumental activities of daily living. Gerontologist 9: 179‐186, 1969. Gerontologist 9: 1979–1986, 1969.
 161.Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer's disease. Arch Pharm Res 33: 1539‐1556, 2010.
 162.Legrand D, Vaes B, Matheï C, Swine C, Degryse JM. The prevalence of sarcopenia in very old individuals according to the european consensus definition: Insights from the belfrail study. Age Ageing 42: 727‐734, 2013.
 163.Leong DP, Teo KK, Rangarajan S, Lopez‐Jaramillo P, Avezum A, Orlandini A, Seron P, Ahmed SH, Rosengren A, Kelishadi R, Rahman O, Swaminathan S, Iqbal R, Gupta R, Lear SA, Oguz A, Yusoff K, Zatonska K, Chifamba J, Igumbor E, Mohan V, Anjana RM, Gu H, Li W, Yusuf S. Prognostic value of grip strength: Findings from the Prospective Urban Rural Epidemiology (PURE) study. Lancet 386: 266‐273, 2015.
 164.Levy WC, Cerqueira MD, Abrass IB, Schwartz RS, Stratton JR. Endurance exercise training augments diastolic filling at rest and during exercise in healthy young and older men. Circulation 88: 116‐126, 1993.
 165.Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, Head D. Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Ann Neurol 68: 311‐318, 2010.
 166.Ling CHY, Taekema D, De Craen AJM, Gussekloo J, Westendorp RGJ, Maier AB. Handgrip strength and mortality in the oldest old population: The Leiden 85‐plus study. Cmaj 182: 429‐435, 2010.
 167.Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 60: 1‐4, 2013.
 168.Lloyd‐Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O'Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel‐Smoller S, Wong N, Wylie‐Rosett J, Hong Y. Heart disease and stroke statistics—2009 update. Circulation 119: 2009.
 169.Loenneke JP, Wilson JM, Marín PJ, Zourdos MC, Bemben MG. Low intensity blood flow restriction training: A meta‐analysis. Eur J Appl Physiol 112: 1849‐1859, 2012.
 170.López‐Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell 153: 1194‐1217, 2013.
 171.Lopez P, Pinto RS, Radaelli R, Rech A, Grazioli R, Izquierdo M, Cadore EL. Benefits of resistance training in physically frail elderly: a systematic review. Aging Clin Exp Res 30: 889‐899, 2018.
 172.Lowery EM, Brubaker AL, Kuhlmann E, Kovacs EJ. The aging lung. Clin Interv Aging 8: 1489‐1496, 2013.
 173.Lucca U, Tettamanti M, Logroscino G, Tiraboschi P, Landi C, Sacco L, Garrì M, Ammesso S, Bertinotti C, Biotti A, Gargantini E, Piedicorcia A, Nobili A, Pasina L, Franchi C, Djade CD, Riva E, Recchia A. Prevalence of dementia in the oldest old: The Monzino 80‐plus population based study. Alzheimers Dement 11: 258‐270.e3, 2015.
 174.Lye M, Donnellan C. Heart disease in the elderly [Online]. Heart 84: 560‐566, 2000. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1017783/
 175.Ma C, Liu A, Sun M, Zhu H, Wu H. Effect of whole‐body vibration on reduction of bone loss and fall prevention in postmenopausal women: A meta‐analysis and systematic review. J Orthop Surg Res 11: 1‐10, 2016.
 176.Maffiuletti NA, Gondin J, Place N, Stevens‐Lapsley J, Vivodtzev I, Minetto MA. Clinical use of neuromuscular electrical stimulation for neuromuscular rehabilitation: What are we overlooking? Arch Phys Med Rehabil 99: 806‐812, 2018.
 177.Maffiuletti NA, Roig M, Karatzanos E, Nanas S. Neuromuscular electrical stimulation for preventing skeletal‐muscle weakness and wasting in critically ill patients: A systematic review. BMC Med 111, 2013.
 178.Maggioni MA, Cè E, Rampichini S, Ferrario M, Giordano G, Veicsteinas A, Merati G. Electrical stimulation versus kinesitherapy in improving functional fitness in older women: A randomized controlled trial. Arch Gerontol Geriatr 50: e19‐e25, 2010.
 179.Mahoney F, Barthel D. Functional evaluation: The Barthel index. Md State Med J 14: 61‐65, 1965.
 180.Mallery L, MacDonald E, Hubley‐Kozey C, Earl M, Rockwood K, MacKnight C. The feasibility of performing resistance exercise with acutely ill hospitalized older adults. BMC Geriatr 3: 1‐18, 2003.
 181.Malmstrom TK, Miller DK, Simonsick EM, Ferrucci L, Morley JE. SARC‐F: A symptom score to predict persons with sarcopenia at risk for poor functional outcomes. J Cachexia Sarcopenia Muscle 7: 28‐36, 2016.
 182.Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. Association of cardiorespiratory fitness with long‐term mortality among adults undergoing exercise treadmill testing. JAMA Netw Open 1: e183605, 2018.
