Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan

Abstract

Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.

Autophagy induction in the treatment of Alzheimer's disease

“…Currently, the means to enhance lysosomal activity are quite limited, with most approaches focus on modulating TFEB activity. Direct and indirect pharmacological agonists of TFEB (e.g., the approved drug digoxin and a curcumin derivative) as well as TFEB overexpression were shown to enhance autophagic/lysosomal activity in neuronal and glial cells in vitro and in vivo (Kilpatrick, Zeng, Hancock, & Segatori, ; Leeman et al, ; Song et al, ; Wang et al, ). In turn, this induction of the lysosomal axis has led to enhanced degradation of protein aggregates, activation of quiescent neurons and increased lifespan in C. elegans .…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Given a central role for the lysosome machinery as the sub-cellular orchestrators of these beneficial effects, it remains to be seen whether administration of small moleculae activators of the lysosome biogenesis program (60, 226) may also confer similar benefits in humans with an accceptable safety profile.…”

Role of RN Autophagy Mediated ERV Suppression in Cellular Senescence

“…Loss of autophagy has been shown to cause premature aging in many species [21,22]. Treatment with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis has shown to extend life span in worms and lessen the metabolic syndrome in mice [23].…”