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Sarcopenic Obesity
C H A P T E R
6 Sarcopenic Obesity Andrea P. Rossi, Sofia Rubele and Mauro Zamboni Department of Medicine, Geriatric Division, University of Verona, Verona, Italy
INTRODUCTION The prevalence of obesity in older adults has increased in recent years; for example, in the United States, nearly 30% in men and in women aged 60 years and over, with increase also in extreme degree obesity [1]. High prevalence of obesity has been observed in Europe [2,3]. With aging, a progressive increase in fat mass, which normally peaks at about age 65 years in men and later in women is observed [4]. Aging is associated also with body fat distribution changes, with visceral abdominal fat increase and subcutaneous abdominal fat decrease [5]. Moreover in the elderly, ectopic fat deposition within nonadipose tissue such as the skeletal and cardiac muscle, liver, and pancreas has been observed [6,7]. This phenomenon occurs even without significant changes in body mass index (BMI) or body weight. On the counterpart, age-associated muscle mass and strength loss occur even in relatively weight stable healthy individuals [8].
SARCOPENIC OBESITY (SO) DEFINITION In 2000, Baumgartner introduced the term of sarcopenic obesity (SO), a condition characterized by coexistence of low muscle mass and a high body fat mass [9]. By the time, more definitions of SO have been proposed (Table 6.1 shows different SO definition). 1. The definition proposed by Baumgartner et al. [9] may underestimate sarcopenia in overweight and obese subjects, thus leading to an underdiagnosis of SO. In general, all the proposed SO definitions raise some concern. The main limitations of both are listed below. 2. All definitions do not take into account quality of muscle parameters and in particular fat infiltration and fibrosis. It has been documented that the amount of triglycerides in
Nutrition and Skeletal Muscle DOI: https://doi.org/10.1016/B978-0-12-810422-4.00006-3
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TABLE 6.1 Sarcopenic and Dynapenic Obesity Definitions and Prevalence Study
Definition of sarcopenic obesity
N
Mean age (SD)
Prevalence
New Mexico Aging Process Study [9]
• Sarcopenia: skeletal muscle mass 22 SD below mean of young population or ,7.26 kg/m2 in men and ,5.45 kg/m2 in women • Obesity: percentage body fat greater than median or .27% in men and .38% in women
831
60 and over
M: 4.4%, F: 3.0%
NHANES III [10]
• Sarcopenia: two lower quartiles of muscle mass (,9.12 kg/m2 in men and ,6.53 kg/m2 in women) • Obesity: two higher quintiles of fat mass ( . 37.2% in men and .40.0% in women)
2982
M: 76.3 (1.7), F: 77.3 (2.2)
M: 9.6%, F: 7.4%
Verona Health ABC Study, Italy [11]
• Sarcopenia: two lower quintiles of muscle mass (,5.7 kg/m2 in women) • Obesity: two higher quintiles of fat mass ( . 42.9% in women)
167
F: 71.7 (2.4)
F:12.4%
InChianti, Italy [12]
• Impaired strength: lower gender-specific tertile of handgrip strength (,32 kg for men and ,18 kg for women) • Obesity BMI $ 30 kg/m2
856
74.3 (6.9)
M: 6.3%, F: 8.7%
LASA [13]
• Impaired strength: lower gender-specific tertile of handgrip strength (,33 kg for men and ,20 kg for women) • Obesity BMI $ 30 kg/m2
1189
75.8 (7.2)
M: 5.1%, F: 8.9%
EXERNET Study, Spain [3]
• Sarcopenia: two lower quintiles of muscle mass (,8.61 kg/m2 in men and ,6.19 kg/m2 in women) • Obesity: two higher quintiles of fat mass ( . 30.3% in men and .40.9% in women)
3176
M: 72.4 (5.5), F: 72.1 (5.2)
M: 17.7%F: 14.0%
Health 2000 Survey, Finland [14]
• Impaired strength: lower gender-specific tertile of handgrip strength (,322 N for men and ,176 N for women) • Obesity BMI $ 30 kg/m2
1413
75.8 (7.1)
M: 6.1%, F: 11.0%
InChianti, Italy [15]
• Sex-specific lowest tertile of handgrip strength (,33 kg in men and ,19 kg in women) • Visceral obesity: sex-specific cutoff based on waist circumference tertiles (99 cm in men and 95 cm in women)
846
74.5 (6.9)
M: 8.1%, F: 12.6%
Verona Health ABC Study, Italy [16]
• Sex-specific lowest tertile of leg strength (15.33 kg in men and ,8.33 kg in women) • Visceral obesity: sex-specific cutoff based on waist circumference tertiles (100 cm in men and 87 cm in women)
262
71.8 (2.2)
12.2%
BMI, body mass index; LASA, Longitudinal Aging Study Amsterdam.