 183.Martínez‐Velilla N, Casas‐Herrero N, Zambon‐Ferraresi F, López Sáez de Asteasu M, Lucia A, Galbete A, García‐Baztán A, Alonso‐Renedo J, González‐Glaría B, Gonzalo‐Lázaro M, Aspezteguía‐Iraizoz I, Gutiérrez‐Valencia M, Rodríguez‐Mañas L, Izquierdo M. Effect of exercise intervention on functional decline in very elderly patients during acute hospitalization: a randomized clinical trial. JAMA Intern Med 179: 28‐36, 2019.
 184.McGlory C, von Allmen MT, Stokes T, Morton RW, Hector AJ, Lago BA, Raphenya AR, Smith BK, McArthur AG, Steinberg GR, Baker SK, Phillips SM, Newman A. Failed recovery of glycemic control and myofibrillar protein synthesis with 2 wk of physical inactivity in overweight, prediabetic older adults. J Gerontol Ser A: 1‐8, 2017.
 185.Mcguire DK, Levine BD, Williamson JW, Snell PG, Blomqvist CG, Saltin B, Mitchell JH. A 30‐year follow‐up of the dallas bed rest and training study: I. effect of age on the cardiovascular response to exercise. Circulation 104: 1350‐1357, 2001.
 186.Mckendry J, Breen L, Shad BJ, Greig CA. Muscle morphology and performance in master athletes: A systematic review and meta‐analyses. Ageing Res Rev 45: 62‐82, 2018.
 187.McNeil CJ, Doherty TJ, Stashuk DW, Rice CL. Motor unit number estimates in the tibialis anterior muscle of young, old, and very old men. Muscle Nerve 31: 461‐467, 2005.
 188.Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F. Proinflammatory cytokines, aging, and age‐related diseases. J Am Med Dir Assoc 14: 877‐882, 2013.
 189.Mignardot JB, Deschamps T, Le Goff CG, Roumier FX, Duclay J, Martin A, Sixt M, Pousson M, Cornu C. Neuromuscular electrical stimulation leads to physiological gains enhancing postural balance in the pre‐frail elderly. Physiol Rep 3: 1‐18, 2015.
 190.Mijnarends D, Luiking Y, Halfens R, Evers S, Lenaerts E, Verlaan S, Wallace M, Schols J, Meijers J. Muscle, health and costs: A glance at their relationship. J Nutr Health Aging 22: 766‐773, 2018.
 191.Millán‐Calenti JC, Tubío J, Pita‐Fernández S, González‐Abraldes I, Lorenzo T, Fernández‐Arruty T, Maseda A. Prevalence of functional disability in activities of daily living (ADL), instrumental activities of daily living (IADL) and associated factors, as predictors of morbidity and mortality. Arch Gerontol Geriatr 50: 306‐310, 2010.
 192.Miokovic T, Armbrecht G, Gast U, Rawer R, Roth HJ, Runge M, Felsenberg D, Belavý DL. Muscle atrophy, pain, and damage in bed rest reduced by resistive (Vibration) exercise. Med Sci Sports Exerc 46: 1506‐1516, 2014.
 193.Monahan KD, Dinenno FA, Tanaka H, Clevenger CM, Desouza CA, Seals DR. Regular aerobic exercise modulates age‐associated declines in cardiovagal baroreflex sensitivity in healthy men. J Physiol 529: 263‐271, 2000.
 194.Morley J, Vellas B, van Kan G, Anker S, Bauer J, Bernabei R, Cesari M, Chumlea W, Doehner W, Evans J, Fried L, Guralnik J, Katz PR, Malmstrom TK, McCarter RJ, Gutierrez Robledo LM, Rockwood K, von Haehling S, Vandewoude MF, Walston J. Frailty consensus: A call to action John. J Am Med Dir Assoc 14: 392‐397, 2013.
 195.Morley JE, Malmstrom TK, Miller DK. A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. J Nutr Health Aging 16: 601‐608, 2012.
 196.Morse CI, Thom JM, Mian OS, Muirhead A, Birch KM, Narici MV. Muscle strength, volume and activation following 12‐month resistance training in 70‐year‐old males. Eur J Appl Physiol 95: 197‐204, 2005.
 197.Motalebi SA, Cheong LS, Iranagh JA, Mohammadi F. Effect of low‐cost resistance training on lower‐limb strength and balance in institutionalized seniors. Exp Aging Res 44: 48‐61, 2018.
 198.Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics Committee, Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: A report from the American Heart Association. Circulation 133: e38‐e360, 2016.
 199.Muller EE, Rigamonti AE, Colonna VDG, Locatelli V, Berti F, Cella SG. GH‐related and extra‐endocrine actions of GH secretagogues in aging. Neurobiol Aging 23: 907‐919, 2002.
 200.Murach KA, Englund DA, Dupont‐Versteegden EE, McCarthy JJ, Peterson CA. Myonuclear domain flexibility challenges rigid assumptions on satellite cell contribution to skeletal muscle fiber hypertrophy. Front Physiol 9: 1‐7, 2018.
 201.Na L, Pan Q, Xie D, Kurichi JE, Streim JE, Bogner HR, Saliba D, Hennessy S. Activity limitation stages are associated with risk of hospitalization among medicare beneficiaries. PM R 9: 433‐443, 2017.
 202.Narici MV, Maganaris CN, Reeves ND, Capodaglio P. Effect of aging on human muscle architecture. J Appl Physiol 95: 2229‐2234, 2003.
