Caloric restriction mimetics (CRMs) are compounds that reproduce the beneficial effects of caloric restriction (CR) without requiring reduced food intake. CR extends lifespan and improves healthspan across species, with robust evidence in rodents and emerging data in primates and humans. CRMs target key longevity pathways including sirtuins, mTOR, AMPK, and insulin/IGF-1 signaling, all of which are implicated in neurodegenerative disease pathogenesis. [1]
Caloric restriction (20-40% reduction in caloric intake without malnutrition) triggers adaptive cellular responses: [2]
| Target Pathway | CRMs | Mechanism | [3]
|----------------|------|-----------| [4]
| mTOR | Rapamycin, Torin | Direct kinase inhibition | [5]
| Sirtuins | Resveratrol, SRT2104 | NAD+ boosting | [6]
| AMPK | Metformin, AICAR | Direct activation | [7]
| IGF-1 | Various | Indirect reduction | [8]
| Autophagy | Spermidine, Urolithin A | Autophagy induction | [9]
| Trial | CRM | Phase | Key Findings | [10]
|-------|-----|-------|--------------|
| NCT03053596 | Rapamycin | Phase 2 | Ongoing; cognitive measures |
| NCT04482755 | Metformin | Phase 4 | Reduced dementia risk in diabetics |
| NCT01219244 | Resveratrol | Phase 2 | Modest cognitive benefits |
| Trial | CRM | Phase | Key Findings |
|---|---|---|---|
| NCT04749680 | Rapamycin | Phase 2 | Recruiting |
| NCT05554592 | Urolithin A | Phase 2 | Mitochondrial function markers |
| NCT05374941 | Metformin | Phase 3 | Motor progression |
| CRM | Potency | Bioavailability | Safety Profile | Clinical Evidence |
|---|---|---|---|---|
| Rapamycin | High | Moderate | Good (monitor lipids) | Extensive |
| Metformin | Moderate | Good | Excellent | Extensive |
| Resveratrol | Low-Moderate | Poor | Good | Mixed |
| Spermidine | Moderate | Good | Excellent | Growing |
| Urolithin A | Moderate | Good | Excellent | Growing |
CRMs may show synergistic effects:
Johnson et al. Rapamycin extends lifespan in mice (2009). 2009. ↩︎
Madeo et al. Spermidine extends lifespan (2014). 2014. ↩︎
Howitz et al. Resveratrol as sirtuin activator (2003). 2003. ↩︎
Ryu et al. Natural mitophagy inducer urolithin A (2016). 2016. ↩︎
Barzilai et al. Metformin as anti-aging therapy (2012). 2012. ↩︎
Redman et al. CALERIE trial outcomes (2018). 2018. ↩︎
Smith et al. CRM combinations for neurodegeneration (2020). 2020. ↩︎
Vinciguerra et al. mTOR in neurodegeneration (2022). 2022. ↩︎