Sarcopenia of aging: underlying cellular mechanisms and protection by calorie restriction

Abstract

Sarcopenia, the loss of muscle mass and function, is a common feature of aging and impacts on individual health and quality of life. Several cellular mechanisms have been involved in the pathogenesis of this syndrome, including mitochondrial dysfunction, altered apoptotic and autophagic signaling, and, more recently, trace metal dyshomeostasis. Calorie restriction (CR) without malnutrition has been shown to ameliorate the age-related loss of muscle mass in a variety a species. Mechanisms of protection span from preservation of mitochondrial functional and structural integrity to mitochondrial biogenesis, reduction of oxidative stress, and favorable modulation of apoptotic and autophagic signaling pathways. Importantly, preliminary evidence indicates that moderate CR may promote muscle mitochondrial biogenesis in middle-aged human subjects. Further research is warranted to investigate whether CR may represent a safe and efficient strategy to delay the onset and mitigate the progression of sarcopenia in older adults.

Fig. 1

Age-related muscle mitochondrial dysfunction results from multiple contributing factors and plays a prominent role in the development of sarcopenia. Calorie restriction preserves mitochondrial function in the aged muscle, thus mitigating fiber atrophy and loss of muscle mass.

Fig. 2

Overview of the apoptotic pathways involved in age-related myocyte elimination and their modulation by calorie restriction.

Fig. 3

Regulatory pathways of autophagy. Autophagy is suppressed by amino acids and growth factors such as insulin, which act through protein kinase B (Akt/PKB). However, when cells are starved for amino acids (Starvation), autophagy is activated via at least two possible signaling pathways: mTor and class III phosphoinositide 3-kinase (PI3K-III). Beclin interacts with and presumably activates the PI3K-III thereby promoting autophagy. This interaction can be inhibited by Bcl₂ or Bcl-X_L, which directly interact with Beclin. Recently, FoxO₃ transcription factor has been associated with increased ubiquitin-proteasome mediated proteolysis, as well as increased autophagy. FoxO is believed to stimulate autophagy via BNIP₃ and LC₃.