Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions

Abstract

Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.

Keywords: cachexia; molecules; pathogenesis; sarcopenia; targeted therapy.

FIGURE 1

The bidirectional regulation between adipose tissue and skeletal muscle occurs through the endocrine pathway. The changes in cytokines and noncoding RNAs induced by aged adipose/muscle lead to unfavorable fat deposition and accumulation, persistent low‐grade inflammation, and impairments of lipolysis, glucose uptake, and insulin sensitivity, contributing to the pathophysiology of sarcopenia and cachexia.

FIGURE 2

Molecules influence sarcopenia and cachexia by mediating the interaction between adipose tissue and skeletal muscle. The figure highlights the cytokines, miRNAs, and lncRNAs potentially involved in sarcopenia and cachexia by regulating the adipose–muscle axis.

FIGURE 3

Novel antisarcopenia strategies. The intricate interplay between inflammation and metabolic dysfunctions in adipose tissue and muscle during aging complicates current treatments that target metabolic defects, dysbiosis, inflammation, or senescent cells in isolation, often resulting in limited success in treating sarcopenia. To address these challenges, we propose a comprehensive approach that combines various therapies, including dietary modifications, potential bariatric surgery, pharmacological interventions, and structured physical exercise. However, it may be essential to incorporate localized heat and cold stimulation alongside resistance training to effectively modify gene expression related to proteolysis and myogenesis, as temperature alone might not suffice. While bariatric surgery is an effective intervention for obesity, it can inadvertently increase the risk of sarcopenia due to accompanying muscle loss. Therefore, optimizing exercise protocols and ensuring adequate protein intake immediately postsurgery could be crucial in mitigating muscle decline. Physical training offers promising avenues for treating sarcopenia by addressing senescence and inflammation, promoting the browning of white adipose tissue (WAT), and positively influencing gut microbiota. This integrated strategy, which tackles inflammation, metabolic disturbances, and their repercussions on muscle health, holds significant potential for effectively managing sarcopenia. WAT, white adipose tissue; NMES, neuromuscular electrical stimulation.

FIGURE 4

Novel anticachexia strategies. Therapeutic approaches for cachexia encompass anti‐inflammatory treatments, nutritional strategies, pharmacological options, and multimodal interventions.

FIGURE 5

Future perspective. A comprehensive understanding of the mechanisms underlying sarcopenia and cachexia is essential. Recent advancements in science and technology allow us to evaluate these conditions at the tissue, cellular, and molecular levels. Early and accurate diagnosis is critical for the effective management of both sarcopenia and cachexia. Future research should prioritize the identification and clinical application of new biomarkers for early detection. Advanced imaging techniques and molecular diagnostics can be utilized to monitor disease progression and evaluate treatment responses. Given the complex factors contributing to sarcopenia and cachexia, reliance on a single treatment method is often inadequate. Therefore, a multifaceted treatment strategy that addresses various pathways and cellular interactions is necessary. Combining medications with cell and gene therapies, as well as employing nanoparticles and gene‐editing technologies, can enhance both the precision and effectiveness of treatments. Ultimately, identifying effective targeted therapies, key regulatory factors, and early diagnostic methods will be crucial for developing future treatments for sarcopenia and cachexia.