 203.Nascimento C de M, Oliveira C de, Firmo JOA, Lima‐Costa MF, Peixoto SV. Prognostic value of disability on mortality: 15‐year follow‐up of the Bambuí cohort study of aging. Arch Gerontol Geriatr 74: 112‐117, 2018.
 204.Newman A, Gottdiener J, McBurnie M, Hirsch C, Kop W, Tracy R, Walston J, Fried L. Associations of subclinical cardiovascular disease with frailty [Online]. J Gerontol – Ser A Biol Sci Med Sci 56: 158‐166, 2001. http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed5&NEWS=N&AN=2001088257
 205.Nijholt W, Scafoglieri A, Jager‐Wittenaar H, Hobbelen JSM, van der Schans CP. The reliability and validity of ultrasound to quantify muscles in older adults: a systematic review. J Cachexia Sarcopenia Muscle 8: 702‐712, 2017.
 206.Nilwik R, Snijders T, Leenders M, Groen BBL, van Kranenburg J, Verdijk LB, Van Loon LJC. The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp Gerontol 48: 492‐498, 2013.
 207.Oliveira L, Oliveira R, Pires‐Oliveira D. Effects of whole body vibration exercises on bone mineral density in postmenopausal women: a systematic review and meta‐analysis. Osteoporos Int 27: 2913‐2933, 2016.
 208.Ozaki H, Miyachi M, Nakajima T, Abe T. Effects of 10 weeks walk training with leg blood flow reduction on carotid arterial compliance and muscle size in the elderly adults. Angiology 62: 81‐86, 2011.
 209.Padula CA, Hughes C, Baumhover L. Impact of a nurse‐driven mobility protocol on functional decline in hospitalized older adults. J Nurs Care Qual 24: 325‐331, 2009.
 210.Paillard T. Muscle plasticity of aged subjects in response to electrical stimulation training and inversion and/or limitation of the sarcopenic process. Ageing Res Rev 46: 1‐13, 2018.
 211.Pavasini R, Guralnik J, Brown JC, di Bari M, Cesari M, Landi F, Vaes B, Legrand D, Verghese J, Wang C, Stenholm S, Ferrucci L, Lai JC, Bartes AA, Espaulella J, Ferrer M, Lim JY, Ensrud KE, Cawthon P, Turusheva A, Frolova E, Rolland Y, Lauwers V, Corsonello A, Kirk GD, Ferrari R, Volpato S, Campo G. Short physical performance battery and all‐cause mortality: Systematic review and meta‐analysis. BMC Med 14: 1‐9, 2016.
 212.Pedersen BK. Physical activity and muscle–brain crosstalk. Nat Rev Endocrinol, 2019. https://www.ncbi.nlm.nih.gov/pubmed/30837717
 213.Peel NM, Kuys SS, Klein K. Gait speed as a measure in geriatric assessment in clinical settings: A systematic review. J Gerontol—Ser A Biol Sci Med Sci 68: 39‐46, 2013.
 214.Perkisas S, Baudry S, Bauer J, Beckwée D, De Cock A‐M, Hobbelen H, Jager‐Wittenaar H, Kasiukiewicz A, Landi F, Marco E, Merello A, Piotrowicz K, Sanchez E, Sanchez‐Rodriguez D, Scafoglieri A, Cruz‐Jentoft A, Vandewoude M. Application of ultrasound for muscle assessment in sarcopenia: Towards standardized measurements. Eur Geriatr Med, 2018.
 215.Perry HM, Miller DK, Patrick P, Morley JE. Testosterone and leptin in older African–American men: Relationship to age, strength, function, and season. Metabolism 49: 1085‐1091, 2000.
 216.Petersen KF, Morino K, Alves TC, Kibbey RG, Dufour S, Sono S, Yoo PS, Cline GW, Shulman GI. Effect of aging on muscle mitochondrial substrate utilization in humans. Proc Natl Acad Sci 112: 11330‐11334, 2015.
 217.Petrella JK, Kim JS, Tuggle SC, Bamman MM. Contributions of force and velocity to improved power with progressive resistance training in young and older adults. Eur J Appl Physiol 99: 343‐351, 2007.
 218.Phillips SM, Mcglory C. The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis. J Physiol 592: 5341‐5343, 2014.
 219.Phillips SM, Glover EI, Rennie MJ. Alterations of protein turnover underlying disuse atrophy in human skeletal muscle. J Appl Physiol 107: 645‐654, 2009.
 220.Pickering GP, Fellmann N, Morio B, Ritz P, Amonchot A, Vermorel M, Coudert J. Effects of endurance training on the cardiovascular system and water compartments in elderly subjects. J Appl Physiol 83: 1300‐1306, 1997.
 221.Pietrangelo T, Mancinelli R, Toniolo L, Cancellara L, Paoli A, Puglielli C, Iodice P, Doria C, Bosco G, D'Amelio L, Di Tano G, Fulle S, Saggini R, Fano G, Reggiani C. Effects of local vibrations on skeletal muscle trophism in elderly people: Mechanical, cellular, and molecular events. Int J Mol Med 24: 503‐512, 2009.
 222.Podsiadlo D, Richardson S. The timed “Up & Go”: A test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 39: 142‐148, 1991.
