Study 1: Low-dose chloroquine treatment extends the lifespan of aged rats.
" To further examine the systemic effects of 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."
I found one reference saying Sprague Dawley rats live 2.5 to 3.5 years. That would be 912 to 1277 days. Seems like the controls in this study died significantly sooner and the treated rats died around the normal life span of this strain as you suggest.
Treatment was initiated at the age of 500 days and continued for 286 days
That is about 2/3 the lifespan of a mouse. So you start at 60, and take it till you’re 90. The dose was 50 mg/kg for the mouse; divided by 12.5, so 4 mg/kg. At 60 kilos, a human has to take 250 mg per day.
According to product information from the FDA website, chloroquine phosphate is 60% chloroquine. Chloroquine phosphate pills come in dosages of 100 mg, 250 mg, 500 mg. So a 500 mg pill of chloroquine phosphate is about 300 mg of chloroquine. And a 100 mg pill of chloroquine phosphate is 60 mg chloroquine.
From the full text:
“Notably, we found that low-dose CQ treatment extended the lifespan of naturally aged rats. The dose of CQ used in this study was only 0.1 mg/kg twice a week, at least 100-fold lower than the dose that was previously used in rodents (Solomon and Lee, 2009). Our results support the potential efficacy of CQ in delaying aging. Furthermore, it has been reported that 3.5 mg/kg of CQ enhanced DNA damage clearance and rescued age-related metabolic shift, suggesting a potential geroprotective effect (Qian et al., 2018). This lifespan extension effect by CQ was also observed recently in nematodes and a progeria mouse model (Qian et al., 2018). Our study shows that low-dose CQ extended the lifespan of naturally aged rodents”, (6% median, and 13% maximum lifespan).
For a 75 kg human, using a dosage scaling factor of 6.2, that would be 0.1 ÷ 6.2 × 75 = 1.2 mg. Rats were given the dose twice per week. Once per week should be sufficient for humans.
The authors also commented on a similar study in progeria mice:
“Treatment of Zmpste24−/− mice (a progeria mouse model with low DNA repair capacity) with CQ given in 0.9% saline twice per week at 3.5 mg/kg body weight for about 3 months, activates Ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase, a key regulator of DNA damage response, promotes DNA damage clearance, ameliorates premature aging and extends lifespan by 19%.”
For a 75 kg human, using a dosage scaling factor of 12.3 for mice to human:
If once weekly, ultra low-dose chloroquine would provide a meaningful antiaging effect, I would personally choose that over a higher daily dosage. One of the reasons they chose such a low dose was apparently to reduce the chances of toxic side effects while keeping the positive benefits. Of particular concern was cardiac toxicity over the long term.
In my previous reply, I listed human dosage scaling for the rat study and also a lifespan study in mice with progeria. For a 75 kg human, the extrapolated doses would be 1.2 mg, and 21.3 mg, respectively. And given the slower metabolism of humans, I’m postulating that once weekly would be sufficient.
In the progeria mouse study , the researchers comment that, “The results showed that at such low doses (3.5 mg/kg twice weekly), CQ has no toxicity and little effect on basal autophagic activity. Moreover, a low dose of CQ prolongs lifespan in progeroid mice.”
And given that chloroquine is an inhibitor of autophagy, capping the dose at this level may help to preserve the autophagic benefits of rapamycin.
I’m not going to “recommend” that anyone attempt using chloroquine for life extension. I’m just discussing how that might be done.
Two findings of the rat study were that, “In this study, we found that low concentrations of CQ alleviated stem cell senescence (and) repressed tissue fibrosis.”
I researched elimination half-life in rats versus humans for chloroquine.
In rats, the elimination half-time has been estimated as 10 days. (1)
In humans, “the most commonly quoted median value for the terminal elimination half-life is 40 days.” (2)
Vergote V, Laenen L, Mols R, Augustijns P, Van Ranst M, Maes P. Chloroquine, an Anti-Malaria Drug as Effective Prevention for Hantavirus Infections. Front Cell Infect Microbiol . 2021;11:580532. Published 2021 Mar 15. doi:10.3389/fcimb.2021.580532
On the difference with Hydroxychloroquine in summary - they are closely related agents with overlapping uses, but hydroxychloroquine has an improved safety profile over the parent chloroquine compound. Knowing the nuance can help ensure the right one is prescribed based on the specific condition being treated and patient factors.
The bioarxiv preprint of that study also showed enhanced survival at 120 weeks in wild-type. These were male C57BL/6J mice twice weekly 3.5mg/kg starting at 12 mo. Additionally, double ATM knockout prevented pro-survival effects of chloroquine.
