You don't need a weatherman: famines, evolution, and intervention into aging

Area of Science:

• Biogerontology
• Evolutionary Biology
• Pharmacology

Background:

• Calorie restriction (CR) is a proven intervention for extending lifespan and healthspan in various organisms.
• Pharmaceuticals mimicking CR's effects (CR mimetics) are being developed, assuming their efficacy translates proportionally to humans (proportionality principle).
• The weather hypothesis (WH), based on evolutionary theory, predicts only a modest lifespan extension (2-3 years) for CR or its mimetics in humans.

Purpose of the Study:

• To evaluate the challenge posed by the WH to the efficacy of CR mimetics.
• To analyze theoretical arguments and interspecies data regarding CR's anti-aging effects.
• To inform optimal resource allocation in therapeutic development for aging.

Main Methods:

• Theoretical evaluation of the weather hypothesis (WH).
• Analysis of interspecies data on calorie restriction (CR).
• Comparison of data with predictions from the proportionality principle (PP) and WH.

Main Results:

• Rodent data show CR's anti-aging effects increase with restriction, even below survivable levels in the wild and without interfering with reproduction, aligning with evolutionary predictions.
• Interspecies data, including human data, support the proportionality principle (PP) over the weather hypothesis (WH).
• This suggests humans may experience proportional aging deceleration with CR or its mimetics.

Conclusions:

• CR mimetics could be as effective in humans as CR is in rodent models, leading to proportional aging deceleration.
• Despite potential efficacy, CR mimetics should not be the primary focus of aging research.
• Targeting molecular aging lesions directly is likely to yield more rapidly developable and effective anti-aging therapies.