Exercise training as S-Klotho protein stimulator in sedentary healthy adults: Rationale, design, and methodology

Francisco J Amaro-Gahete, Alejandro De-la-O, Lucas Jurado-Fasoli, Andrea Espuch-Oliver, Lidia Robles-Gonzalez, Ginés Navarro-Lomas, Tomás de Haro, Pedro Femia, Manuel J Castillo, Angel Gutierrez, Francisco J Amaro-Gahete, Alejandro De-la-O, Lucas Jurado-Fasoli, Andrea Espuch-Oliver, Lidia Robles-Gonzalez, Ginés Navarro-Lomas, Tomás de Haro, Pedro Femia, Manuel J Castillo, Angel Gutierrez

Abstract

Aims: The secreted form of the α-Klotho gene (S-Klotho), which is considered a powerful biomarker of longevity, makes it an attractive target as an anti-ageing therapy against functional decline, sarcopenic obesity, metabolic and cardiovascular diseases, osteoporosis, and neurodegenerative disorders. The S-Klotho plasma levels could be related to physical exercise inasmuch physical exercise is involved in physiological pathways that regulate the S-Klotho plasma levels. FIT-AGEING will determine the effect of different training modalities on the S-Klotho plasma levels (primary outcome) in sedentary healthy adults. FIT-AGEING will also investigate the physiological consequences of activating the klotho gene (secondary outcomes).

Methods: FIT-AGEING will recruit 80 sedentary, healthy adults (50% women) aged 45-65 years old. Eligible participants will be randomly assigned to a non-exercise group, i.e. the control group, (n = 20), a physical activity recommendation from World Health Organization group (n = 20), a high intensity interval training group (n = 20), and a whole-body electromyostimulation group (n = 20). The laboratory measurements will be taken at the baseline and 12 weeks later including the S-Klotho plasma levels, physical fitness (cardiorespiratory fitness, muscular strength), body composition, basal metabolic rate, heart rate variability, maximal fat oxidation, health blood biomarkers, free-living physical activity, sleep habits, reaction time, cognitive variables, and health-related questionnaires. We will also obtain dietary habits data and cardiovascular disease risk factors.

Figures

Fig. 1
Fig. 1
Flow diagram of the study participants.

