Inflammation: Roles in Aging and SarcopeniaFrom the Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania. Address correspondence to: Gordon L. Jensen, Professor and Head, Department of Nutritional Sciences, 126 Henderson South, University Park, PA 16802.
Aging is associated with inflammatory chronic conditions such as obesity,
cardiovascular disease, insulin resistance, and arthritis.
Sarcopenia—muscle loss with aging—is multifactorial with
contributing factors that may include loss of
Key Words: aging • sarcopenia • inflammation • muscle • obesity There is growing recognition of the central roles of inflammatory response in nutrition and medicine.1 Inflammatory chronic conditions such as obesity, cardiovascular disease, insulin resistance, and arthritis are often associated with aging. Although difficult to distinguish from the contributions of such comorbid disease processes, aging itself may be an inflammatory condition.2 Sarcopenia—muscle loss with aging—inflicts a profound burden of functional decline and frailty on older adults. This brief review presents recent research advances suggesting that sarcopenia is a smoldering, low-level inflammatory state related to inflammatory cytokines and oxidative stress. Opportunities for anti-inflammatory interventions to preserve muscle mass and function are highlighted.
The literal Greek-derived meaning of sarcopenia is "poverty of flesh."3 The loss of skeletal muscle mass associated with aging has been characterized with imaging techniques that include dual-energy X-ray absorptiometry (DEXA), computed tomography, and magnetic resonance imaging (MRI). There is a decrease in muscle cross-sectional area, a loss of muscle fibers, and fiber atrophy. Impaired functional outcomes include decreased lower extremity performance and increased risk of falls, physical disability, and frailty.4 Muscle mass is lost at a rate of 1%–2% per year past age 50 years.5,6 Approximately one-third of women and two-thirds of men older than age 60 have sarcopenia in the United States.7,8 The direct healthcare cost of sarcopenia in the U.S. in 2000 has been estimated at $18.5 billion.9
A key question has been whether sarcopenia is a manifestation of adverse
lifestyle factors and/or aging; the answer appears to be both. The
pathophysiology of sarcopenia is likely characterized by withdrawal of or
resistance to anabolic stimuli. Sarcopenia is multifactorial, with
contributing factors that may include loss of
Aging muscle exhibits oxidative damage to DNA, protein, and lipids. This
oxidative injury is associated with atrophy and loss of muscle fibers and
function. Mitochondrial DNA deletions and mutations increase in skeletal
muscle with age. As mitochondrial function deteriorates, there is further free
radical generation and lipid
peroxidation.6
Reactive oxygen species trigger the release of inflammatory cytokines.
Redox-sensitive transcription factors such as NF A recent investigation contrasting older adults in continuing care, intermediate care, and independent care settings found that those in the continuing care environment had greater frailty with lower body mass index (BMI), mid-arm muscle circumference, and triceps skin-fold measurements.15 The continuing care subjects also had higher IL-6 and CRP levels and lower albumin and leptin levels. It was concluded that the frailest older adults had features consistent with cachexia. These observations help to highlight the conundrum regarding coherent definitions for these syndromes. Because we now appreciate that smoldering inflammation is likely an important contributing factor in sarcopenia, does this mean that sarcopenia is really a milder form of a cachexia continuum? This issue is explored in detail in a provocative review by Thomas that is recommended reading.8
As described in a number of presentations at the 2008 Intersociety Workshop on Nutrition and Inflammation, adipose tissue is not simply a benign energy storage depot; rather, abdominal adipocytes contribute proinflammatory adipokines, cytokines, plasminogen activator inhibitor–1 (PAI-1), and free fatty acids, supporting a chronic inflammatory milieu. Nonesterified and trans fatty acids have been implicated in the injury of vascular endothelium. Sarcopenic obesity results from muscle loss in the setting of obesity and is common among aged obese adults or those obese people with severe disease burden or injury.10,16,17 Obese individuals in highly inflammatory states will preferentially mobilize muscle, not fat. Smoldering, low-level inflammation will also contribute to erosion of muscle mass. As obese people age and assume a greater burden of chronic disease, they often become increasingly sedentary, further contributing to loss of muscle mass. Obesity in older adults is associated with increased risk for functional decline and reporting homebound status.18,19 Quality of muscle is also a concern in sarcopenic obesity, as fat-selective MRI reveals increased "marbling" with fat deposition in skeletal muscle.20 Elevated