Rapamycin longevity
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These studies suggest that rapamycin extends lifespan and improves healthspan in various organisms, with effects influenced by dosage, sex, and treatment duration, and involving mechanisms such as metabolic alterations, TORC1 pathway modulation, and improved mitochondrial and cardiovascular function.
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Rapamycin and Longevity: Insights from Recent Research
Introduction to Rapamycin and Longevity
Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) pathway, has garnered significant attention for its potential to extend lifespan across various species, including mammals. This article synthesizes recent research findings on the effects of rapamycin on longevity, highlighting key mechanisms and outcomes.
Mechanisms of Rapamycin-Induced Longevity
mTOR Pathway Inhibition
The mTOR pathway is a critical nutrient-sensing pathway that regulates growth, metabolism, and aging. Inhibition of this pathway by rapamycin has been shown to extend lifespan in several organisms, including yeast, nematodes, fruit flies, and mice . Specifically, rapamycin targets the TORC1 branch of the pathway, which is associated with increased autophagy and altered protein translation, contributing to enhanced longevity.
Metabolic and Endocrine Effects
Rapamycin's impact on metabolism is complex. Initial treatment phases may induce detrimental metabolic effects, such as impaired insulin sensitivity. However, prolonged treatment (e.g., 20 weeks) reverses these effects, leading to improved metabolic profiles, increased oxygen consumption, and enhanced insulin sensitivity, which are consistent with life extension. Notably, rapamycin's metabolic effects differ significantly from those observed with dietary restriction, suggesting distinct underlying mechanisms.
Sex-Dependent and Dose-Dependent Effects
Differential Longevity Benefits
Research indicates that rapamycin extends lifespan more significantly in female mice compared to males, with females showing a 26% increase in median lifespan versus 23% in males. This sex-dependent effect may be due to differences in drug metabolism and blood levels between sexes .
Dose and Timing Variations
The longevity benefits of rapamycin are also dose-dependent and influenced by the timing of administration. For instance, initiating rapamycin treatment at 42 parts per million (ppm) in middle-aged mice significantly increased survival in both sexes, while intermittent dosing regimens were less effective, particularly in females. Additionally, short-term rapamycin treatment in middle-aged mice can increase life expectancy by up to 60% and improve healthspan, indicating that even transient exposure can have lasting benefits.
Healthspan and Functional Benefits
Cardiovascular and Metabolic Health
Late-life rapamycin treatment has been shown to reverse age-related heart dysfunction, improve cardiovascular health, and confer benefits to skeletal and motor functions. These improvements are associated with changes in gene expression related to inflammation, metabolism, and antihypertrophic signaling in cardiac tissue.
Cancer and Disease Modulation
Rapamycin may extend lifespan by reducing the incidence of life-limiting pathologies such as cancer. For example, short-term rapamycin treatment in female mice shifted cancer prevalence towards more aggressive hematopoietic cancers while reducing non-hematopoietic malignancies. This suggests that rapamycin's longevity effects may partly stem from its influence on disease patterns.
Conclusion
Rapamycin has emerged as a potent pharmacological agent for extending lifespan across various species, including mammals. Its effects are mediated through the inhibition of the mTOR pathway, leading to enhanced autophagy, altered metabolism, and improved healthspan. The benefits of rapamycin are dose-dependent, sex-specific, and influenced by the timing of administration. While rapamycin extends lifespan, its impact on aging phenotypes and disease modulation highlights its potential as a therapeutic intervention for age-related diseases. Further research is needed to optimize dosing regimens and fully understand the long-term implications of rapamycin treatment on human health and longevity.
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