References

    1. Wallace R.G., Twomey L.C., Custaud M.-A., Turner J., Moyna N., Cummins P.M., Murphy R.P. The role of epigenetics in cardiovascular health and aging: a focus on physical activity and nutrition. Mech. Ageing Dev. 2017
    1. Murray C.J.L., Barber R.M., Lopez A.D., Vos T. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015;386:2145–2191.
    1. Wilmoth J. Demography of longevity: past, present, and future trends. Exp. Gerontol. 2000;35:1111–1129.
    1. Kingsley D. Aging and health care costs: narrative versus reality. Poverty & Public Policy. 2015;7:3–21.
    1. Lowsky D.J., Olshansky S.J., Bhattacharya J., Goldman D.P. Heterogeneity in healthy aging. J. Gerontol. A. Biol. Sci. Med. Sci. 2014;69:640–649.
    1. Mora J.C., Valencia W.M. Exercise and older adults. Clin. Geriatr. Med. 2018;34:145–162.
    1. Kim J.-H., Hwang K.-H., Park K.-S., Kong I.D., Cha S.-K. Biological role of anti-aging protein Klotho. J. Lifestyle Med. 2015;5:1–6.
    1. Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H., Suga T., Utsugi T., Iwasaki H. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.
    1. Hu M., Shi M., Zhang J., Pastor J., Nakatani T., Lanske B., Moe O. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. Faseb. J. 2010;24:3438–3450.
    1. Hu J., Shi M., Zhang J., Quiñones H., Griffith C., Kuro-o M. Klotho deficiency causes vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 2011;22:124–136.
    1. Cha S.K., Hu M.C., Kurosu H., Kuro-o M., Moe O. Huang, Regulation of renal outer medullary potassium channel and renal K+ excretion by Klotho. Mol. Pharmacol. 2009;76:38–46.
    1. Kim J.-H., Hwang K.-H., Park K.-S., Kong I., Cha S.-K. Biological role of anti-aging protein klotho. J Lifestyle Med. 2015;5:1–6.
    1. Yamamoto M., Clark J., Pastor J.V., Gurnani P., Nandi A., Kurosu H. Regulation of oxidative stress by the anti-aging hormone klotho. Biol. Chem. 2005;280:3829–3834.
    1. Kurosu H., Yamamoto M., Clark J.D., Pastor J.V., Nandi A., Gurnani P., Shimomura I. Suppression of aging in mice by the hormone Klotho. Science. 2005;30:1829–1833. (80)
    1. Doi S., Zou Y., Togao O., Pastor J.V., John G.B., Wang L., Takahashi M. Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J. Biol. Chem. 2011;286:8655–8665.
    1. Segawa H., Yamanaka S., Ohno Y., Onitsuka A., Shiozawa K., Aranami F., Furutani J., Tomoe Y., Ito M., Kuwahata M., Imura A., Nabeshima Y., Miyamoto K. Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. Am. J. Physiol. Ren. Physiol. 2007;292:F769–F779.
    1. Myers J., McAuley P., Lavie C., Despres J., Arena R., Kokkinos P. Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status. Prog. Cardiovasc. Dis. 2015;57:306–314.
    1. Lee M., Artero E.G., Sui X., Blair S. Review: mortality trends in the general population: the importance of cardiorespiratory fitness. J. Psychopharmacol. 2010;24:27–35.
    1. Volaklis K., Halle M. Meisinger, Muscular strength as a strong predictor of mortality: a narrative review. Eur. J. Intern. Med. 2015;26:303–310.
    1. Castillo-Garzón M., Ruiz J., Ortega F., Gutiérrez A. Anti-aging therapy through fitness enhancement. Clin. Interv. Aging. 2006;1:213–220.
    1. Kodama S., Saito K., Tanaka S., Maki M., Yachi Y. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. Jama. 2009;301:2024–2035.
    1. Vrachimis A., Hadjicharalambous M., Tyler C. The effect of circuit training on resting heart rate variability, cardiovascular disease risk factors and physical fitness in healthy untrained adults. Health (Irvine. Calif) 2016;8:144–148.
    1. Schjerve I., Tyldum G.A., Tjønna A.E., Stølen T., Loennechen J.P., Hansen H. Both aerobic endurance and strength training programmes improve cardiovascular health in obese adults. Clin. Sci. 2008;115:283–293.
    1. Cartee G., Hepple R.T., Bamman M.M., Zierath J. Exercise promotes healthy aging of skeletal muscle. Cell Metabol. 2016;23:1034–1047.
