INNOVATIVE NUTRITIONAL STRATEGIES TO COUNTERACT CANCER CACHEXIA

Cachexia is a debilitating, multifactorial syndrome often associated with chronic diseases such as cancer. It is characterized by progressive and involuntary body weight loss, fatigue, reduced food intake, inflammation, and increased muscle protein breakdown. Cancer cachexia (CC) affects 50-80% of cancer patients and contributes to approximately 20% of cancer-related deaths. A major feature of CC is skeletal muscle wasting, triggered by tumor-related factors and systemic inflammation. In this scenario, mitochondrial dysfunction further impairs oxidative metabolism and exacerbates muscle atrophy. Nutritional support is essential in managing CC, helping to maintain body weight, improve quality of life, and protect against therapy-induced toxicity. However, there is no standardized dietary prescription for cancer patients with cachexia. This study investigates two nutritional approaches: supplementation with medium-chain triglycerides (MCT) and a fasting-mimicking diet (FMD). MCT supplementation induces nutritional ketosis, potentially enhancing oxidative metabolism in skeletal muscle through the use of energy-efficient substrates such as fatty acids and ketone bodies (KBs). FMD, as an adjuvant in cancer treatment, has shown both antineoplastic activity and protection against chemotherapy-induced adverse effects; it may also preserve muscle mass and function. The effects of the nutritional strategies reported above on CC in experimental models, namely mice bearing the C26 tumor and mice spontaneously developing colon cancer (VCM) have been evaluated in the present study. MCT supplementation in C26 tumor-bearing mice increased ketonemia but did not prevent CC. Nonetheless, it positively impacted on some markers associated with skeletal muscle metabolism of KBs and autophagy in the cachectic mice. FMD also did not counteract CC in the C26 tumor-bearing mice undergoing Folfox chemotherapy, although it increased the levels of proteins related to mitochondrial function and moderately improved the immunosuppressive phenotype in the spleen. In VCM mice FMD did not significantly impact on tumor progression or CC, although it prevented gut dysbiosis associated with colorectal cancer progression. Additionally, in the VCM mice FMD revealed sex-based differences in body weight, particularly reducing excessive weight gain in males. In conclusion, while MCT supplementation and FMD had moderate effects on tumor hosts, they were insufficient to prevent CC. These findings emphasize the need for a multidisciplinary approach for treating and preventing CC.