Circulating GDF-15 can act via the GFRAL receptor to impair appetite and reduce food intake, which could play an important role in the anorexia of aging and its hypothesized relationship to sarcopenia ( 25, 26). Stimulation of GFRAL by GDF-15 leads to a reduction in appetite, food intake, and body weight in mouse models ( 21–24). The area postrema is a specialized brain region with a semi-permeable blood–brain barrier that allows systemic signals to reach the central nervous system ( 18). The receptor for GDF-15, glial cell line–derived neurotrophic factor family-α-like (GFRAL) ( 21–24), is located in a discrete region of the brainstem, the area postrema, and nucleus tractus solitarius. Various stimuli such as hypoxia, inflammation, oxidative stress, and injury can activate p53, hypoxia-inducible factor-1α, nuclear factor-κB, and other transcription factors to upregulate GDF-15 expression ( 16, 18). GDF-15 is upregulated in many different tissues in response to cellular stress ( 16). The normal range of plasma GDF-15 concentrations in healthy, non-pregnant humans is 200–1200 pg/mL ( 18). GDF-15 is secreted as a 40-kDa propeptide that is cleaved in the endoplasmic reticulum to produce a mature active 25-kDa homodimer in the circulation ( 19, 20). In healthy individuals, GDF-15 is expressed in low amounts in liver, lung, kidney, and a wide variety of other tissues ( 16, 18). Growth and differentiation factor 15 (GDF-15), a divergent member of the transforming growth factor-β superfamily, has recently been implicated in muscle wasting, cachexia, mitochondrial diseases, obesity, and energy balance ( 16, 17). The pathogenesis of sarcopenia still remains poorly understood. However, sarcopenia is often defined by using a threshold of low grip strength or muscle mass, sometimes in combination with slow walking speed ( 12–15). There is currently no consensus operational definition of sarcopenia ( 2). Skeletal muscle strength is predictive of disability ( 10) and mortality ( 11). Low skeletal muscle mass is associated with low strength ( 5), lower extremity physical performance ( 6), functional impairment ( 7), falls ( 8), and physical disability ( 7, 9). Humans lose approximately 20%–40% of both skeletal muscle mass and strength from 20 to 80 years of age ( 3, 4). A decrease in muscle cross-sectional area, loss of muscle fibers, and muscle fiber atrophy occur with advancing age. Aging, Growth and differentiation factor 15, Physical performance, Sarcopenia, Skeletal muscleĪbout one-third of women and one-half of men aged at least 60 years in the United States are estimated to have sarcopenia ( 1), defined as the loss of skeletal muscle mass, strength, and performance with aging ( 2).
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