10 replies to this topic

[smithx]

Do any of the experts here have additional data/opinions, etc. on this?

http://www.scienceda...90106170748.htm

Old Gastrointestinal Drug Slows Aging, Researchers Say

ScienceDaily (Jan. 7, 2009) — Recent animal studies have shown that clioquinol – an 80-year old drug once used to treat diarrhea and other gastrointestinal disorders – can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases. Scientists, however, had a variety of theories to attempt to explain how a single compound could have such similar effects on three unrelated neurodegenerative disorders.

Researchers at McGill University have discovered a dramatic possible new answer: According to Dr. Siegfried Hekimi and colleagues at McGill's Department of Biology, clioquinol acts directly on a protein called CLK-1, often informally called "clock-1," and might slow down the aging process.

The advance online edition of their study was published in Oct. 2008 in the Journal of Biological Chemistry.

"Clioquinol is a very powerful inhibitor of clock-1," explained Hekimi, McGill's Strathcona Chair of Zoology and Robert Archibald & Catherine Louise Campbell Chair in Developmental Biology. "Because clock-1 affects longevity in invertebrates and mice, and because we're talking about three age-dependent neurodegenerative diseases, we hypothesize that clioquinol affects them by slowing down the rate of aging."

Once commonly prescribed in Europe and Asia for gastrointestinal problems like diarrhea and shigella, clioquinol was withdrawn from the market after being blamed for a devastating outbreak of subacute myelo-optic neuropathy (SMON) in Japan in the 1960s. However, because no rigorous scientific study was conducted at the time, and because clioquinol was used safely by millions before and after the Japanese outbreak, some researchers think its connection to SMON has yet to be proven.

The exact mechanism of how clioquinol inhibits CLK-1 is still under investigation, Hekimi said. "One possibility is that metals are involved as clioquinol is a metal chelator," he explained. Chelation is a type of binding to metal ions and is often used to treat heavy metal poisoning.

Hekimi is optimistic but cautious when asked whether clioquinol could eventually become an anti-aging treatment.

"The drug affects a gene which when inhibited can slow down aging," he said. "The implication is that we can change the rate of aging. This might be why clioquinol is able to work on this diversity of diseases that are all age-dependent."

However, he admits to being concerned about how people may interpret his results.

"The danger is that you can buy a kilogram of this compound at a chemical wholesaler, but we don't want people to start experimenting on themselves. Clioquinol can be a very toxic substance if abused, and far more research is required."

[FunkOdyssey]

The danger is that you can buy a kilogram of this compound at a chemical wholesaler

I'm sure it won't be long before it "hits the streets" so to speak, especially after the study's author brought its easy availability to the public's attention. It doesn't sound like it would be much fun though -- another one of those interventions like calorie restriction or methionine restriction that slow aging by slowing *everything*:

The CLK-1 enzyme is responsible for the hydroxylation of 5-demethoxyubiquinone to 5-hydroxyubiquinone.

When ubiquinone biosyntesis is interrupted by the absence of the enzyme, cells accumulate an intermediate of ubiquinone biosynthesis, demethoxyubiquinone (DMQ).

It has been shown that mutations in the gene are associated with increased lifespan (Ewbank et al, 1997; Liu et al, 2005). Defects of the gene slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging (Felkai et al, 1999).

Edited by FunkOdyssey, 08 January 2009 - 03:45 AM.

[StrangeAeons]

The danger is that you can buy a kilogram of this compound at a chemical wholesaler

I'm sure it won't be long before it "hits the streets" so to speak, especially after the study's author brought its easy availability to the public's attention. It doesn't sound like it would be much fun though -- another one of those interventions like calorie restriction or methionine restriction that slow aging by slowing *everything*:

The CLK-1 enzyme is responsible for the hydroxylation of 5-demethoxyubiquinone to 5-hydroxyubiquinone.