 223.Pollock RD, O'Brien KA, Daniels LJ, Nielsen KB, Rowlerson A, Duggal NA, Lazarus NR, Lord JM, Philp A, Harridge SDR. Properties of the vastus lateralis muscle in relation to age and physiological function in master cyclists aged 55–79 years. Aging Cell 17, 2018.
 224.Powers SK, Talbert EE, Adhihetty PJ. Reactive oxygen and nitrogen species as intracellular signals in skeletal muscle. J Physiol 589: 2129‐2138, 2011.
 225.Powers SK, Wiggs MP, Duarte JA., Zergeroglu AM, Demirel HA. Mitochondrial signaling contributes to disuse muscle atrophy. AJP Endocrinol Metab 303: E31‐E39, 2012.
 226.Qiu C, Kivipelto M, Von Strauss E. Epidemiology of Alzhemer's disease: Occurrence, determinants, and strategies. Dialogues Clin Neurosci 11: 111‐128, 2009.
 227.Ramírez‐Campillo R, Castillo A, de la Fuente CI, Campos‐Jara C, Andrade DC, Álvarez C, Martínez C, Castro‐Sepúlveda M, Pereira A, Marques MC, Izquierdo M. High‐speed resistance training is more effective than low‐speed resistance training to increase functional capacity and muscle performance in older women. Exp Gerontol 58: 51‐57, 2014.
 228.Ramírez‐Vélez R, Correa‐Bautista J, García‐Hermoso A, Cano C, Izquierdo M. Reference values for handgrip strength and their association with intrinsic capacity domains among older adults. J Cachexia Sarcopenia Muscle 10: 278‐286, 2019.
 229.Rea IM, Gibson DS, McGilligan V, McNerlan SE, Denis Alexander H, Ross OA. Age and age‐related diseases: Role of inflammation triggers and cytokines. Front Immunol 9: 1‐28, 2018.
 230.Reeves ND, Narici MV, Maganaris CN. In vivo human muscle structure and function: Adaptations to resistance training in old age. Exp Physiol 89: 675‐689, 2004.
 231.Reid KF, Fielding R a. Skeletal muscle power: A critical determinant of physical functioning in older adults. Exerc Sport Sci Rev 40: 4‐12, 2012.
 232.Reid MB, Li YP. Tumor necrosis factor‐α and muscle wasting: A cellular perspective. Respir Res 2: 269‐272, 2001.
 233.Riggs BL. Endocrine causes of age‐related bone loss and osteoporosis [Online]. Novartis Found Symp 242: 244‐247, 2002. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11855691
 234.Rijk JM, Roos PRKM, Deckx L, Van den Akker M, Buntinx F. Prognostic value of handgrip strength in people aged 60 years and older: A systematic review and meta‐analysis. Geriatr Gerontol Int 16: 5‐20, 2016.
 235.Rittweger J. Vibration as an exercise modality: How it may work, and what its potential might be. Eur J Appl Physiol 108: 877‐904, 2010.
 236.Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C, Sayer AA. A review of the measurement of grip strength in clinical and epidemiological studies: Towards a standardised approach. Age Ageing 40: 423‐429, 2011.
 237.Rockwood K, MacKnight C, Bergman H, Hogan D, McDowell I, Mitnitski A. A global clinical measure of fitness and frailty in elderly people. CMAJ 173: 489‐495, 2005.
 238.Rogan S, Taeymans J, Radlinger L, Naepflin S, Ruppen S, Bruelhart Y, Hilfiker R. Effects of whole‐body vibration on postural control in elderly: An update of a systematic review and meta‐analysis. Arch Gerontol Geriatr 73: 95‐112, 2017.
 239.Rosenberg I. Summary comments. Am J Clin Nutr 50: 1231‐1233, 1989.
 240.Rottkamp CA, Nunomura A, Raina AK, Sayre LM, Perry G, Smith MA. Oxidative stress, antioxidants, and Alzheimer disease. Alzheimer Dis Assoc Disord 14: 62‐66, 2000.
 241.Rubin C, Turner S, Bain S, Mallinckrod C, McLeod K. Low mechanical signals strengthen long bones. Nature 412: 603‐604, 2001.
 242.Rudrappa SS, Wilkinson DJ, Greenhaff PL, Smith K, Idris I, Atherton PJ. Human skeletal muscle disuse atrophy: Effects on muscle protein synthesis, breakdown, and insulin resistance: A qualitative review. Front Physiol 7: 1‐10, 2016.
 243.Sander M, Oxlund B, Jespersen A, Krasnik A, Mortensen EL, Westendorp RGJ, Rasmussen LJ. The challenges of human population ageing. Age Ageing 44: 185‐187, 2015.
 244.Santos‐Lozano A, Pareja‐Galeano H, Sanchis‐Gomar F, Quindós‐Rubial M, Fiuza‐Luces C, Cristi‐Montero C, Emanuele E, Garatachea N, Lucia A. Physical activity and alzheimer disease: A protective association. Mayo Clin Proc 91: 999‐1020, 2016.
 245.dos Santos L, Cyrino ES, Antunes M, Santos DA, Sardinha LB. Sarcopenia and physical independence in older adults: The independent and synergic role of muscle mass and muscle function. J Cachexia Sarcopenia Muscle 8: 245‐250, 2017.
 246.Schaap L, Pluijm S, Deeg D, Visser M. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med 119: 526.e9‐526.e17, 2006.
