Disruption of the Muscle–Brain Axis in Ageing: Role of Myokines in Sarcopenia and Neurodegeneration

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Abstract
This narrative review analyzes how myokines act as key links in communication between skeletal muscle and the brain, focusing on the impact of aging on this axis. Although the current literature links defects in this signaling pathway to sarcopenia, neurodegeneration, and cognitive decline, we still do not know exactly what role each molecule plays individually. Among the main gaps in our understanding are questions about how these substances are transported to the nervous system, what their specific receptors are, and what cause-and-effect relationship actually exists between losing muscle mass and developing neurological problems. In fact, in humans, it remains unclear whether myokines actually reach the brain in truly effective concentrations or whether their benefits are due more to peripheral metabolic, vascular, and inflammatory changes. Today, most of the mechanistic evidence comes from animal and cellular models, while observational studies predominate in humans. This is further complicated by uncertainties regarding the actual origin of these proteins in tissues, their passage through the blood–brain barrier, and their measurement in the blood, making it difficult to determine whether these proteins act as causes, consequences, or simply compensatory responses to aging and disease. On the other hand, although exercise remains the most robust tool for maintaining muscle health and protecting cognitive function, it is still unclear whether we could replicate those same benefits by isolating and stimulating specific myokines. The major challenge for the future is to develop human studies that combine standardized biomarkers with long-term monitoring of muscle function, cognition, and brain structure. Only then will we know whether this fascinating muscle–brain axis can move beyond being a promising hypothesis to become a real therapeutic target.

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