Frailty
John E. Morley, MD, BCha,b,*,
Matthew T. Haren, PhDa,b,
Yves Rolland, MDc, Moon Jong Kim, MDd
a
Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 South Grand
Boulevard, M238, St. Louis, MO 63104, USA
b
Veterans Aairs Medical Center, GRECC, #1 Jeerson Barracks Dr., St. Louis,
MO 63125, USA
c
Department of Internal Medicine and Geriatrics, Hopital La Grave-Casselardit,
31300 Toulouse, France
d
Department of Family Medicine, Pochon CHA University, 351 Yatap-dong, Bundang-gu,
Sungnam-si, Kyonggi-do, 463-712, Seoul, South Korea
Introduction
The concept of older people becoming frail is not a new one. The ability
to dene frailty in a clinically meaningful manner has remained elusive,
however. Frailty can be considered to occur when under stressful conditions
an individual has diminished ability to carry out important practiced social
activities of daily living. It represents a form of predisability and, as such,
needs to be distinguished from functional impairment [1,2]. Recently, Linda
Fried and her colleagues at Johns Hopkins University have developed objective criteria for the diagnosis of frailty [3,4]. These are: weight loss of more
than 10 lb in one year, physical exhaustion by self report, weakness as measured by grip strength, decline in walking speed, and low physical activity.
The importance of the recognition of frailty is that frail people are more
likely to be precipitated into disability by exposure to a stressor (eg, inuenza or death of a spouse). Early intervention to reverse some of the aspects
of frailty may delay the onset of disability in an older person (Fig. 1).
The development of frailty depends on the interaction of disease
processes with the normal physiologic processes of aging. Genes, environment, and lifestyle all play a role in the pathway to frailty. In the nal analysis, frail people usually have an excess loss of functional muscle associated
* Corresponding author. Division of Geriatric Medicine, Saint Louis University School
of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104.
E-mail address: morley@slu.edu (J.E. Morley).
0025-7125/06/$ - see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2006.05.019
medical.theclinics.com
838
MORLEY
et al
- Exercise
Socialization
- Adequate Nutrition
Mental Activity
Disease Processes
e.g., anemia, heart failure
Frailty
Stressful Event
Recovery
e.g. influenza
death of a spouse
fall
Recovery
Functional Decline
Disability
Hospitalization
Institutionalization
Death
FRAILTY
839
to consider an older person to be sarcopenic when the lean body mass is less
than two standard deviations of the sex-specic mean in a young healthy
sample. Operationally, this can be dened using the following formula derived from measurements using dual-energy x-ray absorptiometry: Appendicular skeletal mass/height2.
These measurements fail to take into account the quality of muscle and
with aging there can be a marked uncoupling of muscle cross-sectional
area and muscle ber strength. Also, there has been increased awareness recently that with aging there is fat accumulation in muscle (myosteatosis),
which results in a decline in muscle function. Using this denition, the prevalence of sarcopenia is approximately 12% for adults 60 to 70 years of age
rising to 30% by 80 years of age. In most studies, the development of sarcopenia is associated strongly with increased disability, gait and balance disorders, and mortality [6,7]. Muscle strength also declines with aging [8].
A second concept is that whereas obese people often have a larger lean
body mass than normal weight people, a small subset actually are sarcopenic. This group has been called the sarcopenic obese or the fat frail.
In the New Mexico Aging Process Study obese sarcopenia was found to
be the best predictor of future disability and mortality [9]. The risk for developing disability in this prospective study was 2.63. Obesity, in the absence
of adequate exercise, is a cause of frailty [10].
There are multiple causes of sarcopenia (Fig. 2). Genes and early life environment clearly play a role. Several genes have been demonstrated to relate clearly to muscle quality in sports stars. An example that can be
extended to older people is the angiotensin converting enzyme (ACE) alleles.
Emerging evidence suggests the ACE inhibitors may retard the loss of
840
MORLEY
et al
muscle strength in some individuals [11]. People with a single or double I allele for ACE can generate more power when exercising regularly than people
with the D allele. The Hartfordshire cohort study demonstrated that grip
strength at 70 years of age is predicted by birth weight [12]. Epidemiologic
studies have demonstrated that predictors of muscle mass and strength with
aging include testosterone, insulinlike growth factor (IGF)-1, physical activity, energy intake, and age [1214].