 247.Schaap LA, Pluijm SMF, Deeg DJH, Harris TB, Kritchevsky SB, Newman AB, Colbert LH, Pahor M, Rubin SM, Tylavsky FA, Visser M. Higher inflammatory marker levels in older persons: Associations with 5‐year change in muscle mass and muscle strength. J Gerontol – Ser A Biol Sci Med Sci 64: 1183‐1189, 2009.
 248.Schoenfeld BJ. Potential mechanisms for a role of metabolic stress in hypertrophic adaptations to resistance training. Sports Med 43: 179‐194, 2013.
 249.Schulman C, Lunenfeld B. The ageing male. World J Urol 20: 4‐10, 2002.
 250.Schwartz LM, Brown C, McLaughlin K, Smith W, Bigelow C. The myonuclear domain is not maintained in skeletal muscle during either atrophy or programmed cell death. Am J Physiol – Cell Physiol 311: C607‐C615, 2016.
 251.Semba R, Ferrucci L, Sun K, Walswon J, Varadhan R, Guralnik J, Fried L. Oxidative stress and severe walking disability among older women. Am J Med 120: 1084‐1089, 2007.
 252.Semba RD, Ferrucci L, Sun K, Walston J, Varadhan R, Guralnik JM, Fried LP. Oxidative stress is associated with greater mortality in older women living in the community. J Am Geriatr Soc 55: 1421‐1425, 2007.
 253.Senf SM, Dodd SL, McClung JM, Judge AR. Hsp70 overexpression inhibits NF‐ B and Foxo3a transcriptional activities and prevents skeletal muscle atrophy. FASEB J 22: 3836‐3845, 2008.
 254.Sergi G, De Rui M, Veronese N, Bolzetta F, Berton L, Carraro S, Bano G, Coin A, Manzato E, Perissinotto E. Assessing appendicular skeletal muscle mass with bioelectrical impedance analysis in free‐living Caucasian older adults. Clin Nutr 34: 667‐673, 2015.
 255.Serra‐Rexach JA, Bustamante‐Ara N, Hierro Villarán M, González Gil P, Sanz Ibáñez MJ, Blanco Sanz N, Ortega Santamaría V, Gutiérrez Sanz N, Marín Prada AB, Gallardo C, Rodríguez Romo G, Ruiz JR, Lucia A. Short‐term, light‐ to moderate‐intensity exercise training improves leg muscle strength in the oldest old: A randomized controlled trial. J Am Geriatr Soc 59: 594‐602, 2011.
 256.Shackelford LC, LeBlanc a D, Driscoll TB, Evans HJ, Rianon NJ, Smith SM, Spector E, Feeback DL, Lai D. Resistance exercise as a countermeasure to disuse‐induced bone loss. J Appl Physiol 97: 119‐129, 2004.
 257.Shad BJ, Thompson JL, Breen L. Does the muscle protein synthetic response to exercise and amino acid‐based nutrition diminish with advancing age? A systematic review. Am J Physiol Endocrinol Metab 311: E803‐E817, 2016.
 258.Shu HF, Yang T, Yu SX, Huang HD, Jiang LL, Gu JW, Kuang YQ. Aerobic exercise for Parkinson's disease: A systematic review and meta‐analysis of randomized controlled trials. PLoS One 9, 2014.
 259.Siebens H, Aronow H, Edwards D, Ghasemi Z. A randomized controlled trial of exercise to improve outcomes of acute hospitalization in older adults. J Am Geriatr Soc 48: 1545‐1546, 2000.
 260.Simioni C, Zauli G, Martelli AM, Vitale M, Sacchetti G, Gonelli A, Neri LM. Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging. Oncotarget 9: 17181‐17198, 2018.
 261.Sitjà‐Rabert M, Rigau D, Fort Vanmeerghaeghe A, Romero‐Rodríguez D, Bonastre Subirana M, Bonfill X. Efficacy of whole body vibration exercise in older people: A systematic review. Disabil Rehabil 34: 883‐893, 2012.
 262.Slysz J, Stultz J, Burr JF. The efficacy of blood flow restricted exercise: A systematic review & meta‐analysis. J Sci Med Sport 19: 669‐675, 2016.
 263.Soares‐Miranda L, Sattelmair J, Chaves P, Duncan GE, Siscovick DS, Stein PK, Mozaffarian D. Physical activity and heart rate variability in older adults: The cardiovascular health study. Circulation 129: 2100‐2110, 2014.
 264.Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, Macchi C. Physical activity and risk of cognitive decline: A meta‐analysis of prospective studies. J Intern Med 269: 107‐117, 2011.
 265.Sorbini C, Grassi V, Solinas E, Muisan G. Arterial oxygen tension in relation to age in healthy subjects. Respiration 25: 3‐13, 1968.
 266.Sousa AS, Guerra RS, Fonseca I, Pichel F, Ferreira S, Amaral TF. Financial impact of sarcopenia on hospitalization costs. Eur J Clin Nutr 70: 1046‐1051, 2016.
 267.Spahillari A, Mukamal K, Defilippi C, Gottdiener JS, Djoussé L, Lyles MF, Bartz TM, Murthy VL, Shah RV. The association of lean and fat mass with all‐cause mortality in older adults: the cardiovascular health study. Nutr Metab Cardiovasc Dis 26: 1039‐1047, 2016.
