Safe and Orally\nBioavailable Inhibitor of Serine Palmitoyltransferase\nImproves Age-Related Sarcopenia

The accumulation of ceramides and related metabolites\nhas emerged\nas a pivotal mechanism contributing to the onset of age-related diseases.\nHowever, small molecule inhibitors targeting the ceramide <i>de novo</i> synthesis pathway for clinical use are currently\nunavailable. We synthesized a safe and orally bioavailable inhibitor,\ntermed ALT-007, targeting the rate-limiting enzyme of ceramide <i>de novo</i> synthesis, serine palmitoyltransferase (SPT). In\na mouse model of age-related sarcopenia, ALT-007, administered through\nthe diet, effectively restored muscle mass and function compromised\nby aging. Mechanistic studies revealed that ALT-007 enhances protein\nhomeostasis in Caenorhabditis elegans and mouse models of aging and age-related diseases, such as sarcopenia\nand inclusion body myositis (IBM); this effect is mediated by a specific\nreduction in very-long chain 1-deoxy-sphingolipid species, which accumulate\nin both muscle and brain tissues of aged mice and in muscle cells\nfrom IBM patients. These findings unveil a promising therapeutic avenue\nfor developing safe ceramide inhibitors to address age-related neuromuscular\ndiseases.