PATHOGENESIS OF SO
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muscle increases with both ageing and obesity [17,18]: mid-thigh low-density lean tissue, a surrogate of muscle fat infiltration, as evaluated by computed tomography, has been observed to be directly associated with age and adiposity [19]. In fact, both Dual Energy X-ray Absorptiometry (DXA) and Bioelectrical impedence analysis (BIA), the body composition methods usually recommended for definition of sarcopenia, are not able to recognize neither myosteatosis (MS) nor myofibrosis (MF) [13]. 3. SO definition doesn’t take into account muscle function in terms of strength and performance. This raises great concern because it is known that both muscle strength and performance decline quicker than muscle mass with aging. The above-mentioned SO definition does not fit with sarcopenia definition proposed by the European and the International Working Group on Sarcopenia in Older People [20,21], who recommended to consider both, low muscle mass and low muscle function as criteria for the diagnosis of sarcopenia. 4. SO definition uses BMI to quantify the amount of fat, but the most appropriate indices and cutoff of overweight and obesity in the elderly population are still under debate [22]. As with aging, an increase in abdominal fat and in particular in visceral abdominal fat can be observed, even without changes in BMI, the use of indices of fat distribution may be more representative than those of fat mass quantity [22]. Thus, measurements of abdominal circumferences, widely considered good surrogate of fat distribution and in particular of visceral abdominal adipose tissue, may be more adequate than BMI in order to discriminate a population at higher risk for unfavorable outcomes [16]. To bypass this problem, it has been recently suggested to use the ratio between appendicular skeletal mass (ASM)/h2, as evaluated by DXA, and visceral abdominal adipose tissue, as evaluated by computed tomography, as tool for SO definition [23], but this definition is still rising concern in relation with the above-mentioned points 1, 2, and 3 and then cannot be used in clinical practice. More recently, translational definitions of SO have been proposed considering muscle impairment, as expressed by muscle strength, rather than muscle mass, associated with central fat distribution as evaluated with waist circumference, introducing the concept of dynapenic abdominal obesity (DAO). This condition has negative effects on physical function and on the risk of developing mobility disability [24,25]. Separately dynapenia and abdominal obesity have shown associations with important outcomes in older adults, such as worsening disability and mortality [12,24,26 30], but only a few studies have investigated health risk associated with the simultaneous presence of both conditions [14,25,31]. When the definition of SO and DAO has been applied to the same population, the prevalence was, respectively, of 2.8% and 10.6% (Fig. 6.1). It must be noted that only two subjects belonged to both groups [15], Fig. 6.1).
PATHOGENESIS OF SO The age-related reduction in muscle mass and fat mass increase is strictly related with each other from a pathogenic point of view.
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FIGURE 6.1
Sarcopenic obese Thigh CT Lowest tertile BMI>30 kg/m2
n = 24 (2.8%)
Sarcopenic obese and dynapenic abdominal obese n=2
Dynapenic abdominal obese
Prevalence of sarcopenic obese and dynapenic abdominal obese subjects.
Handgrip <30 kg for male, <20 kg for females Waist circumference >100 cm for males, >87 cm for females
n = 90 (10.6%)
The age-related decrease in muscle mass and strength may lead to reduced physical activity. A reduction in muscle mass and physical activity reduces total energy expenditure and may lead to weight gain [32]. Moreover, obesity is associated with subacute low-grade inflammation, resulting from the secretion of many adipokines that may contribute to the progression of sarcopenia, acting both at a local and at systemic level. In fact, several adipokines, in particular tumor necrosis factor (TNF)-alpha, IL-6, and leptin, may lead to progressive loss of muscle mass and further increase in fat mass [33]. Skeletal muscle aging is associated with an impairment in muscle quality characterized by a progressive replacement of muscle by fibrous connective (MF) and adipose tissue (MS) [34]. A number of predictors of MS have been found. MS increases with both, age and adiposity, and has been shown to be associated with the degree of insulin resistance as well as to serum leptin levels [34]. In the Health ABC Study population, thigh intermuscular fat was significantly associated with higher levels of inflammatory markers [35]. Moreover, IL-6 gene expression in subcutaneous adipose tissue near the muscle was positively related to MS deposition suggesting a prevalent role of local tissue inflammation [34]. MF has not been yet extensively studied even though functional consequences of MF are relevant. MF is associated with a decrease in muscle strength, elasticity, and blood supply of muscle fibers, further increasing muscle atrophy [36]. Collagen accumulation increases with age in mice [36]. Muscle stem cells from aged mice tend to convert more to a fibrogenic lineage compared to cells from young muscles [37]. In healthy elderly men undergoing elective vertebral surgery, our study group showed that not only the degree of MS but also that MF was associated with increased adiposity, central fat distribution, and a worse metabolic profile [13].
CLINICAL IMPLICATIONS OF SO Previous studies indicate that when obesity and muscle impairment coexist, they act synergistically on the risk of developing multiple health-related outcomes.