    1. Fritzen A., Madsen A.B., Kleinert M., Treebak J.T., Lundsgaard A.M., Jensen T.E., Frøsig C. Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation. J. Physiol. 2016;594:745–761.
    1. Tanimura T., Aoi W., Takanami Y., Kawai Y., Mizushima K., Naito Y., Yoshikawa T. Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Phys. Rep. 2016;4:128–138.
    1. Phelps M., Pettan-Brewer C., Ladiges W., Yablonka-Reuveni Z. Decline in muscle strength and running endurance in klotho deficient C57BL/6 mice. Biogerontology. 2013;14:729–739.
    1. Mostafidi E., Moeen A., Nasri H., Hagjo A., Ardalan M., Ghorbani-Hagjo A., Ardalan M. Serum klotho levels in trained athletes. Nephro-Urol. Mon. 2016;8:1.
    1. Santos-Dias A., MacKenzie B., Oliveira-Junior M., Moyses R., Consolim-Colombo F., Vieira R. Longevity protein klotho is induced by a single bout of exercise. Br. J. Sports Med. 2016;1:1.
    1. Matsubara T., Miyaki A., Akazawa N., Choi Y., Ra S.-G., Tanahashi K., Kumagai H., Oikawa S., Maeda S. Aerobic exercise training increases plasma Klotho levels and reduces arterial stiffness in postmenopausal women. Am. J. Physiol. Heart Circ. Physiol. 2014;306:H348–H355.
    1. Ahima R. Connecting obesity, aging and diabetes. Nat. Med. 2009;15:996–997.
    1. Saghiv M., Goldhammer E., Sagiv M., Ben-Sira D. Effects of aerobic exercise training on S-Klotho in young and elderly. Jpn. J. Physiol. 2015;1:1–2.
    1. Schulz D., Grimes K.F. Generation of allocation sequences in randomised trials: chance, not choice. Lancet. 2002;359:515–519.
    1. Hawkins D. Chapmanan; London: 1980. Identification of Outliers.
    1. Chow S., Wang H., Shao J. CRC; 2007. Sample Size Calculations in Clinical Research.
    1. Ruiz J.R., Perales M., Pelaez M., Lopez C., Lucia A., Barakat R. Supervised exercise-based intervention to prevent excessive gestational weight gain: a randomized controlled trial. Mayo Clin. Proc. 2013;88:1388–1397.
    1. Sanchez-Delgado G., Martinez-Tellez B., Olza J., Aguilera C.M., Labayen I., Ortega F.B., Ruiz J. Activating brown adipose tissue through exercise (ACTIBATE) in young adults: rationale, design and methodology. Contemp. Clin. Trials. 2015;45:416–425.
    1. Holm S. A simple sequentially rejective multiple test procedure. Scand. J. Stat. 1979;1:65–70.
    1. Hollis F., Campbell S. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999;319:374–670.
    1. Pedersen B., Saltin B.K. Evidence for prescribing exercise as therapy in chronic disease. Scand. J. Med. Sci. Sports. 2006;16:3–63.
    1. WHO . World Health Organ publications; Geneva, Switzerland: 2010. Global Recommendations on Physical Activity for Health.
    1. US . 2016. Department of Health and Human Services. Physical Activity Guidelines.
    1. ACSM American College of Sports Medicine position stand. Progression models in resistance training for healthy adults. Med. Sci. Sports Exerc. 2009;41:687–708.
    1. Garber C.E., Blissmer B., Deschenes M., Franklin B.A., Lamonte M.J., Lee I.M., Swain D. American college of sports medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med. Sci. Sports Exerc. 2011;43:1334–1359.
    1. Marchese A., Hill A.R. Pearson; Sydney (Australia): 2011. The essential guide to fitness: for the fitness instructor.
    1. Schoenfeld B. The mechanisms of muscle hypertrophy and their application to resistance training. J. Strength Condit Res. 2010;24:2857–2872.
    1. Schoenfeld B.J., Ogborn D., Krieger J. Effects of resistance training frequency on measures of muscle hypertrophy: a systematic review and meta-analysis. Sports Med. 2016;1:1–9.
    1. Hwang C.L., Yoo J.K., Kim H.K., Hwang M.H., Handberg E.M., Petersen J.W., Christou D. Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults. Exp. Gerontol. 2016;82:112–119.
    1. Gibala M.J., Little J.P., MacDonald M.J., Hawley J. Physiological adaptations to low-volume, high-intensity interval training in health and disease. J. Physiol. 2012;590:1077–1084.
