Low Dose Chloroquine as a Geroprotective Drug
Researchers here report on the effects of low dose chloroquine on aged tissues in rats. It is not all positive, but the balance of benefits and harms still leads to modest extension of life span. The effects may include suppression of cellular senescence to some degree, but it isn't clear that this is the major driver of benefits. In the wake of deaths during the period in which chloroquine was discussed as a potential treatment for COVID-19, it is worth noting that this is not a safe drug and is to be avoided at higher doses. Chloroquine has a narrow therapeutic window for its originally intended uses, and going over that range will have unpleasant and potentially fatal consequences.
To examine the systemic effects of chloroquine (CQ) in vivo, we treated 24-month-old Sprague Dawley (SD) male rats with CQ twice a week for 5 months at a low dose of 0.1 mg/kg orally by water to avoid potential side effects. Low-dose CQ administration extended the lifespan of rats by approximately 6% in terms of median longevity and by about 13% in terms of maximum longevity. CQ-treated rats also tended to have decreased serum TNF-α levels and reduced the numbers of circulating white blood cells (WBC) and neutrophils (NEU) in old rats, suggestive of attenuated chronic inflammation.
In this study, we found that low concentrations of CQ alleviated stem cell senescence, repressed tissue fibrosis, and extended lifespan. Multi-tissue transcriptomic inspection demonstrated that CQ may have both beneficial and detrimental effects on aged animals in a tissue-specific manner. By surveying the transcriptomic landscape of CQ-treated tissues, we found that low-dose CQ treatment attenuated age-associated gene expression across tissues. The strongest effect was observed in the kidney where we found decreased levels of interferon-stimulated responsive element (ISRE)-containing genes and increased expression of transporter encoding genes. However, CQ also augmented pro-aging transcriptional signatures, which may elicit potential cardiac toxicity without detectable functional impairment during the duration of the experiment.
The role of CQ in counteracting aging may be linked to its ability to inhibit chronic inflammation systematically and alleviate fibrosis. Consistent with our observations, CQ reduces inflammation and effectively decreases the salivary and serum levels of IL-6, a key component of the senescence-associated secretory phenotype (SASP). In summary, our results demonstrate a geroprotective role of low-dose CQ on physiologically aged rats.