Hydroxycitrate is an over-the-counter supplement made from the plant Garcinia cambogia, and it has been promoted for weight loss. A review of trials found that it does indeed promote weight loss, but a small one.
I first came across a mention of hydroxycitrate in an article about potential calorie restriction mimetics. As calorie restriction is, at least at the moment, the gold standard for anti-aging protocols, and has reliably increased lifespan by as much as 50% in virtually all animals it has been tried on, scientists are naturally quite interested in it. The catch is that most people are unwilling or unable to restrict calories – which is one reason intermittent fasting has generated a lot of interest – and so many scientists are looking for calorie restriction (CR) mimetics: drugs or compounds that have some of the same physiological properties as calorie restriction.
Hydroxycitrate promotes autophagy
The property of hydroxycitrate that makes it a potential CR mimetic is that it promotes autophagy, the cellular self-cleansing process that rids cells of junk and that is so important in aging. “Similarly, either knockdown of ACLY or addition of hydroxycitrate (HC), its competitive inhibitor, also reduced cytoplasmic AcCoA levels, induced cytoplasmic protein deacetylation, and strongly stimulated autophagy in vitro.”
Oral administration of HC to WT mice for 2 days triggered a systemic autophagic response comparable to that induced by starvation. Prolonged treatment (2 weeks) with HC is known to cause significant weight loss, and this effect was not accompanied by reduced food intake. Surprisingly, weight reduction by HC was only observed in autophagy-competent wild-type mice, not in autophagy-deficient Atg4b−/− mice.
Hydroxycitrate induces autophagy strongly both in vitro, and in vivo in mice, comparable to that induced by starvation. This gives it the potential to be a powerful anti-aging drug.
It turns out that HC is also being used as part of a trio of OTC drugs that appear to be nearly a cure for cancer. Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin.
Cellular metabolic alterations are now well described as implicated in cancer and some strategies are currently developed to target these different pathways. In previous papers, we demonstrated that a combination of molecules (namely alpha-lipoic acid and hydroxycitrate, i.e. Metabloc™) targeting the cancer metabolism markedly decreased tumor cell growth in mice. In this work, we demonstrate that the addition of capsaicin further delays tumor growth in mice in a dose dependant manner. This is true for the three animal model tested: lung (LLC) cancer, bladder cancer (MBT-2) and melanoma B16F10. There was no apparent side effect of this ternary combination. The addition of a fourth drug (octreotide) is even more effective resulting in tumor regression in mice bearing LLC cancer. These four compounds are all known to target the cellular metabolism not its DNA. The efficacy, the apparent lack of toxicity, the long clinical track records of these medications in human medicine, all points toward the need for a clinical trial. The dramatic efficacy of treatment suggests that cancer may simply be a disease of dysregulated cellular metabolism.
An earlier study showed that this combination is virtually non-toxic, and what is more, as effective as chemotherapy.
The efficacy of this combination appears similar to conventional chemotherapy (cisplatin or 5-fluorouracil) as it resulted in significant tumor growth retardation and enhanced survival. This preliminary study suggests that this combination of drugs is efficient against cancer cell proliferation both in vitro and in vivo. A clinical trial is warranted.
The significance of the statement that these compounds “target the cellular metabolism not its DNA” lies in the metabolic theory of cancer, championed by Thomas Seyfried, which holds that cancer results from metabolic derangements, particularly in mitochondria, and not from DNA mutations. Seyfried is well known for promoting the use of ketogenic diets and intermittent fasting in cancer treatment and prevention.
Hydroxycitrate, as an autophagy promoter, could potentially boost the autophagy response to intermittent fasting. Naturally, being the experimenter that I am, I picked up some hydroxycitrate from Amazon the other day, and I intend to take it while doing my intermittent fast. Of course, you can’t feel autophagy, so I may have nothing further either to experience or report, but if in a few weeks time I feel 30 years younger, I’ll be sure to let you know.