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CLINICAL IMPLICATIONS OF DAO
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In a cross-sectional study participants in the New Mexico Aging Process Study cohort, [9] the odds ratios for disability in sarcopenic, obese, and sarcopenic-obese groups, relative to the group of seniors with a normal body composition, were 2.07, 2.33, and 4.12, respectively. A more recent study by Rolland et al. [11] confirmed these findings showing that compared with women with a healthy body composition, those with SO had a 2.60 higher odds of having difficulty climbing stairs, 2.35 higher odds of having difficulty going down stairs, and 1.54 higher odds of having moving difficulties. Baumgartner et al. [38], in a 8-year follow-up of the New Mexico Aging Process Study, showed that subjects with SO at baseline were two or three times more likely to develop instrumental disability than lean sarcopenic or nonsarcopenic obese subjects. Previous studies evaluated the joint effect of obesity and low muscle strength. Increased fat mass percentage and decreased muscle strength in the Finnish Health 2000 Survey were shown to be associated with higher prevalence of walking limitation compared to those with only high fat percentage or low muscle strength [28]. Association between obesity, metabolic alterations, and cardiovascular diseases has been observed even in older ages [16,22]. Some evidence show association between Sarcopenia, both defined as low muscle mass or low muscle strength, and metabolic alterations, in particular diabetes. Only a few studies evaluated the association between SO and metabolic alterations and their findings are not conclusive. In the cross-sectional analysis of the New Mexico Aging Process Study [38], subjects with SO did not show higher incidence of congestive heart disease and hip fracture. Despite the fact that type 2 diabetes was more frequent in SO subjects, the incidence of type 2 diabetes was not affected by the SO status. Aubertin-Leheudre et al. [39] in a small study sample of postmenopausal women did not observe any difference in cardiovascular and metabolic risk factor profile between obese old women with a normal muscle mass and those with SO. Stephen in 3000 older adults reported that the low muscle mass associated with abdominal obesity was not associated with an increased risk for the development of cardiovascular disease over an 8-year follow-up period [40]. More recently, association between SO, evaluated as ASM to visceral abdominal fat ratio, metabolic syndrome, and arterial stiffness has been observed in 526 apparently healthy adults enrolled in the Korean Sarcopenic Obesity Study, an ongoing prospective observational cohort study [23]. By multiple logistic regression analysis, the odds ratio for metabolic syndrome was 5.43 higher in subjects with SO [23]. These findings seem to suggest that if fat distribution is taken into account in the definition of SO, its association with metabolic syndrome and vascular damage may reach evidence.
CLINICAL IMPLICATIONS OF DAO Dynapenia and obesity also have independent, additive, and negative effects on physical function.
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In a cross-sectional study of 2039 men and women aged 55 years and older, where leg extension strength was measured with a dynamometer, 12% of the nondynapenic and nonobese group had walking disability, compared with 18% of those with obesity alone, 24% of those with dynapenia, and 36% of those with dynapenic obesity [26]. Interestingly, they observed that dynapenic obese subjects had a walking speed of approximately 0.14 m/s so that the nondynapenic and nonobese subjects determine a difference of 2.8 seconds every 20 m distance [26]. A study published in 2010 of 904 men and women aged 67 84 years reported that combining handgrip strength and fat mass is the best predictor of a low physical function score, compared with any other body composition and strength markers [41]. DAO also has shown unfavorable consequences on mobility and autonomy. In a crosssectional study of 2039 men and women aged 55 years and older, where leg extension strength was measured with a dynamometer, Bouchard et al. observed that dynapenic obese subjects had a lower walking speed compared with nondynapenic and nonobese subjects [25]. In a population of 3594 adults ranging in ages between 50 and 91 followed up for 33 years, Scott et al. observed instead that both low handgrip strength and obesity independently predict the risk of death [31]. Moreover in a recent study, DAO showed increased falls risk compared to reference group [15]. Mortality risk associated with obesity coupled with poor strength has been evaluated [42] in a 30-year prospective study in initially healthy men. They observed that overweight persons in the lowest grip strength tertile had 1.39 times higher mortality risk compared to normal weight persons in the highest grip strength tertile. DAO subjects show an unfavorable metabolic profile, high cardiovascular risk, also when compared with sarcopenic obese subjects, suggesting in obese individuals low strength is a predictor of mortality stronger than low muscle mass [43]. DAO shows also an increased risk of worsening disability and mortality than subjects with dynapenia or central fat distribution only [16]. More recently, Rossi et al. in a larger population suggest that dynapenia is related to the risk of death regardless of the presence of central obesity whereas abdominal obesity strongly increases the risk of disability and hospitalization associated with low muscle strength. Identification of elderly subjects with central fat distribution and simultaneous low muscle strength could help, with easily available and inexpensive tools, to select a subgroup of subjects with the highest risk of functional decline and loss of independence [15].
TREATMENT Debate has been raised in the past about the hazard of obesity in the elderly and thus about the need of its treatment. However, since SO is associated with poor outcomes, its treatment should be considered. Weight loss is usually associated with decline in fat mass, as well as decline in fat free and bone mass [44]. However, it seems crucial that any treatment of SO should cause a reduction in fat mass, in particular abdominal fat mass, preserving muscle mass quality and function. Some evidence show that improvement of muscle quality after weight loss as well as of its function may be obtained if physical exercise is combined with dietary counseling and if weight loss is moderate ranging from 5% to 10% of initial body weight.
