Fat and Inflammaging: A Dual Path to Unfitness in Elderly People?

Skeletal muscle mass and strength decrease dramatically with advancing age.1 This decrease in muscle mass, also known as sarcopenia, may contribute to the development of functional limitations and disability in elderly people.2,3 Sarcopenia is a major contributor to frailty, falls, and loss of independence.4 Physical disability occurs frequently in older adults and rises steadily with age in people aged 65 and older.5 An estimated 20% to 30% of community-dwelling adults aged 70 and older report disability in mobility, tasks of household management (instrumental activities of daily living, IADLs), or self-care tasks (activities of daily living, ADLs). Among risk factors associated with disability and frailty, obesity is becoming a major contributor,6,7 which is particularly troubling because of the rise in obesity prevalence in elderly people.8 Although recent studies have shown that overweight and mildly obese older patients may live longer than their normal-weight counterparts, obese elderly people may live a greater portion of their life with some disability.9,10 Furthermore, there is a high prevalence of sarcopenia in obese older adults, which leads to mobility- and strength-based disability.11,12 Obese patients have a lower percentage of body weight as fat-free mass and can exert lower force per unit of cross-sectional muscle area than age- and sex-matched lean, nonfrail adults.13 Therefore obese elderly people are at higher risk for frailty and disability.6,7 Obesity and aging are both associated with metabolic, physiological, and functional changes.14 Increase in fat mass leads to higher production of cytokines that may exert a catabolic effect on muscle15 and enhances the risk of functional decline and frailty in elderly people.16,17 This association between fat mass and inflammation appears to account for most of the relationship between inflammation and sarcopenia, suggesting that obesity-associated inflammation may precede sarcopenia.18 A chronic inflammatory state that has been called “inflammaging(definition),” which results from an upregulation of cellular and molecular processes in response to a variety of stressors, often accompanies aging.19 Inflammaging appears to be an important driving force of several age-related pathologies, such as neurodegeneration, atherosclerosis, diabetes mellitus, and sarcopenia. Two studies in this month's Journal of the American Geriatrics Society contribute to our understanding of the potential role that inflammation and associated strength loss have in the epidemic of mobility disability. In the first study, Stenholm et al. used data from the Health 2000 Survey, a comprehensive nationwide health interview and examination survey in Finland, to show that low-grade inflammation and muscle strength mediate the association between obesity and walking limitation in community-dwelling older adults.20 Body fat percentage, C-reactive protein (CRP), and grip strength were associated with slow walking, independent of health behavioral factors and the presence of comorbidities. A previous cross-sectional study of community-dwelling older women revealed the association between obesity and slow walking and low physical activity.7 Obesity was also independently associated with poorer lower extremity physical performance in homebound older adults.21 In these two studies, however, the role of inflammation in the functional decline was not clear. A recent analysis from the Cardiovascular Health Study showed that high CRP is associated with incident frailty,22 and interleukin (IL)-6 levels were also found to be associated with frailty in community-dwelling older women.23 In the second study, Bautman et al. demonstrate that inflammatory markers are related to poorer muscle endurance (i.e., poorer strength and worse fatigue resistance) and poorer mobility in frail elderly nursing home residents.24 Correlations were found with higher levels of tumor necrosis factor alpha (TNF-α), IL-6, and heat shock protein 70 (Hsp 70). In addition, better fatigue resistance and higher grip work were both associated with less self-perceived tiredness and better balance and mobility. Recently Bautman et al. have shown that independently living elderly subjects with lower grip strength and less hand-muscle fatigue resistance experience more tiredness during their daily activities.25 Body weight appeared to play a role in the relationship between muscle performance and fatigue perception. Daily activities might be more challenging for obese persons than for leaner subjects with the same muscle performance and might thus be more likely to be accompanied by fatigue. Because poorer muscle fatigue resistance and greater fatigue perception are both related to inflammation, adipokines and cytokines may be playing an important pathophysiological role (Figure 1). The evaluation of inflammatory biomakers (CRP, IL-6, TNF-α, Hsp70) together with the assessment of grip strength, walking speed, and fatigue resistance offer the possibility of developing specific interventions for frail elderly people complaining of fatigue to improve muscle endurance and reduce mobility disability. Relationship between obesity and inflammation and poorer physical performance and greater risk of mobility disability and frailty in elderly people (solid lines represent a high degree of likelihood; dashed lines represent potential effects). CRP=C-reactive protein; IL-6=interleukin-6; Hsp70=heat shock protein 70; TNF=α tumor necrosis factor alpha. Inflammatory factors contribute to the onset and progression of loss of muscle mass and strength and mobility decline. Intentional weight loss leads to significant reductions of inflammatory biomarkers in younger obese adults26 and those with prediabetes,27 but it is unknown whether intentional weight loss would lead to similar changes in overweight and obese elderly people with or at high risk for frailty. Recent clinical trials provide initial evidence that exercise, as a way to los