When ubiquinone biosyntesis is interrupted by the absence of the enzyme, cells accumulate an intermediate of ubiquinone biosynthesis, demethoxyubiquinone (DMQ).

It has been shown that mutations in the gene are associated with increased lifespan (Ewbank et al, 1997; Liu et al, 2005). Defects of the gene slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging (Felkai et al, 1999).

That last part of the quote almost sounds like "cryonics lite". I imagine the decreased metabolism might lead to obesity if people don't adjust their dietary intake accordingly, and then you've defeated your purpose. Likewise I can't imagine the metabolic demands of exercise fit in very well with this stuff.

[sUper GeNius]

I'm sure it won't be long before it "hits the streets" so to speak, especially after the study's author brought its easy availability to the public's attention. It doesn't sound like it would be much fun though -- another one of those interventions like calorie restriction or methionine restriction that slow aging by slowing *everything*:

Enter it as a search term on Google shopping. Numerous hits.

[maxwatt]

The danger is that you can buy a kilogram of this compound at a chemical wholesaler

I'm sure it won't be long before it "hits the streets" so to speak, especially after the study's author brought its easy availability to the public's attention. It doesn't sound like it would be much fun though -- another one of those interventions like calorie restriction or methionine restriction that slow aging by slowing *everything*:

The CLK-1 enzyme is responsible for the hydroxylation of 5-demethoxyubiquinone to 5-hydroxyubiquinone.

When ubiquinone biosyntesis is interrupted by the absence of the enzyme, cells accumulate an intermediate of ubiquinone biosynthesis, demethoxyubiquinone (DMQ).

It has been shown that mutations in the gene are associated with increased lifespan (Ewbank et al, 1997; Liu et al, 2005). Defects of the gene slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging (Felkai et al, 1999).

That last part of the quote almost sounds like "cryonics lite". I imagine the decreased metabolism might lead to obesity if people don't adjust their dietary intake accordingly, and then you've defeated your purpose. Likewise I can't imagine the metabolic demands of exercise fit in very well with this stuff.

Interesting that CLK-1 is involved in ubiquinone metabolism, and ubiquinone (CoQ10) has been shown to partially reverse Parkinson's in humans in at least one trial.

Another interesting bit is that an available tricyclic anti-depressant has been shown to extend life-span in nematodes by CR like mechanisms, but not in C. elegans with CLK-1 abnormalities associated with extended life-span and sluggish behavior. It's perhaps as likely to work in humans as Clioquinol, and an anti-depressant sounds like more fun than a diarrhea medicine. It's about a dollar a day from a Swiss pharmacy whose doctors will examine you by chat. (Don't ask me for the link.) Side effects may include increased appetite and weight gain, joint pain, dizziness, fluid retention, jaundice, postural hypotension, male breast enlargement, or bone marrow suppression and other symptoms in a small percentage of cases

Letter
Nature 450, 553-556 (22 November 2007) | doi:10.1038/nature05991; Received 31 July 2007; Accepted 11 October 2007

An antidepressant that extends lifespan in adult Caenorhabditis elegans
Michael Petrascheck1, Xiaolan Ye1 & Linda B. Buck1

Howard Hughes Medical Institute, Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109-1024, USA
Correspondence to: Linda B. Buck1 Correspondence and requests for materials should be addressed to L.B.B. (Email: lbuck at fhcrc.org).

The mechanisms that determine the lifespan of an organism are still largely a mystery1. One goal of ageing research is to find drugs that would increase lifespan and vitality when given to an adult animal. To this end, we tested 88,000 chemicals for the ability to extend the lifespan of adult Caenorhabditis elegans nematodes. Here we report that a drug used as an antidepressant in humans increases C. elegans lifespan. In humans, this drug blocks neural signalling by the neurotransmitter serotonin. In C. elegans, the effect of the drug on lifespan is reduced or eradicated by mutations that affect serotonin synthesis, serotonin re-uptake at synapses, or either of two G-protein-coupled receptors: one that recognizes serotonin and the other that detects another neurotransmitter, octopamine. In vitro studies show that the drug acts as an antagonist at both receptors. Testing of the drug on dietary-restricted animals or animals with mutations that affect lifespan indicates that its effect on lifespan involves mechanisms associated with lifespan extension by dietary restriction. These studies indicate that lifespan can be extended by blocking certain types of neurotransmission implicated in food sensing in the adult animal, possibly leading to a state of perceived, although not real, starvation.