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CONCLUSION
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TABLE 6.2 General Nutritional Recommendation for Sarcopenic Obesity Treatment in the Elderly • Moderate energy restriction (with a maximum energy deficit of 500 kcal/day) with 5% 10% weight loss and very low hypoenergetic diet should be avoided • Diet should enriched in high biological value protein (at least 1.1 1.2 g/kg/day) and supplementation with leucine-enriched amino-acid essential mixture, including whey protein and leucine, should be considered • Dietary treatment should be combined with short-term resistance training and aerobic exercise • Supplementation with vitamin D and calcium is mandatory
Villareal et al. showed that 6-month weight loss treatment aimed to be no more than 1.5% per week combined with exercise training three times per week (with each session lasting 90 minutes) ameliorates function and frailty in obese older subjects [45]. We observed that a moderate weight loss (nearly 5%) in a group of elderly women determines a significant improvement in insulin resistance, fat distribution, and more importantly of muscle lipid infiltration, with just a small decrease in appendicular lean tissue [46]. Exercise has beneficial effects on multiple aspects of SO with increase in muscle protein synthesis, reduction in myostatin expression, increase in intramuscular insulin-like growth factor (IGF)-1, enhanced mitochondrial function, and activation of skeletal muscle satellite cells [45]. Further, the reduction in lean mass associated with weight loss therapy is attenuated when combined with regular exercise and in particular resistance training [47]. Therefore, the most effective treatment strategy for SO should incorporate both, diet induced weight loss and regular exercise program including resistance training. A recent review of literature that aimed to assess studies investigating the effectiveness of exercise or nutritional interventions to improve the body composition, strength, or function in older adults with sarcopenia and obesity found that none of the included studies showed a significant decrease in body fat or increase in either skeletal muscle mass or lean mass [48]. Authors empathized a general lack of published data on this topic and the necessity for new research adopting universally accepted cutoffs for SO. Quality and amount of dietary protein should be relevant when trying to prevent fatfree mass during weight loss. Verreijen et al. in a double-blind randomized-controlled trial in 80 obese older adults found that a high whey protein-, leucine-, and vitamin D-enriched supplement compared to isocaloric control preserves appendicular muscle mass during hypocaloric diet and resistance exercise program and might therefore reduce the risk of sarcopenia [49]. However, some general recommendations should be considered and are summarized in Table 6.2.
CONCLUSION With aging, loss of muscle mass and gain in fat seem to be linked to each other and contribute, in the presence of positive energy balance, to the development of SO.
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Identification of elderly subjects with SO could help to identify a group of subjects at particularly high health risk, and the concept of SO may help to clarify the relation between obesity, morbidity, and mortality in the elderly. Recently, great effort has been done to improve sarcopenia definition in order to get it carried out in the clinical assessment of elderly people. Similar effort seems to be mandatory also for SO definition. Recently proposed DAO definition that requires two measurements that are relatively simple to obtain and interpret, especially in outpatient settings, seems a plausible alterative to the classic SO definition, useful in order to identify older subjects at high risk for unfavorable health outcomes.
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[40] Stephen WC, Janssen I. Sarcopenic-obesity and cardiovascular disease risk in the elderly. J Nutr Health Aging 2009;13:460 6. [41] Choquette S, Bouchard DR, Doyon CY, Se´ne´chal M, Brochu M, Dionne IJ. Relative strength as a determinant of mobility in elders 67 84 years of age. a nuage study: nutritions a determinant of successful aging. J Nutr Health Aging. 2010;14:190 5. [42] Rantanen T, Guralnik JM, Foley D, Masaki K, Leveille S, Curb JD, et al. Midlife hand grip strength as a predictor of old age disability. JAMA 1999;281:558 60. [43] Se´ne´chal M, Dionne IJ, Brochu M. Dynapenic abdominal obesity and metabolic risk factors in adults 50 years of age and older. J Aging Health. 2012;24:812 26. [44] Bouchonville MF, Villareal DT. Sarcopenic obesity—how do we treat it? Curr Opin Endocrinol Diabetes Obes. 2013;20:412 19. [45] Villareal DT, Banks M, Sinacore DR, Siener C, Klein S. Effect of weight loss and exercise on frailty in obese older adults. Arch Intern Med 2006;166:860 6. [46] Mazzali G, Di Francesco V, Zoico E, et al. Interrelations between fat distribution, muscle lipid content, adipocytokines, and insulin resistance: effect of moderate weight loss in older women. Am J Clin Nutr 2006;84: 1193 9. [47] Frimel TN, Sinacore DR, Villareal DT. Exercise attenuates the weight-loss induced reduction in muscle mass in frail obese older adults. Med Sci Sports Exerc. 2008;40:1213 19. [48] Theodorakopoulos C, Jones J, Bannerman E, Greig CA. Effectiveness of nutritional and exercise interventions to improve body composition and muscle strength or function in sarcopenic obese older adults: a systematic review. Nutr Res. 2017;43:3 15. [49] Verreijen AM, Verlaan S, Engherink MF, Swinkels S, de Vogel-van den Bosch, PJM Weijs. A high whey protein-, leucine-, and vitamin D-enriched supplement preserves muscle mass during intentional weight loss in obese older adults: a double blind randomized controlled trial. Am J Clin Nutr. 2015;101:279 86.
Further Reading Unger RH. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 2005;87:57 64.