Muscle is continuously undergoing a process of rejuvenation (Fig. 3).
Muscle proteins are degraded as they become unfolded leading to atrophy,
and cells also can undergo apoptosis (cell death). Rejuvenation occurs because of incorporation of amino acids to drive protein synthesis leading
to muscle hypertrophy and stimulation of stem cells to produce satellite cells
that repair damaged muscle. It needs to be recognized that each time muscle
contracts damage occurs and mechanoreceptors in muscle, such as titin,
stimulate the rejuvenation process. The hypertrophy/atrophy process is regulated by the activation of the PI3K-AKT pathway, which leads to muscle
hypertrophy. This pathway also inhibits muscle atrophy by phosphorylating
forkhead transcription factors (FOXOs) and thus inhibiting the action of
Atrogin I, which carries ubiquitin-tagged proteins to the proteasome (the
cellular death chamber) where they are degraded into small peptides
and amino acids.
The PI3K-AKT pathway is driven by anabolic factors, such as growth
hormone and testosterone, that activate the IGF genes within muscle. There
are three IGF genes. IGF-1 stimulates protein synthesis and muscle hypertrophy. This gene is regulated by growth hormone [15]. Mechanogrowth factor (MGF) is responsible for activating the production of satellite cells and
stimulating the ring of motor unit cells. MGF is stimulated in the rst instance by resistance exercise [16]. Growth hormone can then synergistically
increase this process further but is not eective in the absence of resistance
exercise. This ineectiveness explains why the studies giving growth hormone to older people result in an increase in muscle mass but not in muscle
strength [17,18]. Ghrelin, a growth hormone secretagogue, also increases
FRAILTY
841
muscle mass and food intake [19]. The transgene for MGF, when inserted
into muscle of older rats, has been shown to rejuvenate the muscle [20].
Testosterone is an anabolic hormone that has been demonstrated to increase muscle mass and strength in older hypogonadal men when given at
high doses [2129]. A small number of studies suggest similar eects in
women [30,31]. Testosterone levels decline with aging at the rate of about
1% per year [32,33]. Low testosterone levels are associated with a decrease
in muscle strength and function [34,35]. Androgen deprivation leads to
a loss of muscle mass [36]. In animal models testosterone improves function
in a stroke model [37]. Testosterone replacement results in improved function over a 3-year period in older men [38]. At the cellular level testosterone
stimulates protein synthesis, inhibits the ubiquitin-proteasome pathway, and
most importantly stimulates satellite cell production [3941]. At present, testosterone would appear to be the best pharmacologic agent to treat sarcopenia, but as we have pointed out elsewhere, there are only a limited number of
studies in support of this viewpoint [42]. Dehydroepiandrosterone, a weak
androgen, failed in a well-controlled study to increase muscle mass or
strength at a dose of 50 mg daily given for one year [43].
Myostatin is an inhibitor of muscle regeneration. It has a direct eect inhibiting satellite cell production. A double deletion of the myostatin gene
leads to muscle hypertrophy in mice, cows, and in a single human [44].
Amgen has developed peptobodies to myostatin, which in animal studies
appear to cause muscle hypertrophy.
People who are vitamin D decient have poor muscle function, which is
improved with vitamin D administration [45]. In vitamin Ddecient people
vitamin D supplementation decreases falls and reduces functional impairment [46,47]. Vitamin D levels have been shown to decline throughout the
lifetime in a longitudinal study [48].
Adequate food intake is essential for the maintenance of muscle quality.
Creatine is essential to maintenance of muscle quality [49]. With aging,
many people experience an associated anorexia, which can lead to inadequate protein intake for muscle maintenance [50,51].
Motor unit ring, an important component of muscle maintenance, decreases in people more than 80 years of age [52]. Ciliary neurotrophic factor
(CNTF) levels decline with aging and correlate with the decline in muscle
strength that occurs with aging [53]. CNTF replacement leads to an increase
in muscle mass in animals [54].
The increase in cytokines that occurs with agingdcytokine-related aging
processdis associated with a decline in muscle strength and frailty [55]. Cesari and colleagues [56] showed that high levels of tumor necrosis factora and interleukin-6 are associated with a decline in hand grip strength
and physical performance.
