Skip to main content
SpringerLink
Log in

Sarcopenia: current theories and the potential beneficial effect of creatine application strategies

  • Review Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Sarcopenia, defined as the age-related loss of muscle mass, subsequently has a negative effect on strength, metabolic rate and functionality leading to a reduced quality of life. With the projected increase in life expectancy, the incidence of muscle loss may rise and further drain the health care system, with greater need for hospitalization, treatment, and rehabilitation. Without effective strategies to counteract aging muscle loss, a global health care crisis may be inevitable. Resistance training is well established to increase aging muscle mass and strength. However, muscle and strength loss is still evident in older adults who have maintained resistance training for most of their life, suggesting that other factors such as nutrition may affect aging muscle biology. Supplementing with creatine, a high-energy compound found in red meat and seafood, during resistance training has a beneficial effect on aging muscle. Emerging evidence now suggests that the timing and dosage of creatine supplementation may be important factors for aging muscle accretion. Unfortunately, the long-term effects of different creatine application strategies on aging muscle are relatively unknown.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ansved T, Edstrom L (1990) Effects of age on fibre structure, ultrastructure, and expression of desmin and spectrin in fast-and slow-twitch rat muscles. J Anat 74:61–79

    Google Scholar 

  • Ansved T, Larsson L (1989) The effects of age on contractile, morphometrical and enzyme-histochemical properties of the rat soleus muscle. J Neurol Sci 93:105–124

    Article  PubMed  CAS  Google Scholar 

  • Balagopal P, Schimke JC, Ades P, Adey D, Nair KS (2001) Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise. Am J Physiol Endocrinol Metab 280(2):E203–E208

    PubMed  CAS  Google Scholar 

  • Bales CW, Ritchie CS (2002) Sarcopenia, weight loss, and nutritional frailty in the elderly. Annu Rev Nutr 22:309–323

    Article  PubMed  CAS  Google Scholar 

  • Balsom PD, Soderlund K, Sjodin B, Ekblom B (1995) Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand 154:303–310

    Article  PubMed  CAS  Google Scholar 

  • Bass A, Gutmann E, Hanzlikova V (1975) Biochemical and histochemical changes in energy supply-enzyme pattern of muscles of the rat during old age. Gerontologia 21:31–45

    Article  PubMed  CAS  Google Scholar 

  • Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, Garry PJ, Lindeman RD (1998) Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 147:755–763

    PubMed  CAS  Google Scholar 

  • Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ (1999) Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 107:123–136

    Article  PubMed  CAS  Google Scholar 

  • Bautmans I, Njemini R, Vasseur S, Chabert H, Moens L, Demanet C, Mets T (2005) A fatigue resistance test for elderly persons based on grip strength: reliability and comparison with healthy young subjects. Gerontology 51:253–265

    Article  PubMed  CAS  Google Scholar 

  • Bermon S, Venembre P, Sachet C, Valour S, Dolisi C (1998) Effect of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol Scand 164:147–155

    Article  PubMed  CAS  Google Scholar 

  • Booth FW, Gordon SE, Carlson CJ, Hamilton MT (2000) Waging war on modern chronic diseases: primary prevention through exercise biology. J Appl Physiol 273:774–787

    Google Scholar 

  • Boreham CAG, Watt PW, Williams PE, Merry BJ, Goldspink G, Goldspink DF (1988) Effects of ageing and chronic dietary restriction on the morphology of fast and slow muscles of the rat. J Anat 157:111–125

    PubMed  CAS  Google Scholar 

  • Brack AS, Rando TA (2007) Intrinsic changes and extrinsic influences of myogenic stem cell function during aging. Stem Cell Rev 3:226–237

    Article  PubMed  CAS  Google Scholar 

  • Brody IA (1976) Regulation of isometric contraction in skeletal muscle. Exp Neurol 50:673–683

    Article  PubMed  CAS  Google Scholar 

  • Brose A, Parise G, Tarnopolsky MA (2003) Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J Gerontol A Biol Sci Med Sci 58:11–19

    Article  PubMed  Google Scholar 

  • Burke DG, Chilibeck PD, Parise G, Candow DG, Mahoney D, Tarnopolsky MA (2003) Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med Sci Sports Exerc 35:1946–1955

    Article  PubMed  CAS  Google Scholar 

  • Burke DG, Candow DG, Chilibeck PD, MacNeil LG, Roy BD, Tarnopolsky MA, Ziegenfuss T (2008) Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab 18:389–398