II. PATHOPHYSIOLOGY OF SKELETAL MUSCLE: THE IMPORTANT ROLE OF DIET AND NUTRIENTS
6 Sarcopenic Obesity Andrea P. Rossi, Sofia Rubele and Mauro Zamboni Department of Medicine, Geriatric Division, University of Verona, Verona, Italy
INTRODUCTION The prevalence of obesity in older adults has increased in recent years; for example, in the United States, nearly 30% in men and in women aged 60 years and over, with increase also in extreme degree obesity [1]. High prevalence of obesity has been observed in Europe [2,3]. With aging, a progressive increase in fat mass, which normally peaks at about age 65 years in men and later in women is observed [4]. Aging is associated also with body fat distribution changes, with visceral abdominal fat increase and subcutaneous abdominal fat decrease [5]. Moreover in the elderly, ectopic fat deposition within nonadipose tissue such as the skeletal and cardiac muscle, liver, and pancreas has been observed [6,7]. This phenomenon occurs even without significant changes in body mass index (BMI) or body weight. On the counterpart, age-associated muscle mass and strength loss occur even in relatively weight stable healthy individuals [8].
SARCOPENIC OBESITY (SO) DEFINITION In 2000, Baumgartner introduced the term of sarcopenic obesity (SO), a condition characterized by coexistence of low muscle mass and a high body fat mass [9]. By the time, more definitions of SO have been proposed (Table 6.1 shows different SO definition). 1. The definition proposed by Baumgartner et al. [9] may underestimate sarcopenia in overweight and obese subjects, thus leading to an underdiagnosis of SO. In general, all the proposed SO definitions raise some concern. The main limitations of both are listed below. 2. All definitions do not take into account quality of muscle parameters and in particular fat infiltration and fibrosis. It has been documented that the amount of triglycerides in
Nutrition and Skeletal Muscle DOI: https://doi.org/10.1016/B978-0-12-810422-4.00006-3
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TABLE 6.1 Sarcopenic and Dynapenic Obesity Definitions and Prevalence Study
Definition of sarcopenic obesity
N
Mean age (SD)
Prevalence
New Mexico Aging Process Study [9]
• Sarcopenia: skeletal muscle mass 22 SD below mean of young population or ,7.26 kg/m2 in men and ,5.45 kg/m2 in women • Obesity: percentage body fat greater than median or .27% in men and .38% in women
831
60 and over
M: 4.4%, F: 3.0%
NHANES III [10]
• Sarcopenia: two lower quartiles of muscle mass (,9.12 kg/m2 in men and ,6.53 kg/m2 in women) • Obesity: two higher quintiles of fat mass ( . 37.2% in men and .40.0% in women)
2982
M: 76.3 (1.7), F: 77.3 (2.2)
M: 9.6%, F: 7.4%
Verona Health ABC Study, Italy [11]
• Sarcopenia: two lower quintiles of muscle mass (,5.7 kg/m2 in women) • Obesity: two higher quintiles of fat mass ( . 42.9% in women)
167
F: 71.7 (2.4)
F:12.4%
InChianti, Italy [12]
• Impaired strength: lower gender-specific tertile of handgrip strength (,32 kg for men and ,18 kg for women) • Obesity BMI $ 30 kg/m2
856
74.3 (6.9)
M: 6.3%, F: 8.7%
LASA [13]
• Impaired strength: lower gender-specific tertile of handgrip strength (,33 kg for men and ,20 kg for women) • Obesity BMI $ 30 kg/m2
1189
75.8 (7.2)
M: 5.1%, F: 8.9%
EXERNET Study, Spain [3]
• Sarcopenia: two lower quintiles of muscle mass (,8.61 kg/m2 in men and ,6.19 kg/m2 in women) • Obesity: two higher quintiles of fat mass ( . 30.3% in men and .40.9% in women)
3176
M: 72.4 (5.5), F: 72.1 (5.2)
M: 17.7%F: 14.0%
Health 2000 Survey, Finland [14]
• Impaired strength: lower gender-specific tertile of handgrip strength (,322 N for men and ,176 N for women) • Obesity BMI $ 30 kg/m2
1413
75.8 (7.1)
M: 6.1%, F: 11.0%
InChianti, Italy [15]
• Sex-specific lowest tertile of handgrip strength (,33 kg in men and ,19 kg in women) • Visceral obesity: sex-specific cutoff based on waist circumference tertiles (99 cm in men and 95 cm in women)
846
74.5 (6.9)
M: 8.1%, F: 12.6%
Verona Health ABC Study, Italy [16]
• Sex-specific lowest tertile of leg strength (15.33 kg in men and ,8.33 kg in women) • Visceral obesity: sex-specific cutoff based on waist circumference tertiles (100 cm in men and 87 cm in women)
262
71.8 (2.2)
12.2%
BMI, body mass index; LASA, Longitudinal Aging Study Amsterdam.