Diabetes mellitus is associated with a decline in muscle strength,
increased falls, and a decrease in function [57]. Diabetes is associated with
an increase in angiotensin II, which stimulates caspase 3 to produce cleavage
842
MORLEY
et al
FRAILTY
843
844
MORLEY
et al
[11] Carter CS, Onder G, Kritchevsky SB, et al. Angiotensin-converting enzyme inhibition intervention in elderly persons: eects on body composition and physical performance. J Gerontol Med Sci 2005;60:143746.
[12] Baumgartner RN, Waters DL, Gallagher D, et al. Predictors of skeletal muscle mass in
elderly men and women. Mech Ageing Dev 1999;107:12336.
[13] Szulc P, Duboeuf F, Marchand F, et al. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 2004;80:496503.
[14] Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of
skeletal muscle mass in healthy, older men and women. J Gerontol Med Sci 2002;57A:
M7727.
[15] Kann PH. Growth hormone in anti-aging medicine: a critical review. Aging Male 2003;6:
25763.
[16] Goldspink G. Age-related muscle loss and progressive dysfunction in mechanosensitive
growth factor signaling. Ann N Y Acad Sci 2004;1019:2948.
[17] Johannsson G, Svensson J, Bengtsson BA. Growth hormone and ageing. Growth Horm IGF
Res 2000;10(Suppl B):S2530.
[18] Roubeno R, Rall LC, Veldhuis JD, et al. The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin. J Clin Endocrinol Metab 1998;83:15026.
[19] Lago F, Gonzalez-Juanatey JR, Casanueva FF, et al. Ghrelin, the same peptide for dierent
functions: player or bystander? Vitam Horm 2005;71:40532.
[20] Musaro A, McCullagh KJ, Naya FJ, et al. IGF-1 induces skeletal myocyte hypertrophy
through calcineurin in association with GATA-2 and NF-ATc1. Nature 1999;400:5815.
[21] Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men:
a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:16617.
[22] Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the
investigation, treatment and monitoring of late-onset hypogonadism in males: scientic
background and rationale. Aging Male 2005;8:5974.
[23] Krause W, Mueller U, Mazur A. Testosterone supplementation in the aging male: which
questions have been answered? Aging Male 2005;8:318.
[24] Morley JE, Perry HM 3rd, Kaiser FE, et al. Eects of testosterone replacement therapy in
old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993;41:14952.
[25] Nieschlag E, Swerdlo R, Behre HM, et al. Investigation, treatment and monitoring of lateonset hypogonadism in males. Aging Male 2005;8:568.
[26] Morley JE, Perry HM 3rd. Androgen treatment of male hypogonadism in older males. J Steroid Biochem Mol Biol 2003;85:36773.
[27] Jockenhovel F. Testosterone therapydwhat, when and to whom? Aging Male 2004;7:31924.
[28] Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the
anabolic eects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol
Metab 2005;90:67888.
[29] Wittert GA, Chapman IM, Haren MT, et al. Oral testosterone supplementation increases
muscle and decreases fat mass in healthy elderly males with low-normal gonadal status.
J Gerontol Med Sci 2003;58:61825.
[30] Morley JE, Perry HM 3rd. Androgens and women at the menopause and beyond. J Gerontol
Med Sci. 2003;58A:M40916.
[31] Morley JE, Kaiser FE. Female sexuality. Med Clin N America 2003;87:107790.
[32] Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing
hormone, and follicle-stimulating hormone in healthy older men. Metab Clin Exper 1997;46:
4103.
[33] Li JY, Li XY, Li M, et al. Decline of serum levels of free testosterone in aging healthy Chinese
men. Aging Male 2005;8:2036.
[34] Kratzik CW, Reiter WJ, Riedl AM, et al. Hormone proles, body mass index and aging male
symptoms: results of the Androx Vienna Municipality study. Aging Male 2004;7:18896.
FRAILTY
845
[35] Perry HM 3rd, Miller DK, Patrick P, et al. Testosterone and leptin in older AfricanAmerican men: relationship to age, strength, function, and season. Metab Clin Exper.
2000;49:108591.
[36] Boxer RS, Kenny AM, Dowsett R, et al. The eect of 6 months of androgen deprivation therapy on muscle and fat mass in older men with localized prostate cancer. Aging Male 2005;8:
20712.
[37] Pan Y, Zhang H, Acharya AB, et al. Eect of testosterone on functional recovery in a castrated male rat stroke model. Brain Res 2005;1043:195204.
