Duration of rapamycin treatment has differential effects on metabolism in mice

Area of Science:

• Gerontology
• Metabolic pathways
• Pharmacology

Background:

• The target of rapamycin (TOR) pathway regulates fundamental processes including growth, metabolism, and aging.
• Rapamycin, an inhibitor of mechanistic TOR (mTOR), has demonstrated life extension in mice, but with paradoxical detrimental metabolic effects.
• The mechanism behind rapamycin's life extension and its associated metabolic paradox remained unclear.

Purpose of the Study:

• To investigate the temporal effects of rapamycin treatment on metabolism and lifespan in mice.
• To resolve the paradox of improved survival despite metabolic impairment during rapamycin treatment.
• To elucidate the metabolic alterations underlying rapamycin-induced longevity.

Main Methods:

• Mice were treated with rapamycin, and their metabolic profiles, oxygen consumption, ketogenesis, and insulin sensitivity were assessed over time.
• Comparative analysis of short-term versus prolonged (20 weeks) rapamycin treatment effects.
• Assessment of metabolic changes in relation to observed lifespan extension.

Main Results:

• Detrimental metabolic effects of rapamycin were transient, observed only in early treatment stages.
• Prolonged rapamycin treatment (20 weeks) led to improved metabolic profiles.
• Significant enhancements in oxygen consumption, ketogenesis, and insulin sensitivity were observed with sustained treatment.

Conclusions:

• The "rapamycin paradox" is explained by the transient nature of initial detrimental metabolic effects, which are reversed with prolonged treatment.
• Sustained rapamycin administration induces beneficial metabolic alterations, including enhanced insulin sensitivity.
• These metabolic improvements are likely causally linked to the observed life extension in mice.