Reversal of age-associated frailty by controlled physical exercise: The pre-clinical and clinical evidences

Abstract

Demographic aging is one of the most serious challenges facing our society. Although we live longer, we do not live better because it is considered that approximately 16-20% of our life is spent in late-life morbidity. Older people have the greatest risk of developing frailty increasing the risk of presenting various adverse health events such as low quality of life, disability, hospitalization and even death. Frail men and women over 65 years old have lower muscle quality and muscle mass and higher percentage of body fat than non-frail people of the same age. In this review we will address the main physiological changes in the muscular and nervous system associated to aging. More specifically we will review the changes in muscle mass, quality, and strength relating them with the decrease in capillarization and muscular oxidative capacity as well as with the alterations in protein synthesis in the muscle with aging. The last section of the manuscript will be devoted to the animal models of frailty and the indexes developed to measure frailty in these models. We will finally address the importance of exercise training as an intervention to delay or even reverse frailty.

Keywords

Sarcopenia / Multicomponent exercise / Disability / Skeletal muscle / Healthy aging

Conflict of interest

The authors declare no competing interests.

Submission statement

This manuscript has not been published and is not under consideration for publication elsewhere. If accepted, it will not be published elsewhere including electronically in the same form without the written consent of the copyright-holder.

Each authors’ contributions

CA-C and FM performed the literature search and review and wrote the manuscript. AS-P, AGC, GO-G, ADlR, and AC analyzed and discussed the data and reviewed the manuscript. MCG-C and JV designed and supervised the review, secured funding, and wrote the manuscript. All authors discussed the results, commented on and approved the last version of the manuscript.

References

[1] A.J. Cruz-Jentoft, G. Bahat, J. Bauer, et al.. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing, 48 (1) ( 2019), pp. 16-31

[2] L. Rodriguez-Manas, L.P. Fried. Frailty in the clinical scenario. Lancet, 385 (9968) ( 2015), pp. e7-e9

[3] B. Vellas, D. Scrase, G.A. Rosenberg, S. Andrieu, I. Araujo de Carvalho, L.T. Middleton. Editorial: WHO guidelines on community-level interventions to manage declines in intrinsic capacity: the road for preventing cognitive declines in older age?. J Prev Alzheimers Dis, 5 (3) ( 2018), pp. 165-167

[4] L.P. Fried, C.M. Tangen, J. Walston, et al.. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci, 56 (3) ( 2001), pp. M146-M156

[5] K. Rockwood, A. Mitnitski. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci, 62 (7) ( 2007), pp. 722-727

[6] L.P. Fried. Interventions for human frailty: physical activity as a model. Cold Spring Harb Perspect Med, 6 (6) ( 2016)

[7] J.E. Morley, T.K. Malmstrom. Frailty, sarcopenia, and hormones. Endocrinol Metab Clin North Am, 42 (2) ( 2013), pp. 391-405

[8] G.N. Williams, M.J. Higgins, M.D. Lewek. Aging skeletal muscle: physiologic changes and the effects of training. Phys Ther, 82 (1) ( 2002), pp. 62-68

[9] F.J. Tarazona-Santabalbina, M.C. Gomez-Cabrera, P. Perez-Ros, et al.. A multicomponent exercise intervention that reverses frailty and improves cognition, emotion, and social networking in the community-dwelling frail elderly: a randomized clinical trial. J Am Med Dir Assoc, 17 (5) ( 2016), pp. 426-433

[10] J. Vina, F.J. Tarazona-Santabalbina, P. Perez-Ros, et al.. Biology of frailty: modulation of ageing genes and its importance to prevent age-associated loss of function. Mol Asp Med, 50 ( 2016), pp. 88-108

[11] M.S. Fragala, A.M. Kenny, G.A. Kuchel. Muscle quality in aging: a multi-dimensional approach to muscle functioning with applications for treatment. Sport Med, 45 (5) ( 2015), pp. 641-658

[12] C.M. Nascimento, M. Ingles, A. Salvador-Pascual, M.R. Cominetti, M.C. Gomez-Cabrera, J. Vina. Sarcopenia, frailty and their prevention by exercise. Free Radic Biol Med, 20 (132) ( 2019), pp. 42-49

[13] J. Vina, A. Salvador-Pascual, F. Jose Tarazona-Santabalbina, L. Rodriguez-Manas, M. Carmen Gomez-Cabrera. Exercise training as a drug to treat age associated frailty. Free Radic Biol Med, 98 ( 2016), pp. 159-164

[14] T.P. Gavin, R.M. Kraus, J.A. Carrithers, J.P. Garry, R.C. Hickner. Aging and the skeletal muscle angiogenic response to exercise in women. J Gerontol A Biol Sci Med Sci, 70 (10) ( 2015), pp. 1189-1197

[15] M.C. Gomez-Cabrera, E. Domenech, M. Romagnoli, et al.. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr, 87 (1) ( 2008), pp. 142-149

[16] F. Derbre, M. Carmen Gomez-Cabrera, A. Lucia Nascimento, et al.. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1 alpha to exercise training. Age, 34 (3) ( 2012), pp. 669-679

