Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism

Abstract

Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%. Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.

Chloroquine Defeats Aging?

“…Related to the work of Li et al, Doeppner et al (2022) also reported a chloroquine-mediated increase in the lifespan of rodents, in this case mice 17 .…”

“…LC3-II is generated by the conjugation of cytosolic LC3-I to phosphatidylethanolamine on the surface of nascent autophagosomes. Doeppner et al showed that the CQ-treated mice exhibited a dose-dependent increase in LC3B-II as well as p62 in the liver and heart, as con rmed by transmission electron microscopy 17 .…”

Translatability of life‐extending pharmacological treatments between different species

“…The role of CQ as an autophagy inhibitor has garnered recent attention, with investigations focusing on its potential opposing effect to spermidine on lifespan in model organisms (Doeppner et al., 2022). Against all odds, male NMRI mice treated with chloroquine at a dose of 50 mg/kg/day, starting at 500 days old and continuing for 286 days, significantly outlived the control group, with an average lifespan of 786 days compared to 689 days in the controls.…”

“…Various treatments including rapamycin, resveratrol, spermidine, and others have been proposed as potential lifespan‐extending treatments (Doeppner et al., 2022). However, despite the promising results obtained in organism models such as yeast, worms, and flies, the translatability of these interventions across species of increasing complexity and to humans is still uncertain.…”

Cytoprotective effect of chloroquine against metal(loid)s and PM 2.5 toxicity in the A549 lung cell line

“…The increment in ubiquitin and 20s proteasome subunit in denervated muscles of CQ-treated rats was reported (Kimura et al, 2009). In addition, CQ treatment (50 mg/kg during 250) expanded the median and maximum lifespan of male mice, this effect was related to an increment in the autophagosome-like structures containing cytoplasmic organelles with changes in the proteasome activity (Doeppner et al, 2022). The discrete data of oxidation protein in the co-exposure CQ-metal(loid) could be mediated by autophagic-lysosome-and ubiquitin-proteasome-proteolysis pathways, that need further studies.…”