A joint study by University of East Anglia and University of Glasgow performs a meta-analysis of 167 experiments across eight vertebrate species, showing rapamycin reliably matches the life-extension benefits of intermittent fasting without requiring dietary restriction, highlighting its promise for further aging therapeutics.
Key points
Meta-analysis of 167 experiments across eight vertebrate species reveals rapamycin matches lifespan gains of intermittent fasting.
Rapamycin extends life in fish, rodents, and primates regardless of sex or feeding protocol, whereas metformin lacks consistent benefits.
Study employs systematic review methodology to benchmark rapamycin against calorie restriction, supporting its potential for human aging trials.
Why it matters:
The study underscores drug repurposing potential for practical, less restrictive longevity interventions with significant implications for aging therapeutics.
Q&A
What is rapamycin?
How does dietary restriction extend lifespan?
What is a meta-analysis in this context?
Why did metformin show no lifespan benefit?
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Academy
Rapamycin and mTOR in Longevity Science
Introduction
Rapamycin, also known as sirolimus, is a small‐molecule inhibitor of the mechanistic target of rapamycin (mTOR) pathway. The mTOR pathway integrates signals from nutrients, growth factors, and cellular energy status to regulate cell growth, protein synthesis, and autophagy. In aging research, modulation of mTOR has emerged as a key strategy for extending healthspan and lifespan.
mTOR Pathway Basics
The mTOR pathway consists of two distinct complexes: mTORC1 and mTORC2. mTORC1 senses amino acids and growth signals to promote protein synthesis and inhibit autophagy, while mTORC2 regulates cell survival and metabolism. Inhibition of mTORC1 by rapamycin mimics a nutrient‐low state, activating cellular stress responses that enhance maintenance and repair mechanisms.
How Rapamycin Works
Rapamycin binds to the intracellular protein FKBP12, forming a complex that directly inhibits mTORC1. This leads to:
- Increased autophagy: Cells clear damaged organelles and proteins more effectively.
- Reduced inflammation: Lower mTOR activity decreases pro‐inflammatory signaling.
- Enhanced stress resistance: Cells become more resilient to oxidative and metabolic stress.
Together, these changes slow age‐related decline in multiple tissues.
Preclinical Evidence for Lifespan Extension
Studies in yeast, worms, flies, and mammals consistently show that rapamycin extends lifespan. Key findings include:
- Mouse studies demonstrate a 10–25% increase in median and maximum lifespan when rapamycin is administered in middle age.
- Fish and rat models also exhibit significant longevity gains and improved health markers such as preserved cognitive function and reduced cancer incidence.
- Meta‐analyses comparing rapamycin to dietary restriction reveal equivalent lifespan extension across vertebrate species, offering a pharmacological alternative to rigorous fasting regimens.
Safety, Dosage, and Side Effects
While rapamycin shows promise, its immunosuppressive origins raise concerns:
- Optimal dosing: Low, intermittent dosing appears to maximize benefits while minimizing adverse effects.
- Side effects: Potential issues include glucose intolerance, dyslipidemia, and increased infection risk. Clinical trials in healthy older adults are evaluating safe dosing protocols.
Clinical Translation and Future Directions
Ongoing human trials aim to assess rapamycin’s impact on age‐related conditions such as cognitive decline, frailty, and immune aging. Future research priorities:
- Developing mTORC1‐selective inhibitors with fewer side effects.
- Identifying biomarkers to monitor mTOR inhibition and biological aging.
- Combining rapamycin with other geroprotective agents for synergistic effects.
By elucidating the link between nutrient sensing, cellular maintenance, and organismal aging, rapamycin research paves the way for targeted interventions that promote healthy longevity.
