Atypical tetracyclines promote longevity and ferroptotic neuroprotection via translation attenuation

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Tetracyclines exhibit neuroprotective and geroprotective effects independent of antibiotic activity.
• The precise mechanisms underlying these non-antibiotic effects remain largely unknown.
• Previous research has not fully elucidated the distinct molecular pathways involved.

Purpose of the Study:

• To systematically profile tetracyclines and identify the shared mechanism of their neuroprotective effects.
• To differentiate between mitochondrial-targeting tetracyclines (MitoTets) and cytosolic-targeting tetracyclines (CytoTets).
• To explore the potential of CytoTets as a therapeutic strategy for neurodegenerative diseases.

Main Methods:

• Systematic profiling of widely used tetracyclines, including impurities and degradation products.
• Investigation of translation attenuation as a common mechanism.
• Characterization of ISR-dependent (MitoTets) and ISR-independent (CytoTets) pathways.
• Assessment of neuroprotection in mouse and human neuron models, including ferroptosis assays.

Main Results:

• Translation attenuation is identified as the shared mechanism for tetracycline's neuroprotective and longevity effects.
• Two distinct classes of tetracyclines were uncovered: MitoTets (e.g., doxycycline) activating the Integrated Stress Response (ISR).
• Atypical CytoTets (e.g., 4-epiminocycline) directly inhibit cytosolic ribosomes, bypass ISR, and protect against ferroptosis.
• CytoTets demonstrated neuroprotective effects in both mouse and human neurons.

Conclusions:

• Tetracyclines represent a tunable chemical scaffold for targeting translation in aging and neurodegeneration.
• CytoTets offer a promising, non-antibiotic, brain-penetrant therapeutic avenue for neurological disorders.
• Understanding these distinct mechanisms allows for targeted development of novel neuroprotective agents.