PATHOGENESIS OF SO
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muscle increases with both ageing and obesity [17,18]: mid-thigh low-density lean tissue, a surrogate of muscle fat infiltration, as evaluated by computed tomography, has been observed to be directly associated with age and adiposity [19]. In fact, both Dual Energy X-ray Absorptiometry (DXA) and Bioelectrical impedence analysis (BIA), the body composition methods usually recommended for definition of sarcopenia, are not able to recognize neither myosteatosis (MS) nor myofibrosis (MF) [13]. 3. SO definition doesn’t take into account muscle function in terms of strength and performance. This raises great concern because it is known that both muscle strength and performance decline quicker than muscle mass with aging. The above-mentioned SO definition does not fit with sarcopenia definition proposed by the European and the International Working Group on Sarcopenia in Older People [20,21], who recommended to consider both, low muscle mass and low muscle function as criteria for the diagnosis of sarcopenia. 4. SO definition uses BMI to quantify the amount of fat, but the most appropriate indices and cutoff of overweight and obesity in the elderly population are still under debate [22]. As with aging, an increase in abdominal fat and in particular in visceral abdominal fat can be observed, even without changes in BMI, the use of indices of fat distribution may be more representative than those of fat mass quantity [22]. Thus, measurements of abdominal circumferences, widely considered good surrogate of fat distribution and in particular of visceral abdominal adipose tissue, may be more adequate than BMI in order to discriminate a population at higher risk for unfavorable outcomes [16]. To bypass this problem, it has been recently suggested to use the ratio between appendicular skeletal mass (ASM)/h2, as evaluated by DXA, and visceral abdominal adipose tissue, as evaluated by computed tomography, as tool for SO definition [23], but this definition is still rising concern in relation with the above-mentioned points 1, 2, and 3 and then cannot be used in clinical practice. More recently, translational definitions of SO have been proposed considering muscle impairment, as expressed by muscle strength, rather than muscle mass, associated with central fat distribution as evaluated with waist circumference, introducing the concept of dynapenic abdominal obesity (DAO). This condition has negative effects on physical function and on the risk of developing mobility disability [24,25]. Separately dynapenia and abdominal obesity have shown associations with important outcomes in older adults, such as worsening disability and mortality [12,24,26 30], but only a few studies have investigated health risk associated with the simultaneous presence of both conditions [14,25,31]. When the definition of SO and DAO has been applied to the same population, the prevalence was, respectively, of 2.8% and 10.6% (Fig. 6.1). It must be noted that only two subjects belonged to both groups [15], Fig. 6.1).
PATHOGENESIS OF SO The age-related reduction in muscle mass and fat mass increase is strictly related with each other from a pathogenic point of view.
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6. SARCOPENIC OBESITY
FIGURE 6.1
Sarcopenic obese Thigh CT Lowest tertile BMI>30 kg/m2
n = 24 (2.8%)
Sarcopenic obese and dynapenic abdominal obese n=2
Dynapenic abdominal obese
Prevalence of sarcopenic obese and dynapenic abdominal obese subjects.
Handgrip <30 kg for male, <20 kg for females Waist circumference >100 cm for males, >87 cm for females
n = 90 (10.6%)
The age-related decrease in muscle mass and strength may lead to reduced physical activity. A reduction in muscle mass and physical activity reduces total energy expenditure and may lead to weight gain [32]. Moreover, obesity is associated with subacute low-grade inflammation, resulting from the secretion of many adipokines that may contribute to the progression of sarcopenia, acting both at a local and at systemic level. In fact, several adipokines, in particular tumor necrosis factor (TNF)-alpha, IL-6, and leptin, may lead to progressive loss of muscle mass and further increase in fat mass [33]. Skeletal muscle aging is associated with an impairment in muscle quality characterized by a progressive replacement of muscle by fibrous connective (MF) and adipose tissue (MS) [34]. A number of predictors of MS have been found. MS increases with both, age and adiposity, and has been shown to be associated with the degree of insulin resistance as well as to serum leptin levels [34]. In the Health ABC Study population, thigh intermuscular fat was significantly associated with higher levels of inflammatory markers [35]. Moreover, IL-6 gene expression in subcutaneous adipose tissue near the muscle was positively related to MS deposition suggesting a prevalent role of local tissue inflammation [34]. MF has not been yet extensively studied even though functional consequences of MF are relevant. MF is associated with a decrease in muscle strength, elasticity, and blood supply of muscle fibers, further increasing muscle atrophy [36]. Collagen accumulation increases with age in mice [36]. Muscle stem cells from aged mice tend to convert more to a fibrogenic lineage compared to cells from young muscles [37]. In healthy elderly men undergoing elective vertebral surgery, our study group showed that not only the degree of MS but also that MF was associated with increased adiposity, central fat distribution, and a worse metabolic profile [13].
CLINICAL IMPLICATIONS OF SO Previous studies indicate that when obesity and muscle impairment coexist, they act synergistically on the risk of developing multiple health-related outcomes.