    1. Ulbrich A., Angarten V.G., Netto A.S., Sties S.W., Bündchen D.C., de Mara L.S., de Carvalho T. Comparative effects of high intensity interval training versus moderate intensity continuous training on quality of life in patients with heart failure: study protocol for a randomized controlled trial. Clin. Trials Regul. Sci. Cardiol. 2016;13:21–28.
    1. Hwang C.L., Chou C.H., Wu Y. Effect of aerobic interval training on exercise capacity and metabolic risk factors in people with cardiometabolic disorders: a meta-analysis. J Cardiopulm Rehabil Prev. 2011;31
    1. Buchheit M., Laursen P. High-intensity interval training, solutions to the programming puzzle. Sports Med. 2013;43:313–338.
    1. Lunt H., Draper N., Marshall H.C., Logan F.J., Hamlin M.J., Shearman J.P., Frampton C. High intensity interval training in a real world setting: a randomized controlled feasibility study in overweight inactive adults, measuring change in maximal oxygen uptake. PLoS One. 2014;9
    1. Borg G.A. Psychophysical bases of perceived exertion. Med. Sci. Sports Exerc. 1982;14:377–381.
    1. Herbert P., Grace F.M., Sculthorpe N. Exercising caution: prolonged recovery to a single session of high intensity interval training in older men. J Am Gerontol Soc. 2015;1:13–19.
    1. Filipovic A., Kleinöder H., Plück D., Hollmann W., Bloch W., Grau M. Influence of whole-body electrostimulation on human red blood cell deformability. J. Strength Condit Res. 2015;29:2570–2578.
    1. Kemmler W., Von-Stengel S., Schwarz J., Mayhew J. Effect of whole-body electromyostimulation on energy expenditure during exercise. J. Strength Condit Res. 2012;26:240–245.
    1. Kemmler W., Schliffka R., Mayhew J., von Stengel S. Effects of whole-body electromyostimulation on resting metabolic rate, body composition, and maximum strength in postmenopausal women: the training and electrostimulation trial. J. Strength Condit Res. 2010;24:1880–1887.
    1. Kemmler W., Teschler M., Weißenfels A., Bebenek M., Fröhlich M., Kohl M., von Stengel S. Effects of whole-body electromyostimulation versus high-intensity resistance exercise on body composition and strength: a randomized controlled study. Complement. Altern. Med. 2016;1:1–9.
    1. Kemmler W., Teschler M., Bebenek M., Von Stengel S. (Very) high Creatinkinase concentration after exertional whole-body electromyostimulation application: health risks and longitudinal adaptations. Wien Med. Wochenschr. 2015;165:427–435.
    1. Finsterer J., Stöllberger C. Severe rhabdomyolysis after MIHA-bodytec® electrostimulation with previous mild hyper-CK-emia and non-compaction. Int. J. Cardiol. 2015;180:100–102.
    1. Malnick S., Band Y., Alin P., Maffiuletti N. It's time to regulate the use of whole body electrical stimulation. BMJ. 2016;352:1693.
    1. Kemmler W., Froehlich M., Stengel V., Kleinöder H. Whole-body electromyostimulation–the need for common sense! Rationale and guideline for a safe and effective training. Dtsch. Z. Sportmed. 2016;67
    1. Verdijk L.B., Koopman R., Schaart G., Meijer K., Savelberg H.H., Loon L. Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly. Am. J. Physiol. Metab. 2007;292:151–157.
    1. Deschenes M. Effects of aging on muscle fibre type and size. Sports Med. 2004;34:809–824.
    1. Filipovic A., Kleinöder H., Dörmann U., Mester J. Electromyostimulation—a systematic review of the influence of training regimens and stimulation parameters on effectiveness in electromyostimulation training of selected strength parameters. J. Strength Condit Res. 2011;25:3218–3230.
    1. Borg A., Kaijser E. A comparison between three rating scales for perceived exertion and two different work tests. Scand. J. Med. Sci. Sports. 2006;16:57–69.
