GDF11/Myostatin and aging

aging of a multicellular organism is an intricate process that results from signaling events and age-related degeneration in cells, tissues, and organ systems. Studies in model organisms have provided evidence of unanticipated connection between local and systemic aging [1]. Research in this field is defining the key tissues that govern an organism's lifespan and the signals that convey information about the aging of cells and tissues throughout the organism [1]. Skeletal muscle is now being recognized as a prominent tissue with the capacity to influence systemic aging and lifespan [2, 3]. Many epidemiologic studies in humans have pointed to a remarkable connection between muscle strength and the morbidity and mortality linked to many age-related diseases [2]. The association between muscle function and aging has been corroborated by studies in model organisms. In mice and Drosophila, several muscle-restricted genetic interventions induce physiological responses in other tissues, such as regulation of lipid homeostasis in adipose tissue, regulation of insulin release, increased proteostasis, and decreased incidence of many age-related diseases [2, 3]. Although some of these systemic effects may be due to indirect effects of muscles' metabolic demand [2], there is also growing evidence for an endocrine role for skeletal muscle. In particular, muscle-derived cytokines and growth factors known as myokines are becoming recognized as important systemic regulators of metabolic homeostasis and may signal to many target tissues [2]. Using transgenic RNAi screening, we recently discovered several myokines that regulate lifespan and muscle aging in the fruit fly Drosophila melanogaster [4]. Among the myokines regulating the lifespan of Drosophila, we found Myoglianin, a TGF-beta ligand expressed primarily by skeletal muscle and glia [4]. Myoglianin RNAi in muscle shortens lifespan and increases the percentage of age-related climbing defects in the flies while its overexpression has converse effects. Myoglianin expression is increased by the transcription factor Mnt in muscle, and Mnt extends lifespan [4]. Modulation of Mnt and myoglianin expression levels in muscle leads to a partial decrease in rRNA levels and nucleolar function in muscle, a response that itself is sufficient to extend lifespan and that is known to be induced by many interventions that Editorial delay aging [4]. In addition to autocrine effects, myoglianin overexpression in muscle non-autonomously decreases the size and function of the nucleolus in Drosophila adipocytes by activating p38 MAPK [4], a known transducer of non-canonical TGF-beta signaling. Together these findings indicate that muscle-derived Myoglianin systemically regulates nucleolar function across …