    Article  PubMed  CAS  Google Scholar 

  • Butterfield GE, Thompson J, Rennie MJ, Marcus R, Hintz RL, Hoffman AR (1997) Effect of rhGH and rhIGF-I treatment on protein utilization in elderly women. Am J Physiol 272:E94–E99

    PubMed  CAS  Google Scholar 

  • Candow DG, Chilibeck PD (2008) Timing of creatine or protein supplementation and resistance training in the elderly. Appl Physiol Nutr Metab 33:184–190

    Article  PubMed  CAS  Google Scholar 

  • Candow DG, Chilibeck PD, Facci M, Abeysekara S, Zello GA (2006) Protein supplementation before and after resistance training in older men. Eur J Appl Physiol 97:548–556

    Article  PubMed  CAS  Google Scholar 

  • Candow DG, Little JP, Chilibeck PD, Abeysekara S, Zello GA, Kazachkov M, Cornish SM, Yu PH (2008) Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc 40:1645–1652

    Article  PubMed  CAS  Google Scholar 

  • Chakravarthy MV, Booth FW, Spangenburg EE (2001) The molecular response of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats. Int J Sport Nutr Exerc Metab 11:S44–S48

    PubMed  CAS  Google Scholar 

  • Chilibeck PD, Stride D, Farthing JP, Burke DG (2004) Effect of creatine ingestion after exercise on muscle thickness in males and females. Med Sci Sports Exerc 36:1781–1788

    Article  PubMed  CAS  Google Scholar 

  • Chrusch MJ, Chilibeck PD, Chad KE, Davison KS, Burke DG (2001) Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc 33:2111–2117

    Article  PubMed  CAS  Google Scholar 

  • Combaret L, Dardevet D, Béchet D, Taillandier D, Mosoni L, Attaix D (2009) Skeletal muscle proteolysis in aging. Curr Opin Clin Nutr Metab Care 12:37–41

    Article  PubMed  Google Scholar 

  • Cribb PJ, Hayes A (2006) Effects of supplement timing and resistance exercise on skeletal muscle hypertrophy. Med Sci Sports Exerc 38:1918–1925

    Article  PubMed  Google Scholar 

  • Dangott B, Schultz E, Mozdziak PE (2000) Dietary creatine monohydrate supplementation increases satellite cell mitotic activity during compensatory hypertrophy. Int J Sports Med 12:13–16

    Article  Google Scholar 

  • DeCoster W, deReuck J, Sieben G, Nander Eecken H (1981) Early ultrastructural changes in aging rat gastrocnemius muscle: a stereological study. Muscle Nerve 4:111–116

    Article  CAS  Google Scholar 

  • Deschenes MR (2004) Effects of aging on muscle fibre type and size. Sports Med 34:809–824

    Article  PubMed  Google Scholar 

  • Eijnde BO, Van Leemputte M, Goris M, Labarque V, Taes Y, Verbessem P, Vanhees L, Ramaekers M, Vanden Eynde B, Van Schuylenbergh R, Dom R, Richter EA, Hespel P (2003) Effects of creatine supplementation and exercise training on fitness in males 55 to 75 years old. J Appl Physiol 95:818–828

    PubMed  CAS  Google Scholar 

  • Esmarck B, Andersen JL, Olsen S, Richter EA, Mizuno M, Kjaer M (2001) Timing of postexercise protein intake is important for muscle hypertrophy with resistance training in elderly humans. J Physiol 535:301–311

    Article  PubMed  CAS  Google Scholar 

  • Evans WJ (1995) What is sarcopenia? J Gerontol A Biol Sci Med Sci 50:5–8

    Article  PubMed  Google Scholar 

  • Francaux M, Poortmans JR (1999) Effects of training and creatine supplement on muscle strength and body mass. Eur J Appl Physiol 80:165–168

    Article  CAS  Google Scholar 

  • Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans WJ (1988) Strength conditioning in older men: skeletal muscle hypertrophy and improved function. J Appl Physiol 64:1038–1044

    PubMed  CAS  Google Scholar 

  • Gopinath SD, Rando TA (2008) Stem cell review series: aging of the skeletal muscle stem cell niche. Aging Cell 7:590–598