I have the full paper if anyone wants to read it.

[Mixter]

Wikipedia says it has a neurotoxic action. This mechanism should be
further clarified before anyone takes it against aging, since that would only
make sense with long-term consumption. Otherwise, interesting.

[Sillewater]

Interesting paper about Cloq and SMON:

J Neurol Sci. 2004 Mar 15;218(1-2):85-90.
Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban.
Konagaya M, Matsumoto A, Takase S, Mizutani T, Sobue G, Konishi T, Hayabara T, Iwashita H, Ujihira T, Miyata K, Matsuoka Y.

Department of Neurology, Suzuka National Hospital, 3-2-1 Kasado, Suzuka, Mie 5138501, Japan. konagaya@suzuka.hosp.go.jp
Abstract
One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

[AgeVivo]

Clioquinol has been used for many years by a large part of the Japanese population in case of gastroinstestinal troubles.

- likely benefits: partial prevention of Alzheimer, Parkinson, Hungtington
- likely risks: subacute myelo-optico-neuropathy

Considering the very large number of people who took that drug, the numbers above and some numbers I rapidly looked at in pubmed.org, it seems to me that the risks are actually very small compared to the benefits.

- I'm surprised to see that it is not beeing tested on mouse lifespan
by the ITP (http://www.nia.nih.g...dsInTesting.htm)
nor by Spindler's lab (http://www.mfoundati...amp;postcount=4)
- anyone here to have time to collect and compare the statistics of benefits and risks? Perhaps we could then suggest clioquinol to the ITP

[AgeVivo]

Actually I've taken some time to dig. In general Clioquinol seems really safe and healthy.

http://cancerres.aac.../full/67/4/1636 :

Although clioquinol use was thought to be associated with occurrence of subacute myelo-optic neuropathy in Japan (25–27), this conclusion was not supported by the subsequent epidemiologic analysis (28). Instead, decreased levels of vitamin B₁₂ may play a role in this syndrome (26). In fact, clioquinol may be used safely in humans with vitamin B₁₂ supplementation (29). Recent studies also show the potential use of clioquinol for treatment of Alzheimer's disease (30) and Huntington's disease (31). Two clioquinol clinical trials for Alzheimer's disease showed no toxicity in any patients and some clinical benefit in some patients (29, 32). Most recently, it was reported that in an in vivo lymphoma xenografts mouse model, clioquinol inhibited tumor growth (33), although the detailed mechanism of action is unclear.

http://www.ncbi.nlm....09/?tool=pubmed

several inconsistencies for the CQL theory of SMON have now emerged
- first, CQL had been widely used in Japan for nearly 20 years before SMON occurred
- Secondly, the SMON epidemic began to subside several months before CQL sales were suspended
- Fourthly, there was no dose-response relationship.
- Finally, SMON rarely, if ever, occurred outside Japan.

We should discuss about clioquinol outside of the supplement forum because it has a serious basis and many imminst users probably do not see this thread.

Edited by AgeVivo, 01 May 2010 - 02:25 PM.

[AgeVivo]

(PS: Sillewater, mixter, other people: if you believe I discarded toxicity a bit too fast, do not hesitate to say so)

[AgeVivo]

Appearently clioquinol did not do so well against Alzheimer so an I.V. injection of a similar compound, "PBT2", which seems to work better, is currently tested in a clinical trial. That's what I understand: http://alzheimers.in...scope=762104261