 268.Spina RJ, Turner MJ, Ehsani AA. Beta‐adrenergic‐mediated improvement in left ventricular function by exercise training in older men [Online]. Am J Physiol 274: H397‐H404, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9486240
 269.Steffl M, Sima J, Shiells K, Holmerova I. The increase in health care costs associated with muscle weakness in older people without long‐ term illnesses in the Czech Republic: results from the survey of health, ageing and retirement in Europe (SHARE). Clin Interv Aging 12: 2003‐2007, 2017.
 270.Straight CR, Lindheimer JB, Brady AO, Dishman RK, Evans EM. Effects of resistance training on lower‐extremity muscle power in middle‐aged and older adults: A systematic review and meta‐analysis of randomized controlled trials. Sports Med 46: 353‐364, 2016.
 271.Stratton JR, Cerqueira MD, Schwartz RS, Levy WC, Veith RC, Kahn SE, Abrass IB. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 86: 504‐512, 1992.
 272.Studenski S. Gait speed and survival in older adults. JAMA 305: 50, 2011.
 273.Subra J, Gillette‐Guyonnet S, Cesari M, Oustric S, VellaS B. The integration of frailty into clinical practice: Preliminary results from the gérontopôle. J Nutr Health Aging 16: 714‐720, 2012.
 274.Suetta C, Frandsen U, Mackey AL, Jensen L, Hvid LG, Bayer ML, Petersson SJ, Schrøder HD, Andersen JL, Aagaard P, Schjerling P, Kjaer M. Ageing is associated with diminished muscle re‐growth and myogenic precursor cell expansion early after immobility‐induced atrophy in human skeletal muscle. J Physiol 591: 3789‐3804, 2013.
 275.Sun N, Youle R, Finkel T. The mitochondrial basis of aging. Mol Cell 61: 654‐666, 2016.
 276.Takano H, Morita T, Iida H, Asada KI, Kato M, Uno K, Hirose K, Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T. Hemodynamic and hormonal responses to a short‐term low‐intensity resistance exercise with the reduction of muscle blood flow. Eur J Appl Physiol 95: 65‐73, 2005.
 277.Tanner RE, Brunker LB, Agergaard J, Barrows KM, Briggs RA, Kwon OS, Young LM, Hopkins PN, Volpi E, Marcus RL, Lastayo PC, Drummond MJ. Age‐related differences in lean mass, protein synthesis and skeletal muscle markers of proteolysis after bed rest and exercise rehabilitation. J Physiol 593: 4259‐4273, 2015.
 278.Thom JM, Morse CI, Birch KM, Narici MV. Influence of muscle architecture on the torque and power‐velocity characteristics of young and elderly men. Eur J Appl Physiol 100: 613‐619, 2007.
 279.Thomas AW, Davies NA, Moir H, Watkeys L, Ruffino JS, Isa SA, Butcher LR, Hughes MG, Morris K, Webb R. Exercise‐associated generation of PPAR ligands activates PPAR signaling events and upregulates genes related to lipid metabolism. J Appl Physiol 112: 806‐815, 2012.
 280.Thurlbeck W, Angus G. Growth and aging of the normal human lung. Chest 67: 3S‐7S, 1975.
 281.Ticinesi A, Meschi T, Narici MV, Lauretani F, Maggio M. Muscle ultrasound and sarcopenia in older individuals: A clinical perspective. J Am Med Dir Assoc 18: 290‐300, 2017.
 282.Tosato M, Marzetti E, Cesari M, Savera G, Miller RR, Bernabei R, Landi F, Calvani R. Measurement of muscle mass in sarcopenia: From imaging to biochemical markers. Aging Clin Exp Res 29: 19‐27, 2017.
 283.Tschopp M, Sattelmayer MK, Hilfiker R. Is power training or conventional resistance training better for function in elderly persons? A meta‐analysis. Age Ageing 40: 549‐556, 2011.
 284.Valenzuela PL, Morales JS, Pareja‐Galeano H, Izquierdo M, Emanuele E, de la Villa P, Lucia A. Physical strategies to prevent disuse‐induced functional decline in the elderly. Ageing Res Rev 47: 80‐88, 2018.
 285.Vasunilashorn S, Coppin AK, Patel KV, Lauretani F, Ferrucci L, Bandinelli S, Guralnik JM. Use of the short physical performance battery score to predict loss of ability to walk 400 meters: Analysis from the InCHIANTI study. Journals Gerontol—Ser A Biol Sci Med Sci 64: 223‐229, 2009.
 286.Vechin F, Libardi C, Conceiao M, Damas F, Lixandrao M, Berton R, Tricoli V, Roschel H, Cavaglieri C, Chacon‐Mikahil M, Ugrinowitsch C. Comparisons between low‐intensity resistance training with blood flow restriction and high‐intensity resistance training on quadriceps muscle mass and strength in elderly. J Strength Cond Res 29: 1071‐1076, 2015.
 287.Velloso CP. Regulation of muscle mass by growth hormone and IGF‐I. BrJPharmacol 154: 557‐568, 2008.
 288.Vigelsø A, Gram M, Wiuff C, Andersen JL, Helge JW, Dela F. Six weeks' aerobic retraining after two weeks' immobilization restores leg lean mass and aerobic capacity but does not fully rehabilitate leg strength in young and older men. J Rehabil Med 47: 552‐560, 2015.