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CLINICAL IMPLICATIONS OF DAO
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In a cross-sectional study participants in the New Mexico Aging Process Study cohort, [9] the odds ratios for disability in sarcopenic, obese, and sarcopenic-obese groups, relative to the group of seniors with a normal body composition, were 2.07, 2.33, and 4.12, respectively. A more recent study by Rolland et al. [11] confirmed these findings showing that compared with women with a healthy body composition, those with SO had a 2.60 higher odds of having difficulty climbing stairs, 2.35 higher odds of having difficulty going down stairs, and 1.54 higher odds of having moving difficulties. Baumgartner et al. [38], in a 8-year follow-up of the New Mexico Aging Process Study, showed that subjects with SO at baseline were two or three times more likely to develop instrumental disability than lean sarcopenic or nonsarcopenic obese subjects. Previous studies evaluated the joint effect of obesity and low muscle strength. Increased fat mass percentage and decreased muscle strength in the Finnish Health 2000 Survey were shown to be associated with higher prevalence of walking limitation compared to those with only high fat percentage or low muscle strength [28]. Association between obesity, metabolic alterations, and cardiovascular diseases has been observed even in older ages [16,22]. Some evidence show association between Sarcopenia, both defined as low muscle mass or low muscle strength, and metabolic alterations, in particular diabetes. Only a few studies evaluated the association between SO and metabolic alterations and their findings are not conclusive. In the cross-sectional analysis of the New Mexico Aging Process Study [38], subjects with SO did not show higher incidence of congestive heart disease and hip fracture. Despite the fact that type 2 diabetes was more frequent in SO subjects, the incidence of type 2 diabetes was not affected by the SO status. Aubertin-Leheudre et al. [39] in a small study sample of postmenopausal women did not observe any difference in cardiovascular and metabolic risk factor profile between obese old women with a normal muscle mass and those with SO. Stephen in 3000 older adults reported that the low muscle mass associated with abdominal obesity was not associated with an increased risk for the development of cardiovascular disease over an 8-year follow-up period [40]. More recently, association between SO, evaluated as ASM to visceral abdominal fat ratio, metabolic syndrome, and arterial stiffness has been observed in 526 apparently healthy adults enrolled in the Korean Sarcopenic Obesity Study, an ongoing prospective observational cohort study [23]. By multiple logistic regression analysis, the odds ratio for metabolic syndrome was 5.43 higher in subjects with SO [23]. These findings seem to suggest that if fat distribution is taken into account in the definition of SO, its association with metabolic syndrome and vascular damage may reach evidence.
CLINICAL IMPLICATIONS OF DAO Dynapenia and obesity also have independent, additive, and negative effects on physical function.
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6. SARCOPENIC OBESITY
In a cross-sectional study of 2039 men and women aged 55 years and older, where leg extension strength was measured with a dynamometer, 12% of the nondynapenic and nonobese group had walking disability, compared with 18% of those with obesity alone, 24% of those with dynapenia, and 36% of those with dynapenic obesity [26]. Interestingly, they observed that dynapenic obese subjects had a walking speed of approximately 0.14 m/s so that the nondynapenic and nonobese subjects determine a difference of 2.8 seconds every 20 m distance [26]. A study published in 2010 of 904 men and women aged 67 84 years reported that combining handgrip strength and fat mass is the best predictor of a low physical function score, compared with any other body composition and strength markers [41]. DAO also has shown unfavorable consequences on mobility and autonomy. In a crosssectional study of 2039 men and women aged 55 years and older, where leg extension strength was measured with a dynamometer, Bouchard et al. observed that dynapenic obese subjects had a lower walking speed compared with nondynapenic and nonobese subjects [25]. In a population of 3594 adults ranging in ages between 50 and 91 followed up for 33 years, Scott et al. observed instead that both low handgrip strength and obesity independently predict the risk of death [31]. Moreover in a recent study, DAO showed increased falls risk compared to reference group [15]. Mortality risk associated with obesity coupled with poor strength has been evaluated [42] in a 30-year prospective study in initially healthy men. They observed that overweight persons in the lowest grip strength tertile had 1.39 times higher mortality risk compared to normal weight persons in the highest grip strength tertile. DAO subjects show an unfavorable metabolic profile, high cardiovascular risk, also when compared with sarcopenic obese subjects, suggesting in obese individuals low strength is a predictor of mortality stronger than low muscle mass [43]. DAO shows also an increased risk of worsening disability and mortality than subjects with dynapenia or central fat distribution only [16]. More recently, Rossi et al. in a larger population suggest that dynapenia is related to the risk of death regardless of the presence of central obesity whereas abdominal obesity strongly increases the risk of disability and hospitalization associated with low muscle strength. Identification of elderly subjects with central fat distribution and simultaneous low muscle strength could help, with easily available and inexpensive tools, to select a subgroup of subjects with the highest risk of functional decline and loss of independence [15].
TREATMENT Debate has been raised in the past about the hazard of obesity in the elderly and thus about the need of its treatment. However, since SO is associated with poor outcomes, its treatment should be considered. Weight loss is usually associated with decline in fat mass, as well as decline in fat free and bone mass [44]. However, it seems crucial that any treatment of SO should cause a reduction in fat mass, in particular abdominal fat mass, preserving muscle mass quality and function. Some evidence show that improvement of muscle quality after weight loss as well as of its function may be obtained if physical exercise is combined with dietary counseling and if weight loss is moderate ranging from 5% to 10% of initial body weight.