    1. Von-Stengel S., Bebenek M., Engelke K., Wolfgang K. Whole-body electromyostimulation to fight osteopenia in elderly females: the randomized controlled training and electrostimulation trial (TEST-III) J. Osteoporos. 2015;11:1–7.
    1. Balke R., Ware B. An experimental study of physical fitness of Air Force personnel. United States Armed Forces Med. Journal. 1959;10:675–688.
    1. Wei M., Kampert J.B., Barlow C.E., Nichaman M.Z., Gibbons L.W., Paffenbarger R.S., Blair S. Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. Jama. 1999;282:1547–1553.
    1. Sui X., LaMonte M.J., Laditka N., Hardin J.W., Chase N., Hooker S.P., Blair S. Cardiorespiratory fitness and adiposity as mortality predictors in older adults. J. Am. Med. Assoc. 2007;298:2507–2516.
    1. Ortega F.B., Lee D.C., Katzmarzyk T., Ruiz J.R., Sui X., Church T.S., Blair S. The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness. Eur. Heart J. 2013;34:389–397.
    1. Pallarés J., Morán-Navarro R. Methodological approach to the cardiorespiratory endurance training. J. Sport Heal. Res. 2012;4:119–136.
    1. Poole D.C., Jones A.M. Measurement of the maximum oxygen uptake V̇O2max: V̇O2peak is no longer acceptable. J. Appl. Physiol. 2017;122:997–1002.
    1. Artero E.G., Espada-Fuentes J.C., Argüelles-Cienfuegos J., Román A., Gómez-López P.J., Gutiérrez A. Effects of whole-body vibration and resistance training on knee extensors muscular performance. Eur. J. Appl. Physiol. 2012;112:1371–1378.
    1. Ruiz-Ruiz J., Mesa J., Gutiérrez A., Castillo M. Hand size influences optimal grip span in women but not in men. J. Hand Surg. Am. 2002;27:897–901.
    1. McGill S., Childs A., Liebenson C. Endurance times for low back stabilization exercises: clinical targets for testing and training from a normal database. Arch. Phys. Med. Rehabil. 1999;80:941–944.
    1. Shamsi M.B., Rezaei M., Zamanlou M., Sadeghi M., Pourahmadi M. Does core stability exercise improve lumbopelvic stability (through endurance tests) more than general exercise in chronic low back pain? A quasi-randomized controlled trial. Physiother. Theory Pract. 2016;32:171–178.
    1. Willson J., Dougherty C.P., Ireland M.L., Davis I. Core stability and its relationship to lower extremity function and injury. J. Am. Acad. Orthop. Surg. 2005;13:316–325.
    1. Fullmer S., Benson-Davies S., Earthman C.P., Frankenfield D.C., Gradwell E., Lee P., Trabulsi J. Evidence analysis library review of best practices for performing indirect calorimetry in healthy and Non-critically ill individuals. J. Acad. Nutr. Diet. 2015;115:1417–1446.
    1. Compher C., Frankenfield D., Keim N., Roth-Yousey L. Best practice methods to apply to measurement of resting metabolic rate in adults: a systematic review. J. Am. Diet Assoc. 2006;106:881–903.
    1. Achten M., Gleeson A.E., Jeukendrup A. Determination of the exercise intensity that elicits maximal fat oxidation. Med. Sci. Sports Exerc. 2002;34:92–97.
    1. Tarvainen M.P., Niskanen P., Lipponen J.A., Ranta-Aho P.O., Karjalainen P. Kubios HRV–heart rate variability analysis software. Comput. Meth. Progr. Biomed. 2014;113:210–220.
    1. John N.A., Saranya K., Dhanalakshmi Y., John J. Aging-mediated neuromuscular instability and delayed choice reaction time. Int. J. Med. Sci. Publ. Health. 2016;5
    1. Bright P., Hale E., Gooch V.J., Myhill T., van der Linde I. The national adult reading test: restandardisation against the wechsler adult intelligence scale. Neuropsychol. Rehabil. 2016;1:1–9.
    1. Tian Y., Xu S. Association of sarcopenic obesity with the risk of all-cause mortality: a meta-analysis of prospective cohort studies. Geriatr. Gerontol. Int. 2016;16:155–166.
    1. Strawbridge W.J., Wallhagen M., Cohen R. Successful aging and well-being: self-rated compared with rowe and kahn. Gerontol. 2002;42:727–733.
    1. Rowe R., Kahn J. Human aging: usual and successful. Science. 1987;237:143–149.
    1. Kuro-o M. Klotho. Pflügers Arch. J. Physiol. 2010;459:333–343.

Source: PubMed

3
Iratkozz fel