 289.Vinstrup J, Skals S, Calatayud J, Jakobsen MD, Sundstrup E, Pinto MD, Izquierdo M, Wang Y, Zebis MK, Andersen LL. Electromyographic evaluation of high‐intensity elastic resistance exercises for lower extremity muscles during bed rest. Eur J Appl Physiol 117: 1329‐1338, 2017.
 290.Visser M, Fuerst T, Lang T, Salamone L, Harris TB, Health FT, Absorptiometry ACSD‐E, Group BCW. Validity of fan‐beam dual‐energy X‐ray absorptiometry for measuring fat‐free mass and leg muscle mass. J Appl Physiol 87: 1513‐1520, 1999.
 291.Volpato S, Cavalieri M, Sioulis F, Guerra G, Maraldi C, Zuliani G, Fellin R, Guralnik JM. Predictive value of the short physical performance battery following hospitalization in older patients. J Gerontol – Ser A Biol Sci Med Sci 66 A: 89‐96, 2011.
 292.Volpi E, Sheffield‐Moore M, Rasmussen B, Wolfe R. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 286: 1206‐1212, 2001.
 293.de Vries NM, van Ravensberg CD, Hobbelen JSM, Olde Rikkert MGM, Staal JB, Nijhuis‐van der Sanden MWG. Effects of physical exercise therapy on mobility, physical functioning, physical activity and quality of life in community‐dwelling older adults with impaired mobility, physical disability and/or multi‐morbidity: A meta‐analysis. Ageing Res Rev 11: 136‐149, 2012.
 294.Wall BT, Snijders T, Senden JMG, Ottenbros CLP, Gijsen AP, Verdijk LB, Van Loon LJC. Disuse impairs the muscle protein synthetic response to protein ingestion in healthy men. J Clin Endocrinol Metab 98: 4872‐4881, 2013.
 295.Watanabe K, Holobar A, Kouzaki M, Ogawa M, Akima H, Moritani T. Age‐related changes in motor unit firing pattern of vastus lateralis muscle during low‐moderate contraction. Age (Omaha) 38, 2016.
 296.Watenpaugh DE, Ballard RE, Schneider SM, Lee SM, Ertl AC, William JM, Boda WL, Hutchinson KJ, Hargens AR. Supine lower body negative pressure exercise during bed rest maintains upright exercise capacity. J Appl Physiol 89: 218‐227, 2000.
 297.Wernbom M, Apro W, Paulsen G, Nilsen TS, Blomstrand E, Raastad T. Acute low‐load resistance exercise with and without blood flow restriction increased protein signalling and number of satellite cells in human skeletal muscle. Eur J Appl Physiol 113: 2953‐2965, 2013.
 298.Wilkes E, Selby A, Atherton P, Patel R, Rankin D, Smith K, Rennie M. Blunting of insulin inhibition of proteolysis in legs of older subjects may contribute to age‐related sarcopenia. Am J Clin Nutr 90: 1343‐1350, 2009.
 299.Wilkinson DJ, Piasecki M, Atherton PJ. The age‐related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. Ageing Res Rev 47: 123‐132, 2018.
 300.Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M, Sato Y, Yamasoba T, Nakajima T. Muscle size and arterial stiffness after blood flow‐restricted low‐intensity resistance training in older adults. Scand J Med Sci Sport 24: 799‐806, 2014.
 301.Yazdanyar A, Newman A. The burden of cardiovascular disease in the elderly: Morbidity, mortality, and costs. Clin Geriatr Med 25: 563‐567, 2009.
 302.Yoshiko A, Hioki M, Kanehira N, Shimaoka K, Koike T, Sakakibara H, Oshida Y, Akima H. Three‐dimensional comparison of intramuscular fat content between young and old adults. BMC Med Imaging 17: 1‐8, 2017.
 303.Yuki A, Ando F, Otsuka R, Shimokata H. Low free testosterone is associated with loss of appendicular muscle mass in Japanese community‐dwelling women. Geriatr Gerontol Int 15: 326‐333, 2015.
 304.Yuki A, Otsuka R, Kozakai R, Kitamura I, Okura T, Ando F, Shimokata H. Relationship between low free testosterone levels and loss of muscle mass. Sci Rep 3: 1‐5, 2013.
 305.Zanchi NE, Lancha AH. Mechanical stimuli of skeletal muscle: Implications on mTOR/p70s6k and protein synthesis. Eur J Appl Physiol 102: 253‐263, 2008.
 306.Zheng SX, Vrindts Y, Lopez M, De Groote D, Zangerle PF, Collette J, Franchimont N, Geenen V, Albert A, Reginster JY. Increase in cytokine production (IL‐1β, IL‐6, TNF‐α but not IFN‐γ, GM‐CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis. Maturitas 26: 63‐71, 1997.
 307.Zisberg A, Shadmi E, Gur‐Yaish N, Tonkikh O, Sinoff G. Hospital‐associated functional decline: The role of hospitalization processes beyond individual risk factors. J Am Geriatr Soc 63: 55‐62, 2015.
 308.Zisberg A, Shadmi E, Sinoff G, Gur‐Yaish N, Srulovici E, Admi H. Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc 59: 266‐273, 2011.