    Article  PubMed  CAS  Google Scholar 

  • Gotshalk LA, Volek JS, Staron RS, Denegar CR, Hagerman FC, Kraemer WJ (2002) Creatine supplementation improves muscular performance in older men. Med Sci Sports Exerc 34:537–543

    Article  PubMed  CAS  Google Scholar 

  • Gotshalk LA, Kraemer WJ, Mendonca MA, Vingren JL, Kenny AM, Spiering BA, Hatfield DL, Fragala MS, Volek JS (2008) Creatine supplementation improves muscular performance in older women. Eur J Appl Physiol 102:223–231

    Article  PubMed  CAS  Google Scholar 

  • Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL (1996) Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol 271:821–826

    Google Scholar 

  • Greenhaff PL, Casey A, Short AH, Harris R, Soderland K, Hultman E (1993) Influence of oral creatine supplementation on muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci 84:565–571

    PubMed  CAS  Google Scholar 

  • Guerrero-Ontiveros ML, Wallimann T (1998) Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: down-regulation of the expression of creatine transporter in skeletal muscle. Mol Cell Biochem 184:427–437

    Article  PubMed  CAS  Google Scholar 

  • Harris RC, Soderland K, Hultman E (1992) Elevation of creatine in resting and exercise muscle of normal subjects by creatine supplementation. Clin Sci 83:367–374

    PubMed  CAS  Google Scholar 

  • Hawke TJ, Garry DJ (2001) Myogenic satellite cells: physiology to molecular biology. J Appl Physiol 91:534–541

    PubMed  CAS  Google Scholar 

  • Hepple RT (2003) Sarcopenia—a critical perspective. Sci Aging Knowledge Environ 46:pe31

    Google Scholar 

  • Hepple RT, Ross KT, Rempfer AB (2004) Fiber atrophy and hypertrophy in skeletal muscles of late middle-aged Fischer 344 × Brown Norway F1-hybrid rats. J Gerontol A Biol Sci Med Sci 59:108–117

    Article  PubMed  Google Scholar 

  • Hespel P, Op’t Eijnde B, Van Leemputte M, Urso B, Greenhaff PL, Labarque V, Dymarkowski S, Van Hecke P, Richter EA (2001) Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J Physiol 536:625–633

    Article  PubMed  CAS  Google Scholar 

  • Hughes VA, Frontera WR, Roubenoff R, Evans WJ, Singh MA (2002) Longitudinal changes in body composition in older men and women: role of body weight change and physical activity. Am J Clin Nutr 76:473–481

    PubMed  CAS  Google Scholar 

  • Ingwall JS, Weiner CD, Morales MF, Stockdale FE (1974) Specificity of creatine in the control of muscle protein synthesis. J Cell Physiol 63:145–151

    Google Scholar 

  • Jakobi JM, Rice CL, Curtin SV, Marsh GD (2001) Neuromuscular properties in older men following acute creatine supplementation. Eur J Appl Physiol 84:312–328

    Article  Google Scholar 

  • Jejurikar SS, Henkelman EA, Cederna PS, Marcelo CL, Urbanchek MG, Kuzon WM Jr (2006) Aging increases the susceptibility of skeletal muscle derived satellite cells to apoptosis. Exp Gerontol 41:828–836

    Article  PubMed  CAS  Google Scholar 

  • Johnston AP, De Lisio M, Parise G (2008) Resistance training, sarcopenia, and the mitochondrial theory of aging. Appl Physiol Nutr Metab 33:191–199

    Article  PubMed  CAS  Google Scholar 

  • Kadi F (2000) Adaptation of human skeletal muscle to training and anabolic steroids. Acta Physiol Scand 646:1–52

    CAS  Google Scholar 

  • Karakelides H, Nair KS (2005) Sarcopenia of aging and its metabolic impact. Curr Top Dev Biol 68:123–148

    Article  PubMed  CAS  Google Scholar 

  • Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR (2006) A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 291:E381–E387

    Article  PubMed  CAS  Google Scholar 

  • Kreider RB, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J, Cantler E, Almada AL (1998) Effects of creatine supplementation on body composition, strength and sprint performance. Med Sci Sports Exerc 30:73–82

    PubMed  CAS  Google Scholar 

  • Ladner KJ, Caligiuri MA, Guttridge DC (2003) Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. J Biol Chem 278:2294–2303