[17] R.T. Hepple.Mitochondrial involvement and impact in aging skeletal muscle. Front Aging Neurosci, 6 ( 2014), p. 211

[18] F. Derbre, A. Gratas-Delamarche, M. Carmen Gomez-Cabrera, J. Vina. Inactivity-induced oxidative stress: a central role in age-related sarcopenia?. Eur J Sport Sci, 14 ( 2014), pp. S98-S108

[19] T.J. Doherty, W.F. Brown. The estimated numbers and relative sizes of thenar motor units as selected by multiple point stimulation in young and older adults. Muscle Nerve, 16 (4) ( 1993), pp. 355-366

[20] S.M. Ling, R.A. Conwit, L. Ferrucci, E.J. Metter. Age-associated changes in motor unit physiology: observations from the Baltimore Longitudinal Study of Aging. Arch Phys Med Rehabil, 90 (7) ( 2009), pp. 1237-1240

[21] H. Yamada, T. Masuda, M. Okada. Age-related EMG variables during maximum voluntary contraction. Percept Mot Skills, 95 (1) ( 2002), pp. 10-14

[22] R. Merletti, L.R. Lo Conte, C. Cisari, M.V. Actis. Age related changes in surface myoelectric signals. Scand J Rehabil Med, 24 (1) ( 1992), pp. 25-36

[23] F. Lauretani, C.R. Russo, S. Bandinelli, et al.. Age-associated changes in skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia. J Appl Physiol, 95 (5) ( 1985), pp. 1851-1860. 2003

[24] H.C. Dreyer, S. Fujita, J.G. Cadenas, D.L. Chinkes, E. Volpi, B.B. Rasmussen. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol, 576 (Pt 2) ( 2006), pp. 613-624

[25] C. Rommel, S.C. Bodine, B.A. Clarke, et al.. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3) K/Akt/GSK3 pathways. Nat Cell Biol, 3 (11) ( 2001), pp. 1009-1013

[26] C. Guillet, M. Prod'homme, M. Balage, et al.. Impaired anabolic response of muscle protein synthesis is associated with S6K 1 dysregulation in elderly humans. FASEB J, 18 (13) ( 2004), pp. 1586-1587

[27] A. Yorke, A.E. Kane, C.L. Hancock Friesen, S.E. Howlett, S. O'Blenes. Development of a rat clinical frailty index. J Gerontol A Biol Sci Med Sci, 72 (7) ( 2017), pp. 897-903

[28] M.G. Miller, N. Thangthaeng, B. Shukitt-Hale. A clinically relevant frailty index for aging rats. J Gerontol A Biol Sci Med Sci, 72 (7) ( 2017), pp. 892-896

[29] J. Walston, N. Fedarko, H. Yang, et al.. The physical and biological characterization of a frail mouse model. J Gerontol A Biol Sci Med Sci, 63 (4) ( 2008), pp. 391-398

[30] D. Jurk, C. Wilson, J.F. Passos, et al.. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun, 2 ( 2014), p. 4172

[31] T. Takeda, M. Hosokawa, K. Higuchi, M. Hosono, I. Akiguchi, H. Katoh. A novel murine model of aging, Senescence-Accelerated Mouse (SAM). Arch Gerontol Geriatr, 19 (2) ( 1994), pp. 185-192

[32] W. Derave, B.O. Eijnde, M. Ramaekers, P. Hespel. Soleus muscles of SAMP8 mice provide an accelerated model of skeletal muscle senescence. Exp Gerontol, 40 (7) ( 2005), pp. 562-572

[33] I. Martinez de Toda, A. Garrido, C. Vida, M.C. Gomez-Cabrera, J. Vina, M. De la Fuente. Frailty quantified by the "Valencia score" as a potential predictor of lifespan in mice. J Gerontol A Biol Sci Med Sci, 73 (10) ( 2018), pp. 1323-1329

[34] A.E. Kane, S.N. Hilmer, J. Mach, S.J. Mitchell, R. de Cabo, S.E. Howlett. Animal models of frailty: current applications in clinical research. Clin Interv Aging, 11 ( 2016), pp. 1519-1529

[35] R.J. Parks, E. Fares, J.K. Macdonald, et al.. A procedure for creating a frailty index based on deficit accumulation in aging mice. J Gerontol A Biol Sci Med Sci, 67 (3) ( 2012), pp. 217-227

[36] J.C. Whitehead, B.A. Hildebrand, M. Sun, et al.. A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci, 69 (6) ( 2014), pp. 621-632

[37] H. Liu, T.G. Graber, L. Ferguson-Stegall, L.V. Thompson. Clinically relevant frailty index for mice. J Gerontol A Biol Sci Med Sci, 69 (12) ( 2013), pp. 1485-1491

[38] T.G. Graber, L. Ferguson-Stegall, H. Liu, L.V. Thompson. Voluntary aerobic exercise reverses frailty in old mice. J Gerontol A Biol Sci Med Sci, 70 (9) ( 2015), pp. 1045-1058