 

Teaching Material

P. L. Valenzuela, A. Castillo-García, J. S. Morales, M. Izquierdo, J. A. Serra-Rexach, A. Santos-Lozano, A. Lucia. Physical Exercise in the Oldest Old. Compr Physiol 9: 2019, 1281-1304.

Didactic Synopsis

Major Teaching Points:

  • Aging is associated with an increased risk for intrinsic capacity decline, which is largely a result of a multisystem deterioration including changes at the endocrine, neuromuscular, metabolic, and cardiorespiratory level.
  • Lifetime physical exercise can help to maintain (or at least attenuate the loss of) many of the properties (notably, muscle mass, functional ability, cardiorespiratory function) affected by aging and especially by inactive aging.
  • Exercise programs are also beneficial in frail elders, including institutionalized or hospitalized individuals.
  • Multicomponent exercise programs (especially if combining aerobic and resistance training) provide multiple systemic benefits, including improvements in neuromuscular, endocrine, cardiovascular, cardiorespiratory, metabolic and cognitive function.
  • Exercise interventions—or alternatively, passive strategies such as neuromuscular electrical stimulation if volitional exercise is not feasible—should be implemented during disuse situations such as hospitalization.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 Teaching points: This figure illustrates how societies are expected to age from 2015 to 2050. Particularly, the oldest old (i.e., those aged > 80 years) are expected to triple in this time period, being the most rapidly expanding population segment.

Figure 2 Teaching points: This figure illustrates the nine candidate hallmarks of aging proposed by López-Otín et al. (169). Primary hallmarks (colored in blue) are negative processes that progressively hasten aging, antagonistic hallmarks (colored in red) are necessary processes that can became negative if present in excess, and integrative hallmarks (colored in yellow) are those that directly affect tissue homeostasis and function.

Figure 3 Teaching points: This figure illustrates the multisystem physiological changes that occur with aging and that eventually result in loss of muscle mass and functional decline. Briefly, aging is characterized by a pro-inflammatory status, reduced myogenic and regenerative capacity, decreased cardiorespiratory function, impaired protein turnover, loss of muscle mass and function, impaired endocrine function (reduced anabolic response), and mitochondrial dysfunction (with subsequent oxidative stress).

Figure 4 Teaching points: This figure illustrates an algorithm for the diagnosis of sarcopenia. If an individual present with low muscle strength, which can be assessed through handgrip strength or the chair to stand test, muscle mass (ideally assessed with dual-energy X-ray absorptiometry) should be measured to confirm the presence of sarcopenia. If sarcopenia is diagnosed, the physical performance should be assessed (through walking tests or the short physical performance battery [SPPB]) to quantify the severity of this condition.

Figure 5 Teaching points: This figure illustrates the relationship between sarcopenia, frailty, and overall functional decline in the elderly. Sarcopenia refers to an excessive loss of muscle mass and function that can also affect physical performance. In contrast, frailty refers to a wider concept that not only involves sarcopenia but also a deterioration in multiple physiological systems (e.g., impaired endocrine, immune and musculoskeletal function, and also impaired cognition) that eventually result in negative consequences to physical, cognitive, and social dimensions.

Figure 6 Teaching points: This figure illustrates how the risk of functional decline in the elderly decreases with greater levels of physical activity.

Figure 7 Teaching points: This figure illustrates how lifelong physical activity can help to prevent loss of muscle quantity and quality during aging.

Figure 8 Teaching points: This figure illustrates the multisystem benefits that physical exercise provides on the oldest old. Briefly, it increases muscle mass and improves neuromuscular function, increases muscle protein turnover and energy expenditure, improves body composition, and enhances cardiovascular and respiratory function.

Figure 9 Teaching points: This figure illustrates the multisystem benefits that aerobic and resistance exercise provide in the elderly.

Figure 10 Teaching points: This figure illustrates how muscle protein synthesis (MPS) and breakdown (MPB) vary with advancing age. Aging is accompanied by a decreased anabolic response to lifestyle stimuli such as physical activity and nutrition, also known as ‘anabolic resistance’, which results in a slight imbalance in muscle protein turnover and eventually in a loss of muscle mass. In addition, in some situations such as chronic diseases or frailty, MPB can be aggravated as a result of an excessive pro-inflammatory status, which results in a further imbalance in muscle protein turnover.

Figure 11 Teaching points: This figure illustrates some physical interventions that can be implemented to prevent disuse-induced adaptations in the elderly. These interventions include both active and passive strategies, the latter being feasible even when volitional exercise cannot be performed.

 


Related Articles:

Exercise Physiology of Normal Development, Sex Differences, and Aging
Aging: Current Concepts
Mechanisms Modulating Skeletal Muscle Phenotype
Teaching Material

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Pedro L. Valenzuela, Adrián Castillo‐García, Javier S. Morales, Mikel Izquierdo, José A. Serra‐Rexach, Alejandro Santos‐Lozano, Alejandro Lucia. Physical Exercise in the Oldest Old. Compr Physiol 2019, 9: 1281-1304. doi: 10.1002/cphy.c190002