Metformin Still Dubious as a Calorie Restriction Memetic

One of the many ways in which FDA regulation corrupts research and development in medicine is the creation of a strong financial incentive to reuse existing drugs. It's much less expensive to obtain regulatory approval for a new marginal use of a drug already approved for other uses than it is to obtain regulatory approval for a completely new drug or other medical technology that might be far better. This discourages real progress in favor of something that only looks a little like progress: many of the existing stable of drugs are decades old, yet resources that might otherwise go to breaking new ground are instead poured into shoving these old square pegs into as many round holes as possible.

Given this it should be no great surprise to see that as work on the biology of calorie restriction has progressed, an increasing amount of time and money has been devoted to attempts to reuse existing drugs as calorie restriction mimetics - i.e. to find approved drugs that produce at least some of the same changes in metabolism, and with as few side-effects as possible. One of these drugs is metformin, but as I noted in a post earlier this year, it really isn't much to write home about, given that results from a range of studies are all over the map. It may or may not be useful or beneficial, and certainly doesn't show the clear benefits to health and life expectancy produced by calorie restriction itself:

Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

Today I thought I'd direct your attention to a recent paper that shows metformin failing to do much for fly life spans:

Activation of AMPK by the Putative Dietary Restriction Mimetic Metformin Is Insufficient to Extend Lifespan in Drosophila

The biguanide drug, metformin, commonly used to treat type-2 diabetes, has been shown to extend lifespan and reduce fecundity in C. elegans through a dietary restriction-like mechanism via the AMP-activated protein kinase (AMPK) and the AMPK-activating kinase, LKB1.

We have investigated whether the longevity-promoting effects of metformin are evolutionarily conserved using the fruit fly, Drosophila melanogaster. We show here that while feeding metformin to adult Drosophila resulted in a robust activation of AMPK and reduced lipid stores, it did not increase lifespan in either male or female flies. In fact, we found that when administered at high concentrations, metformin is toxic to flies. Furthermore, no decreases in female fecundity were observed except at the most toxic dose. Analysis of intestinal physiology after metformin treatment suggests that these deleterious effects may result from disruptions to intestinal fluid homeostasis.

Thus, metformin appears to have evolutionarily conserved effects on metabolism but not on fecundity or lifespan.

Nonetheless, money continues to flow for this and similar work.

Comments

This is a disappointing article compared to the usual high standards of fight aging.

The issue is not the compound used, in this case an old drug, but the impact on biological function that is aspired to. If your mode of action is correct then you want the compound that corresponds to that mode of action. If this compound is an old drug or combination of old drugs then this may have great advantages in medicine as their safety profile is better understood.

One miscomprehension is that high binding affinity to a single target is responsible for efficacy of most drugs. Increasingly in many cases this looks untrue with the nature of biological systems meaning a spectral impact with much lower binding affinities associated with the different parts of the compounds biological interaction spectrum. Additionally this provokes knock-on network impact away from the binding sites.

As a consequence 'old' compounds are as good as young ones, whatever fits the mode of action devised by proper assessment of the biological systems is a good candidate. If they are known to be safe so much the better. The chemistry roots of the pharmaceutical patent system may mean a composition of matter patent cannot be obtained but this is a separate discussion with use patents still available.

What we agree with, is that fishing around with old drugs not based on starting with a properly evaluated mode of action is a waste of valuable research money. The starting point must be analysis and interpretation of the relevant biological systems and evaluating a mode of action for efficacy as a consequence. If this is what was meant, we agree and apologise for our misunderstanding.

Posted by: Network Pharmacology Blog at October 26th, 2012 5:19 AM

I respect Reason's scepticism, and agree that funding SENS is our best chance at doing more than moderately extend median healthy lifespans (in our lifetime).

In the meantime however, extending median lifespans is nothing to sneeze at. In practical terms for many of us it could mean the difference between living long enough to reach SENS therapies within our lifetimes or just missing the boat. Sure, slowing down aging or even just compressing morbidity by tweaking metabolism isn't the end-all solution, but it could buy us some time while we figure out how to adequately fund SENS-like approaches to true anti-aging medicine while neutralizing the toxic, crippling effect of over-regulation.

Case in point, Metformin does seem to mimic many of the effects of calorie restriction without actual restriction of calories and at least for some of us (myself included) it makes true calorie restriction much easier by reducing the side effects of debilitating hunger and the wasting away of muscle.

Metformin leads to a 40% increase in the median lifespan of rats and it would not be unreasonable to speculate that it might do the same for people. Better yet, it has a good enough safety profile that we can do more than speculate idly regarding its effects on healthy non-diabetic humans.

Here's my anecdotal report of a small group of non-diabetics experimenting with clinically effective doses of Metformin:

http://www.longecity.org/forum/topic/61671-experimenting-with-metformin-as-a-calorie-restriction-mimetic-in-healthy-non-diabetics/

Posted by: Charles McManis at February 6th, 2013 11:12 PM

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