In a previous study, chloroquine (CLQ) administration extended lifespan in middle-aged male NMRI mice without systemic toxicity, challenging the view that blockage of autophagy is uniformly detrimental. Here, we evaluated a modified step-down intermittent CLQ regimen in aged female Sprague-Dawley rats designed to minimize long-term toxicity while maintaining biological activity. CLQ treatment significantly extended median lifespan and increased maximum lifespan by 19%. Treated rats exhibited a significant ~10-12% reduction in food consumption compared with controls, which may have partially contributed to the longevity effects observed in this study. CLQ administration was also associated with changes in endocrine and metabolic parameters, including alterations in the IGF axis, improved lipid profiles, preserved diurnal thermoregulation, stable reproductive hormone levels, and reduced mammary gland proliferative lesions without evidence of hepatic or renal toxicity within the parameters measured. These findings indicate that intermittent CLQ treatment is associated with extended lifespan and coordinated physiological adaptations in aged rats, while the underlying molecular mechanisms remain to be determined.
