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.

Background: The diversity between the muscle cellular interactome of dependent and independent elderly people is based on the interrelationships established between different cellular mechanisms, and alteration of this balance modulates cellular activity in muscle tissue with important functional implications.Methods: Thirty patients (85 ± 8 years old, 23% female) scheduled to undergo hip fracture surgery participated in this study. During the surgical procedures, skeletal muscle tissue was obtained from the Vastus lateralis. Two groups of participants were studied based on their Barthel index: 15 functional‐independent individuals (100‐90) and 15 severely functional‐dependent individuals (40‐0). The expression of proteins from the most important cellular mechanisms was studied by western blot.Results: Compared with independent elderly patients, dependent elderly showed an abrupt decrease in the capacity of protein synthesis; this decrease was only partially compensated for at the response to unfolded or misfolded proteins (UPR) level due to the increase in IRE1 (P < 0.001) and ATF6 (P < 0.05), which block autophagy, an essential mechanism for cell survival, by decreasing the expression of Beclin‐1, LC3, and p62 (P < 0.001) and the antioxidant response. This lead to increased oxidative damage to lipids (P < 0.001) and that damage was directly associated with the mitochondrial impairment induced by the significant decreases in the I, III, IV, and V mitochondrial complexes (P < 0.01), which drastically reduced the energy capacity of the cell. The essential cellular mechanisms were generally impaired and the triggering of apoptosis was induced, as shown by the significantly elevated levels of most proapoptotic proteins (P < 0.05) and caspase‐3/7 (P < 0.001) in dependents. The death of highly damaged cells is not detrimental to organs as long as the regenerative capacity remains unaltered, but in the dependent patients, this ability was also significantly altered, which was revealed by the reduction in the myogenic regulatory factors and satellite cell marker (P < 0.001), and the increase in myostatin (P < 0.01). Due to the severely disturbed cell interactome, the muscle contractile capacity showed significant damage.Conclusions: Functionally dependent patients exhibited severe alterations in their cellular interactome at the muscle level. Cell apoptosis was caused by a decrease in successful protein synthesis, to which the cellular control systems did not respond adequately; autophagy was simultaneously blocked, the mitochondrion malfunctioned, and as the essential recovery mechanisms failed, these cells could not be replaced, resulting in the muscle being condemned to a loss of mass and functionality.

There are several neurological diseases under which processes related to adult brain neurogenesis, such cell proliferation, neural differentiation and neuronal maturation, are affected. Melatonin can exert a relevant benefit for treating neurological disorders, given its well-known antioxidant and anti-inflammatory properties as well as its pro-survival effects. In addition, melatonin is able to modulate cell proliferation and neural differentiation processes in neural stem/progenitor cells while improving neuronal maturation of neural precursor cells and newly created postmitotic neurons. Thus, melatonin shows relevant pro-neurogenic properties that may have benefits for neurological conditions associated with impairments in adult brain neurogenesis. For instance, the anti-aging properties of melatonin seem to be linked to its neurogenic properties. Modulation of neurogenesis by melatonin is beneficial under conditions of stress, anxiety and depression as well as for the ischemic brain or after a brain stroke. Pro-neurogenic actions of melatonin may also be beneficial for treating dementias, after a traumatic brain injury, and under conditions of epilepsy, schizophrenia and amyotrophic lateral sclerosis. Melatonin may represent a pro-neurogenic treatment effective for retarding the progression of neuropathology associated with Down syndrome. Finally, more studies are necessary to elucidate the benefits of melatonin treatments under brain disorders related to impairments in glucose and insulin homeostasis.

Sarcopenia, a complex and debilitating condition characterized by progressive deterioration of skeletal muscle, is the primary cause of age-associated disability and significantly impacts healthspan in elderly patients. Despite its prevalence among the aging population, the underlying molecular mechanisms are still under investigation. The NLRP3 inflammasome is crucial in the innate immune response and has a significant impact on diseases related to inflammation and aging. Here, we investigated the expression of the NLRP3 inflammasome pathway and pro-inflammatory cytokines in skeletal muscle and peripheral blood of dependent and independent patients who underwent hip surgery. Patients were categorized into independent and dependent individuals based on their Barthel Index. The expression of NLRP3 inflammasome components was significantly upregulated in sarcopenic muscle from dependent patients, accompanied by higher levels of Caspase-1, IL-1β and IL-6. Among older dependent individuals with sarcopenia, there was a significant increase in the MYH3/MYH2 ratio, indicating a transcriptional shift in expression from mature to developmental myosin isoforms. Creatine kinase levels and senescence markers were also higher in dependent patients, altogether resembling dystrophic diseases and indicating muscle degeneration. In summary, we present evidence for the involvement of the NLRP3/ASC/NEK7/Caspase-1 inflammasome pathway with activation of pro-inflammatory SASP in the outcome of sarcopenia in the elderly.

Adult hippocampal neurogenesis is altered during aging and under different neuropsychiatric and neurodegenerative diseases. Melatonin shows neurogenic and neuroprotective properties during aging and neuropathological conditions. In this study, we evaluated the effects of chronic treatment with melatonin on different markers of neurodegeneration and hippocampal neurogenesis using immunohistochemistry in the aged and neurodegenerative brains of SAMP8 mice, which is an animal model of accelerated senescence that mimics aging-related Alzheimer’s pathology. Neurodegenerative processes observed in the brains of aged SAMP8 mice at 10 months of age include the presence of damaged neurons, disorganization in the layers of the brain cortex, alterations in neural processes and the length of neuronal prolongations and β-amyloid accumulation in the cortex and hippocampus. This neurodegeneration may be associated with neurogenic responses in the hippocampal dentate gyrus of these mice, since we observed a neurogenic niche of neural stem and progenitor/precursors cells in the hippocampus of SAMP8 mice. However, hippocampal neurogenesis seems to be compromised due to alterations in the cell survival, migration and/or neuronal maturation of neural precursor cells due to the neurodegeneration levels in these mice. Chronic treatment with melatonin for 9 months decreased these neurodegenerative processes and the neurodegeneration-induced neurogenic response. Noticeably, melatonin also induced recovery in the functionality of adult hippocampal neurogenesis in aged SAMP8 mice.

Despite efforts to elucidate the cellular adaptations induced by obesity, cellular bioenergetics is currently considered a crucial target. New strategies to delay the onset of the hazardous adaptations induced by obesity are needed. Therefore, we evaluated the effects of 4 weeks of melatonin treatment on mitochondrial function and lipid metabolism in the livers of leptin-deficient mice. Our results revealed that the absence of leptin increased lipid storage in the liver and induced significant mitochondrial alterations, which were ultimately responsible for defective ATP production and reactive oxygen species overproduction. Moreover, leptin deficiency promoted mitochondrial biogenesis, fusion, and outer membrane permeabilization. Melatonin treatment reduced the bioenergetic deficit found in ob/ob mice, alleviating some mitochondrial alterations in the electron transport chain machinery, biogenesis, dynamics, respiration, ATP production, and mitochondrial outer membrane permeabilization. Given the role of melatonin in maintaining mitochondrial homeostasis, it could be used as a therapeutic agent against adipogenic steatosis.