    Article  PubMed  CAS  Google Scholar 

  • Larsson L, Salviati G (1989) Effects of age on calcium transport activity of sarcoplasmic reticulum in fast- and slow-twitch rat muscle fibres. J Physiol 419:253–264

    PubMed  CAS  Google Scholar 

  • Larsson L, Yu F, Hook P, Ramamurthy B, Marx JO, Pircher P (2001) Effects of aging on regulation of muscle contraction at the motor unit, muscle cell, and molecular levels. Int J Sport Nutr Exerc Metab 11:28–43

    Google Scholar 

  • Lukaski HC, Mendez J, Buskirk ER, Cohn SH (1981) Relationship between endogenous 3-methylhistidine excretion and body composition. Am J Physiol 240:302–307

    Google Scholar 

  • Lykken GI, Jacob RA, Munoz JM, Sandstead HH (1980) A mathematical model of creatine metabolism in normal males-comparison between theory and experiment. Am J Clin Nutr 33:2674–2685

    PubMed  CAS  Google Scholar 

  • Marcell TJ (2003) Sarcopenia: causes, consequences, and preventions. J Gerontol A Biol Sci Med Sci 58:911–916

    Article  Google Scholar 

  • Marx JO, Kraemer WJ, Kolluri R, Pircher P, Larsson L (2002) The effects of aging on myosin heavy chain concentration in skeletal muscle fibers of young and old men. J Gerontol A Biol Sci Med Sci 57:232–238

    Article  Google Scholar 

  • Marzetti E, Lees HA, Wohlgemuth SE, Leeuwenburgh C (2009) Sarcopenia of aging: underlying cellular mechanisms and protection by calorie restriction. Biofactors 35:28–35

    Article  PubMed  CAS  Google Scholar 

  • Mauro A (1961) Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 9:493–495

    Article  PubMed  CAS  Google Scholar 

  • Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olsen JL, Seutta C, Kjaer M (2006) Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol 1:525–534

    Article  Google Scholar 

  • Papadimitropoulos EA, Coyte PC, Josse RG, Greenwood CE (1997) Current and projected rates of hip fracture in Canada. CMAJ 157:1357–1363

    PubMed  CAS  Google Scholar 

  • Persky AM, Brazeau GA (2001) Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev 53:161–176

    PubMed  CAS  Google Scholar 

  • Phillips SM (2004) Protein requirements and supplementation in strength sports. Nutrition 20:689–695

    Article  PubMed  CAS  Google Scholar 

  • Piers LS, Soares MJ, McCormack LM, O’Dea K (1998) Is there evidence for an age-related reduction in metabolic rate? J Appl Physiol 85:2196–2204

    PubMed  CAS  Google Scholar 

  • Rawson ES, Clarkson PM (2000) Acute creatine supplementation in older men. Int J Sport Nutr Exerc Metab 21:71–75

    CAS  Google Scholar 

  • Rawson ES, Wehnert ML, Clarkson PM (1999) Effects of 30 days of creatine ingestion in older men. Eur J Appl Physiol 80:139–144

    Article  CAS  Google Scholar 

  • Rennie MJ, Millward DL (1983) 3-Methylhistidine excretion and urinary 3-methylhistidine/creatinine ratios are poor indicators of skeletal muscle protein breakdown. Clin Sci 65:217–225

    PubMed  CAS  Google Scholar 

  • Rennie MJ, Tipton KD (2000) Protein and amino acid metabolism during and after exercise and the effects of nutrition. Annu Rev Nutr 20:457–483

    Article  PubMed  CAS  Google Scholar 

  • Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW (2004) Control of the size of the human muscle mass. Annu Rev Physiol 66:799–828

    Article  PubMed  CAS  Google Scholar 

  • Robinson TM, Sewell DA, Hultman E, Greenhaff PL (1999) Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol 87:598–604

    PubMed  CAS  Google Scholar 

  • Rooyackers OE, Adey DB, Ades PA, Nair KS (1996) Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proc Natl Acad Sci 93:15364–15369

    Article  PubMed  CAS  Google Scholar 

  • Roubenoff R (2000) Sarcopenia and its implications of the elderly. Eur J Clin Nutr 54:S40–S47

    PubMed  Google Scholar 

  • Roubenoff R (2003) Sarcopenia: effects on body composition and function. J Gerontol A Biol Sci Med Sci 58:1012–1017