[38] Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with nasteride
increases physical performance, grip strength, and lean body mass in older men with low
serum T. J Clin Endocrinol Metab 2005;90:150210.
[39] Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab
Care 2004;7:2717.
[40] Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, et al. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: upregulation by androgen treatment. J Clin
Endocrinol Metab 2004;7:2717.
[41] Morley JE, Kim MJ, Haren MT. Frailty and hormones. Rev Endocrine Metab Dis 2005;6:
1018.
[42] Morley JE. Hormones and the aging process. J Am Geriatr Soc 2003;51(7 Suppl):S3337.
[43] Percheron G, Hogrel JY, Denot-Ledunois S, et al. Eect of 1-year oral administration of
dehydroepiandrosterone to 60- to 80-year-old individuals on muscle function and crosssectional area: a double-blind placebo-controlled trial. Arch Intern Med 2003;163:7207.
[44] Walsh FS, Celeste AJ. Myostatin: a modulator of skeletal-muscle stem cells. Biochem Soc
Trans 2005;33:15137.
[45] Sato Y, Iwamoto J, Kanoko T, et al. Low-dose vitamin D prevents muscular atrophy and
reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis 2005;20:18792.
[46] Schacht E, Richy F, Reginster JY. The therapeutic eects of alfacalcidol on bone strength,
muscle metabolism and prevention of falls and fractures. J Musculoskelet Neuronal Interact
2005;5:27384.
[47] Kannus P, Sievanen H, Palvanen M, et al. Prevention of falls and consequent injuries in
elderly people. Lancet 2005;366:188593.
[48] Perry HM 3rd, Horowitz M, Morley JE, et al. Longitudinal changes in serum 25-hydroxyvitamin D in older people. Metab Clin Exper 1999;48:102832.
[49] Chrusch MJ, Chilibeck PD, Chad KE, et al. Creatine supplementation combined with
resistance training in older men. Med Sci Sports Exerc 2001;33:21117.
[50] Wilson MM, Morley JE. Invited review: aging and energy balance. J Appl Physiol 2003;95:
172836.
[51] Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin Nutr 1997;66:76073.
[52] Roos MR, Rice CL, Connelly DM, et al. Quadriceps muscle strength, contractile properties,
and motor unit ring rates in young and old men. Muscle Nerve 1999;22:1094103.
[53] Roth SM, Schrager MA, Ferrell RE, et al. CNTF genotype is associated with muscular
strength and quality in humans across the adult age span. J Appl Physiol 2001;90:120510.
[54] Marques MJ, Neto HS. Ciliary neurotrophic factor stimulates in vivo myotube formation in
mice. Neurosci Lett 1997;234:436.
[55] Morley JE, Baumgartner RN. Cytokine-related aging process. J Gerontol Med Sci. 2004;
59A:M9249.
[56] Cesari M, Penninx BW, Lauretani F, et al. Hemoglobin levels and skeletal muscle: results
from the InCHIANTI study. J Gerontol Med Sci 2004;59A:24954.
[57] Morley JE. Diabetes mellitus: a major disease of older persons. J Gerontol Med Sci. 2000;
55A:M2556.
[58] Frisoli A Jr, Chaves PH, Pinheiro MM, et al. The eect of nandrolone decanoate on bone
mineral density, muscle mass, and hemoglobin levels in elderly women with osteoporosis:
846
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
MORLEY
et al
FRAILTY
847
[84] Ble A, Volpato S, Zuliani G, et al. Executive function correlates with walking speed in older
persons: the InCHIANTI study. J Am Geriatr Soc 2005;53:4105.
[85] Kamel HK, Perry HM 3rd, Morley JE. Hormone replacement therapy and fractures in older
adults. J Am Geriatr Soc 2001;49:17987.
[86] Fiatarone-Singh MA. Exercise in the oldest old: some new insights and unanswered
questions. J Am Geriatr Soc 2002;50:208991.
[87] Asthana S, Bhasin S, Butler RN, et al. Masculine vitality: pros and cons of testosterone in
treating the andropause. J Gerontol Med Sci. 2004;59:4615.
[88] Miller DK, Morrison MJ, Blair DS, et al. Predilection for frailty remedial strategies among
black and white seniors. South Med J 1998;91:37580.