intracellular triglyceride concentrations in skeletal muscle are associated with decreased insulin sensitivity.21 High levels of food energy consumption and intakes of saturated and trans fats may contribute. The Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors Study17 found that IL-6 and CRP were positively associated with BMI and total fat mass, and inversely associated with fat-adjusted appendicular lean mass. Obesity remained significantly associated with elevated IL-6 and CRP levels, even after adjustments for sarcopenia. These observations suggest that obesity-related inflammation may have a role in age-related sarcopenia. The far-reaching impact of obesity-related inflammation is evidenced by findings from the National Health and Nutrition Examination Survey IV (NHANES IV) that African Americans, Hispanics, and women are more likely to have elevated CRP levels and that obesity is the largest single risk factor for every CRP above normal.22
Potential interventions for sarcopenia include nutritional supplements, physical activity/resistance exercise, caloric restriction, anabolic hormones, anti-inflammatory agents, and antioxidants.8,10 Nutritional supplements have been disappointing as stand-alone treatments for sarcopenia, but protein-calorie supplements may have some benefits in combination with resistance strength training.23 Resistance exercise training is feasible and can improve muscle mass, strength, and balance in frail older adults.23 Higher levels of physical activity are associated with reduced levels of IL-6 and CRP among community-dwelling older adults.13 Caloric restriction is subject to active investigation in humans as an antiaging intervention.6,24 Caloric restriction in rodents and nonhuman primates can decrease reactive oxygen species/oxidative stress and decrease inflammatory cytokines.
The key question is whether these supportive findings can be extended to
humans. It may be possible to use caloric restriction to blunt loss of muscle
mass and function with aging. Weight loss in obese subjects decreases
proinflammatory and increases anti-inflammatory factors by regulating the
expression of inflammation-related genes in white adipose tissue to a more
favorable inflammatory
profile.25 The
observed improvement in inflammatory status in obese subjects who lose weight
has implications for reducing risk for the development of sarcopenic obesity.
There has been considerable interest in using anabolic hormones, including
human growth hormone, insulin-like growth factor–1, testosterone, and
dehydroepiandrosterone (DHEA) to prevent or treat
sarcopenia.8,10,26-28
These are promising approaches that can increase muscle mass, but questions
remain concerning long-term safety and cost that mitigate endorsement at this
time. Anti-inflammatory agents are also of interest, including nonsteroidal
anti-inflammatory drugs, Cox-2 inhibitors, anticytokines, and fish
oil/
The pathophysiology of sarcopenia is undoubtedly multifactorial, but research findings suggest that sarcopenia is a low-level, smoldering inflammatory state driven by cytokines and oxidative stress. Successful interventions are therefore likely to require a multifaceted approach that also targets inflammation. Primary therapy for adults with sarcopenia should include resistance exercise, which has been demonstrated to improve both muscle mass and strength. A key question is whether sarcopenia is truly a distinct syndrome or actually a milder form of a cachexia continuum. Improved understanding can help to clarify appropriate approaches to prevention and treatment.
Financial disclosure: none declared. The 2008 Intersociety Research Workshop: Nutrition and Inflammation: Research Makes the Connection, was supported by grant number U13DK064190 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health.
Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 6,
656-659 (2008)
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-motor neuron input,
changes in anabolic hormones, decreased intake of dietary protein, and decline
in physical activity. Research findings suggest that sarcopenia is a
smoldering inflammatory state driven by cytokines and oxidative stress.
Elevated levels of interleukin-6 and C-reactive protein are often detected.
Sarcopenic obesity manifests the added inflammatory burden of adiposity and
associated adipokines. Potential interventions for sarcopenia include
nutritional supplements, physical activity/resistance exercise, caloric
restriction, anabolic hormones, anti-inflammatory agents, and antioxidants. A
key question is whether sarcopenia is truly a distinct syndrome or a milder
form of a cachexia continuum. 
Top
Sarcopenia
Sarcopenic Obesity
B upregulate IL-6.
Cytokines may mediate direct catabolic effects while promoting anorexia,
insulin resistance, and reduced growth hormone and insulin-like growth
factor–1 levels. Elevated IL-6 and CRP levels were associated with loss
of strength over a 3-year follow-up in the Longitudinal Aging Study
Amsterdam.
-3 fatty
acids.