    Article  PubMed  Google Scholar 

  • Roubenoff R, Hughes VA (2000) Sarcopenia: current concepts. J Gerontol A Biol Sci Med Sci 55:M716–M724

    Article  PubMed  CAS  Google Scholar 

  • Ryall JG, Schertzer JD, Lynch GS (2008) Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness. Biogerontology 9:213–228

    Article  PubMed  CAS  Google Scholar 

  • Sehl ME, Yates FE (2001) Kinetics of human aging: I. Rates of senescence between ages 30 and 70 years in healthy people. J Gerontol A Biol Sci Med Sci 56:B198–B208

    Article  PubMed  CAS  Google Scholar 

  • Short KR, Nair KS (2001) Muscle protein metabolism and the sarcopenia of aging. Int J Sport Nutr Exerc Metab 11:S119–S127

    PubMed  CAS  Google Scholar 

  • Sipilä S, Elorinne M, Alen M, Suominen H, Kovanen V (1997) Effects of strength and endurance training on muscle fibre characteristics in elderly women. Clin Physiol 17:459–474

    Article  PubMed  Google Scholar 

  • Smith SA, Montain SJ, Matott RP, Zientara GP, Jolesz FA, Fielding RA (1998) Creatine supplementation and age influence muscle metabolism during exercise. J Appl Physiol 85:1349–1356

    PubMed  CAS  Google Scholar 

  • Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63

    Article  PubMed  CAS  Google Scholar 

  • Tarnopolsky M, Zimmer A, Paikin J, Safdar A, Aboud A, Pearce E, Roy B, Doherty T (2007) Creatine monohydrate and conjugated linoleic acid improve strength and body composition following resistance exercise in older adults. PLoS ONE 2(10):e991

    Article  PubMed  Google Scholar 

  • Thompson LV (2009) Age-related muscle dysfunction. Exp Gerontol 44:106–111

    Article  PubMed  CAS  Google Scholar 

  • Tipton KD, Rasmussen BB, Miller SL, Wolf SE, Owens-Stovall SK, Petrini BE, Wolfe RR (2001) Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise. Am J Physiol Endocrinol Metab 281:197–206

    Google Scholar 

  • Trappe S (2001) Master athletes. Int J Sport Nutr Exerc Metab 11:196–207

    Google Scholar 

  • Verdijk LB, Koopman R, Schaart G, Meijer K, Savelberg HH, van Loon LJ (2007) Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly. Am J Physiol Endocrinol Metab 292:E151–E157

    Article  PubMed  CAS  Google Scholar 

  • Vierck J, O’Reilly B, Hossner K, Antonio J, Byrne K, Bucci L, Dodson M (2000) Satellite cell regulation following myotrauma caused by resistance exercise. Cell Biol Int 24:263–272

    Article  PubMed  CAS  Google Scholar 

  • Viner RI, Ferrington DA, Hühmer AF, Bigelow DJ, Schöneich C (1996) Accumulation of nitrotyrosine on the SERCA2a isoform of SR Ca-ATPase of rat skeletal muscle during aging: a peroxynitrite-mediated process? FEBS Lett 379:286–290

    Article  PubMed  CAS  Google Scholar 

  • Walker JB (1979) Creatine: biosynthesis, regulation and function. Adv Enzymol Relat Areas Mol Biol 50:177–242

    PubMed  CAS  Google Scholar 

  • Welle S, Thornton CA (1998) High-protein meals do not enhance myofibrillar synthesis after resistance exercise in 62- to 75-yr-old men and women. Am J Physiol 274:677–683

    Google Scholar 

  • Welle S, Thornton C, Statt M, McHenry B (1996) Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years old. J Clin Endocrinol Metab 81:3239–3243

    Article  PubMed  CAS  Google Scholar 

  • Willoughby DS, Rosene JM (2003) Effects of oral creatine and resistance training on myogenic regulatory factor expression. Med Sci Sports Exerc 35:923–929

    Article  PubMed  CAS  Google Scholar 

  • Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Kinesiology and Health Studies, Centre on Aging and Health, University of Regina, Regina, SK, S4S 0A2, Canada

    Darren G. Candow

Authors
  1. Darren G. Candow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Darren G. Candow.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Candow, D.G. Sarcopenia: current theories and the potential beneficial effect of creatine application strategies. Biogerontology 12, 273–281 (2011). https://doi.org/10.1007/s10522-011-9327-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-011-9327-6

Keywords

Search

Navigation