Chloroquine defeats aging?

Abstract


Autophagy
Autophagy, literally "self-eating," was rst described by Christian De Duve, who shared the 1974 Nobel prize for his discovery of lysosomes.
Autophagy is an evolutionarily conserved catabolic process wherein lysosomes degrade various cellular components to maintain cytoplasmic quality control and thus cellular homeostasis. Several distinct forms of autophagy include macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Dysregulation of this critical process has been associated with many pathological processes including infectious, metabolic, and neurodegenerative disorders, as well as cancer and autoimmunity. Reduced autophagy was identi ed by López-Otín et al.

Chloroquine
Native peoples of South America have long used an extract of the bark of  8,9 . Furthermore, at the time, azithromycin, quercetin, and HCQ were proposed as "o -the-shelf" treatments for SARS-CoV2 infection 10 .
Quercetin has a senolytic activity 11 and HCQ is known to inhibit beta-galactosidase, a marker of senescence 12  Work by Fifan et al. 18 and others 19,20 demonstrated that the polyamine spermidine increased the maximum life span of C. elegans and the median life span of mice (~10%). Because spermidine increases autophagy, they hypothesized that treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Remarkably, addition of chloroquine (50 mg/kg) to the drinking water extended overall lifespan of middle-aged male NMRI mice (n = 28; treatment initiated at age 500 days) by 11.4% (786 days) compared to control mice (n = 28; 689 days, p = 0.0002).
Median life span of the middle-aged mice increased by 11.4%. Studies of chloroquine by these two groups and other data dating back a couple decades suggest the e ect is real, although the precise mechanism is not clear. Mechanistic studies carried out by both groups suggest a variety of mechanisms, though this "ball of yarn" is far from being unraveled.

Mechanism studies
As noted above, CQ treatment was initiated at age 500 days when the mice weighed on average ~35 gm. Over the next 100 days, the control animals gained weight, reaching a maximum of 45 gm. In contrast, the CQ-treated animals did not gain signi cant weight over the duration of the experiment (almost 800 days). While the control animals consumed more liquid (p = 0.002), the food consumed by both groups was equal (~4 gm/day) ruling out the idea that CQ somehow reduced food intake through an arti cial "calorie restriction" e ect.
Previously, CQ (at 60 mg/kg) was reported to impair autophagosome-lysosome fusion rather than a ecting the acidity and/or degradative activities of lysosomes 21  Curiously, the treated animals exhibited increased liver glycogen and reduced serum insulin growth factor binding protein 3 (IGFBP3), though no di erence in IGF-1, IRS, or growth hormone levels 23,24 . CQ treatment elicited a decrease in glycogenolysis in the liver.

Medical Implications
As noted above, CQ and HCQ are widely used drugs 38  Since then, some of these ideas have been put to the test or are being tested .
With regard to development of CQ/HCQ, suitable biomarkers will need to be validated. At low doses, CQ or HCQ seem to qualify for evaluation in humans. However, the safety pro le of this class of drugs will need to be considered. For instance, periodic eye exams and cardiac monitoring are routine 40 at doses commonly used in rheumatology 38 . Clearly these anti-malarials have come a long way from the rainforests of South America!