The final eLife paper makes make no mention of survival data, although they mention pro-healthspan effect. I wonder why.
we intraperitoneally administrated 12-month-old ‘old’ male mice with low-dose CQ (3.5 mg/kg) twice a week. Remarkably, compared with the saline-treated group, CQ treatment inhibited glycolysis, lowered serum lactate level, and attenuated body weight decline
However, the recent protein & cell paper showed a concerning outcome even with 0.1mg/kg
However, CQ also had adverse effects on aged hearts at the transcriptional level. Most pro-aging DEGs were enriched in the heart, with an overrepresentation of cardiac disease-related gene sets. Consistently, the clinical cardiovascular toxicity of CQ has been reported (Wozniacka et al., 2006). For example, the treatment with chloroquine or hydroxychloroquine decreases myocardial cell discharge, leading to aberrant cardiac electrical conduction and a prolonged corrected QT interval based on electrocardiography (Wozniacka et al., 2006; Solomon and Lee, 2009).
You didn’t include the last sentence of that paragraph. I’m copying below because it’s important.
“By contrast, although CQ has noticeable effects in hearts at the transcriptional level, extremely low-dose CQ may not affect normal heart function as assessed by transthoracic echocardiography and overall physiological health.”
What they’re saying is that unfavorable gene expression in the heart is still above detection threshold even with very low dose CQ, but that it didn’t lead to detectable functional changes at that dosage. In other words, they found a sweet spot where cardiac toxicity was minimized while still preserving the positive effects of CQ. But I agree that it may still be concerning because these are rats, not people. They close their paper by saying that any clinical trials in people should monitor for the same.
They also write in their paper:
" Notably, the cardiac function seems not adversely affected by low dose of CQ treatment in aged rats (Fig. (Fig.2C).2C). Collectively, these data suggest that the low-dose CQ treatment alleviates aging phenotypes in a tissue-specific manner without detectable cardiac side effects."
The studies used chloroquine and not hydroxychloroquine. A new study would be needed to know if hydroxychloroquine also extends lifespan.
However, the chloroquine is microdosed in the rat study at 0.1 mg/kg ( ≈ 0.0161 mg/kg human).
I haven’t decided yet whether I will microdose with chloroquine. Buy-pharma does sell it as a syrup, which is what would be needed to measure out an amount so small (using a 1.0 or 0.5 ml oral syringe).
One possible explanation for chloroquine’s negative effects on heart transcriptome is autophagy inhibition combined with NRF2 activation.
The Dark Side of Nrf2 in the Heart
Although the precise mechanisms activating Nrf2-mediated cardiac damage are unclear, myocardial autophagy inhibition may be one of the critical triggers…
…the clinical phase III trial testing the therapeutic effect of Bardoxolone methyl, a potent Nrf2 activator, on chronic renal disease associated with type 2 diabetes was terminated because of an increased rate of cardiovascular events, including heart failure and deaths (de Zeeuw et al., 2013). The underlying mechanism remains to be determined. Given that autophagy inhibition also occurs in diabetic hearts (Ouyang et al., 2014; Kobayashi and Liang, 2015), it is intriguing whether the “dark” side of Nrf2 activation contributes to the failure of the Bardoxolone methyl clinical trial.
Activation of the Keap1/Nrf2 stress response pathway in autophagic vacuolar myopathies
we treated differentiated C2C12 mouse myotubes with autophagy inhibitor CQ. As expected, CQ treatment resulted in accumulation of LC3-II and SQSTM1 proteins in a concentration- and time-dependent manner (Fig. 7a). In parallel with these changes, there was a mild decrease in the soluble sarcoplasmic Keap1 protein level (presumably reflecting its redistribution into insoluble protein aggregates) and an increase in the nuclear Nrf2 protein level in the CQ-treated compared to the vehicle-treated C2C12 myotubes; paralleling autophagy inhibition, an increase in the nuclear Nrf2 level occurred in a concentration-dependent manner, with the active Nrf2 fraction continuing to increase over the 24 h treatment interval (Fig. 7a). To establish whether this increase in the nuclear Nrf2 protein level was accompanied by an increase in transcription of Nrf2 target genes, we examined mRNA levels of the six Nrf2-regulated antioxidant enzymes that were evaluated in human AVM specimens (Fig. 6a). Mimicking the changes that follow autophagy inhibition in vivo, CQ treatment of C2C12 cells in vitro resulted in a statistically significant increase in the mRNA expression level of all but one gene tested