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CONCLUSION
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TABLE 6.2 General Nutritional Recommendation for Sarcopenic Obesity Treatment in the Elderly • Moderate energy restriction (with a maximum energy deficit of 500 kcal/day) with 5% 10% weight loss and very low hypoenergetic diet should be avoided • Diet should enriched in high biological value protein (at least 1.1 1.2 g/kg/day) and supplementation with leucine-enriched amino-acid essential mixture, including whey protein and leucine, should be considered • Dietary treatment should be combined with short-term resistance training and aerobic exercise • Supplementation with vitamin D and calcium is mandatory
Villareal et al. showed that 6-month weight loss treatment aimed to be no more than 1.5% per week combined with exercise training three times per week (with each session lasting 90 minutes) ameliorates function and frailty in obese older subjects [45]. We observed that a moderate weight loss (nearly 5%) in a group of elderly women determines a significant improvement in insulin resistance, fat distribution, and more importantly of muscle lipid infiltration, with just a small decrease in appendicular lean tissue [46]. Exercise has beneficial effects on multiple aspects of SO with increase in muscle protein synthesis, reduction in myostatin expression, increase in intramuscular insulin-like growth factor (IGF)-1, enhanced mitochondrial function, and activation of skeletal muscle satellite cells [45]. Further, the reduction in lean mass associated with weight loss therapy is attenuated when combined with regular exercise and in particular resistance training [47]. Therefore, the most effective treatment strategy for SO should incorporate both, diet induced weight loss and regular exercise program including resistance training. A recent review of literature that aimed to assess studies investigating the effectiveness of exercise or nutritional interventions to improve the body composition, strength, or function in older adults with sarcopenia and obesity found that none of the included studies showed a significant decrease in body fat or increase in either skeletal muscle mass or lean mass [48]. Authors empathized a general lack of published data on this topic and the necessity for new research adopting universally accepted cutoffs for SO. Quality and amount of dietary protein should be relevant when trying to prevent fatfree mass during weight loss. Verreijen et al. in a double-blind randomized-controlled trial in 80 obese older adults found that a high whey protein-, leucine-, and vitamin D-enriched supplement compared to isocaloric control preserves appendicular muscle mass during hypocaloric diet and resistance exercise program and might therefore reduce the risk of sarcopenia [49]. However, some general recommendations should be considered and are summarized in Table 6.2.
CONCLUSION With aging, loss of muscle mass and gain in fat seem to be linked to each other and contribute, in the presence of positive energy balance, to the development of SO.
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Identification of elderly subjects with SO could help to identify a group of subjects at particularly high health risk, and the concept of SO may help to clarify the relation between obesity, morbidity, and mortality in the elderly. Recently, great effort has been done to improve sarcopenia definition in order to get it carried out in the clinical assessment of elderly people. Similar effort seems to be mandatory also for SO definition. Recently proposed DAO definition that requires two measurements that are relatively simple to obtain and interpret, especially in outpatient settings, seems a plausible alterative to the classic SO definition, useful in order to identify older subjects at high risk for unfavorable health outcomes.
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[40] Stephen WC, Janssen I. Sarcopenic-obesity and cardiovascular disease risk in the elderly. J Nutr Health Aging 2009;13:460 6. [41] Choquette S, Bouchard DR, Doyon CY, Se´ne´chal M, Brochu M, Dionne IJ. Relative strength as a determinant of mobility in elders 67 84 years of age. a nuage study: nutritions a determinant of successful aging. J Nutr Health Aging. 2010;14:190 5. [42] Rantanen T, Guralnik JM, Foley D, Masaki K, Leveille S, Curb JD, et al. Midlife hand grip strength as a predictor of old age disability. JAMA 1999;281:558 60. [43] Se´ne´chal M, Dionne IJ, Brochu M. Dynapenic abdominal obesity and metabolic risk factors in adults 50 years of age and older. J Aging Health. 2012;24:812 26. [44] Bouchonville MF, Villareal DT. Sarcopenic obesity—how do we treat it? Curr Opin Endocrinol Diabetes Obes. 2013;20:412 19. [45] Villareal DT, Banks M, Sinacore DR, Siener C, Klein S. Effect of weight loss and exercise on frailty in obese older adults. Arch Intern Med 2006;166:860 6. [46] Mazzali G, Di Francesco V, Zoico E, et al. Interrelations between fat distribution, muscle lipid content, adipocytokines, and insulin resistance: effect of moderate weight loss in older women. Am J Clin Nutr 2006;84: 1193 9. [47] Frimel TN, Sinacore DR, Villareal DT. Exercise attenuates the weight-loss induced reduction in muscle mass in frail obese older adults. Med Sci Sports Exerc. 2008;40:1213 19. [48] Theodorakopoulos C, Jones J, Bannerman E, Greig CA. Effectiveness of nutritional and exercise interventions to improve body composition and muscle strength or function in sarcopenic obese older adults: a systematic review. Nutr Res. 2017;43:3 15. [49] Verreijen AM, Verlaan S, Engherink MF, Swinkels S, de Vogel-van den Bosch, PJM Weijs. A high whey protein-, leucine-, and vitamin D-enriched supplement preserves muscle mass during intentional weight loss in obese older adults: a double blind randomized controlled trial. Am J Clin Nutr. 2015;101:279 86.
Further Reading Unger RH. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 2005;87:57 64.
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