[39] M.C. Gomez-Cabrera, R. Garcia-Valles, L. Rodriguez-Mañas, et al.. A new frailty score for experimental animals based on the clinical phenotype: inactivity as a model of frailty. J Gerontol A Biol Sci Med Sci, 72 (7) ( 2017), pp. 885-891

[40] F. Landi, R. Calvani, M. Tosato, et al.. Protein intake and muscle health in old age: from biological plausibility to clinical evidence. Nutrients, 8 (5) ( 2016)

[41] R. Garcia-Valles, M.C. Gomez-Cabrera, L. Rodriguez-Manas, et al.. Life-long spontaneous exercise does not prolong lifespan but improves health span in mice. Longev Heal, 2 (1) ( 2013), p. 14

[42] K.L. Seldeen, G. Lasky, M.M. Leiker, M. Pang, K.E. Personius, B.R. Troen. High intensity interval training improves physical performance and frailty in aged mice. J Gerontol A Biol Sci Med Sci, 73 (4) ( 2018), pp. 429-437

[43] J. Vina, L. Rodriguez-Manas, A. Salvador-Pascual, F. Jose Tarazona-Santabalbina, M. Carmen Gomez-Cabrera. Exercise: the lifelong supplement for healthy ageing and slowing down the onset of frailty. J Physiol-London, 594 (8) ( 2016), pp. 1989-1999

[44] J. Gudlaugsson, V. Gudnason, T. Aspelund, et al.. Effects of a 6-month multimodal training intervention on retention of functional fitness in older adults: a randomized-controlled cross-over design. Int J Behav Nutr Phys Act, 9 ( 2012), p. 107

[45] M.Y. Jeon, H. Jeong, J. Petrofsky, H. Lee, J. Yim. Effects of a randomized controlled recurrent fall prevention program on risk factors for falls in frail elderly living at home in rural communities. Med Sci Monit, 20 ( 2014), pp. 2283-2291

[46] H.C. Lee, K.C. Chang, J.Y. Tsauo, et al.. Effects of a multifactorial fall prevention program on fall incidence and physical function in community-dwelling older adults with risk of falls. Arch Phys Med Rehabil, 94 (4) ( 2013), pp. 606-615. 615.e601

[47] T.P. Ng, L. Feng, M.S. Nyunt, et al.. Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: a randomized controlled trial. Am J Med, 128 (11) ( 2015), pp. 1225-1236. e1221

[48] E. Rosendahl, N. Lindelöf, H. Littbrand, et al.. High-intensity functional exercise program and protein-enriched energy supplement for older persons dependent in activities of daily living: a randomised controlled trial. Aust J Physiother, 52 (2) ( 2006), pp. 105-113

[49] J.A. Serra-Rexach, N. Bustamante-Ara, M. Hierro Villaran, et al.. 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 (4) ( 2011), pp. 594-602

[50] A. Zech, M. Drey, E. Freiberger, et al.. Residual effects of muscle strength and muscle power training and detraining on physical function in community-dwelling prefrail older adults: a randomized controlled trial. BMC Geriatr, 12 ( 2012), p. 68

[51] T. Ikezoe, Y. Asakawa, H. Shima, K. Kishibuchi, N. Ichihashi. Daytime physical activity patterns and physical fitness in institutionalized elderly women: an exploratory study. Arch Gerontol Geriatr, 57 (2) ( 2013), pp. 221-225

[52] J.A. Hess, M. Woollacott, N. Shivitz. Ankle force and rate of force production increase following high intensity strength training in frail older adults. Aging Clin Exp Res, 18 (2) ( 2006), pp. 107-115

[53] A.I. Kryger, J.L. Andersen. Resistance training in the oldest old: consequences for muscle strength, fiber types, fiber size, and MHC isoforms. Scand J Med Sci Sport, 17 (4) ( 2007), pp. 422-430

[54] L.P. Lustosa, J.P. Silva, F.M. Coelho, D.S. Pereira, A.N. Parentoni, L.S. Pereira. Impact of resistance exercise program on functional capacity and muscular strength of knee extensor in pre-frail community-dwelling older women: a randomized crossover trial. Rev Bras Fisioter, 15 (4) ( 2011), pp. 318-324

[55] E.L. Cadore, A. Casas-Herrero, F. Zambom-Ferraresi, et al.. Multicomponent exercises including muscle power training enhance muscle mass, power output, and functional outcomes in institutionalized frail nonagenarians. Age (Dordr), 36 (2) ( 2014), pp. 773-785

[56] M. Giné-Garriga, M. Guerra, V.B. Unnithan. The effect of functional circuit training on self-reported fear of falling and health status in a group of physically frail older individuals: a randomized controlled trial. Aging Clin Exp Res, 25 (3) ( 2013), pp. 329-336

[57] M. Giné-Garriga, M. Guerra, E. Pagès, T.M. Manini, R. Jiménez, V.B. Unnithan. The effect of functional circuit training on physical frailty in frail older adults: a randomized controlled trial. J Aging Phys Act, 18 (4) ( 2010), pp. 401-424