1. Academic Validation
  2. Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia

Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia

  • ACS Pharmacol Transl Sci. 2024 Dec 29;8(1):203-215. doi: 10.1021/acsptsci.4c00587.
Johanne Poisson 1 Ioanna Daskalaki 1 Vijay Potluri 2 Jean-David Morel 1 Sandra Rodriguez-Lopez 1 Alessia De Masi 1 Giorgia Benegiamo 1 Suresh Jain 2 Tanes Lima 1 Johan Auwerx 1
Affiliations

Affiliations

  • 1 Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
  • 2 Intonation Research Laboratories, Hyderabad 500076, India.
Abstract

The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide de novo synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting Enzyme of ceramide de novo synthesis, serine palmitoyltransferase (SPT). In a mouse model of age-related sarcopenia, ALT-007, administered through the diet, effectively restored muscle mass and function compromised by aging. Mechanistic studies revealed that ALT-007 enhances protein homeostasis in Caenorhabditis elegans and mouse models of aging and age-related diseases, such as sarcopenia and inclusion body myositis (IBM); this effect is mediated by a specific reduction in very-long chain 1-deoxy-sphingolipid species, which accumulate in both muscle and brain tissues of aged mice and in muscle cells from IBM patients. These findings unveil a promising therapeutic avenue for developing safe ceramide inhibitors to address age-related neuromuscular diseases.

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