In a world in which life expectancy is increasing, understanding and promoting healthy aging becomes a contemporary demand. In the elderly, a sterile, chronic and low-grade systemic inflammation known as “inflammaging” is linked with many age-associated diseases. Considering sarcopenia as a loss of strength and mass of skeletal muscle related to aging, correlations between these two terms have been proposed. Better knowledge of the immune system players in skeletal muscle would help to elucidate their implications in sarcopenia. Characterizing the activators of damage sensors and the downstream effectors explains the inference with skeletal muscle performance. Sarcopenia has also been linked to chronic diseases such as diabetes, metabolic syndrome and obesity. Implications of inflammatory signals from these diseases negatively affect skeletal muscle. Autophagic mechanisms are closely related with the inflammasome, as autophagy eliminates stress signaling sent by damage organelles, but also acts with an immunomodulatory function affecting immune cells and cytokine release. The use of melatonin, an antioxidant, ROS scavenger and immune and autophagy modulator, or senotherapeutic compounds targeting senescent cells could represent strategies to counteract inflammation. This review aims to present the many factors regulating skeletal muscle inflammaging and their major implications in order to understand the molecular mechanisms involved in sarcopenia.

Aging is characterized by a progressive loss of skeletal muscle mass and function (sarcopenia). Obesity exacerbates age-related decline and lead to frailty. Skeletal muscle fat infiltration increases with aging and seems to be crucial for the progression of sarcopenia. Additionally, skeletal muscle plasticity modulates metabolic adaptation to different pathophysiological situations. Thus, cellular bioenergetics and mitochondrial profile were studied in the skeletal muscle of overweight aged people without reaching obesity to prevent this extreme situation. Overweight aged muscle lacked ATP production, as indicated by defects in the phosphagen system, glycolysis and especially mostly by oxidative phosphorylation metabolic pathway. Overweight subjects exhibited an inhibition of mitophagy that was linked to an increase in mitochondrial biogenesis that underlies the accumulation of dysfunctional mitochondria and encourages the onset of sarcopenia. As a strategy to maintain cellular homeostasis, overweight subjects experienced a metabolic switch from oxidative to lactic acid fermentation metabolism, which allows continued ATP production under mitochondrial dysfunction, but without reaching physiological aged basal levels. This ATP depletion induced early signs of impaired contractile function and a decline in skeletal muscle structural integrity, evidenced by lower levels of filamin C. Our findings reveal the main effector pathways at an early stage of obesity and highlight the importance of mitochondrial metabolism in overweight and obese individuals. Exploiting mitochondrial profiles for therapeutic purposes in humans is an ambitious strategy for treating muscle impairment diseases.

Although numerous studies have demonstrated the harmful effect of excessive fructose consumption at the systemic level, there is little information on its effects in the central nervous system. The purpose of the present work was to study the cellular alterations related to oxidative stress and protein quality control systems induced by a high-fructose diet in the brain of Syrian hamsters and their possible attenuation by exogenous melatonin. High-fructose intake induced type II diabetes together with oxidative damage, led to alterations of the unfolded protein response by activating the eIF2α branch, and impaired the macroautophagic machinery in the brain, favoring the accumulation of aggregates labeled for selective degradation and neurodegeneration markers such as β-amyloid (1-42), tau-p-S199, and tau-p-S404. Melatonin attenuated the manifestation of type II diabetes and reduced oxidative stress, deactivated eIF2α, and decreased tau-p-S404 levels in the brain of animals fed a high-fructose diet.

Obesity is a health problem caused by a diet rich in energy and the sedentary lifestyle of modern societies. A leptin deficiency is one of the worst causes of obesity, since it results in morbid obesity, a chronic disease without a cure. Leptin is an adipokine secreted in a manner dependent on the circadian rhythm that ultimately reduces food intake. We studied cellular alterations in brain of leptin-deficient obese animals and tested whether these alterations are reflected in abnormal behaviors. Obesity induced increases in oxidative stress and the unfolded protein response caused by endoplasmic reticulum stress. However, the subsequent signaling cascade was disrupted, blocking possible systemic improvements and increasing the production of misfolded proteins that trigger autophagy. Up-regulated autophagy was not indefinitely maintained and misfolded proteins accumulated in obese animals, which led to aggresome formation. Finally, neurodegenerative markers together with anxiety and stress-induced behaviors were observed in leptin-deficient mice. As oxidative stress has an essential role in the development of these harmful effects of obesity, melatonin, a powerful antioxidant, might counteract these effects on the brain. Following treatment with melatonin, the animals' antioxidant defenses were improved and misfolded protein, proteasome activity, and autophagy decreased. Aggresome formation was reduced due to the reduction in the levels of misfolded proteins and the reduction in tubulin expression, a key element in aggresome development. The levels of neurodegenerative markers were reduced and the behaviors recovered. The data support the use of melatonin in therapeutic interventions to reduce brain damage induced by leptin deficiency-dependent obesity.