Montag, 14. Dezember 2015

Optimizing resource use - Chronic toxicity and preclinical studies

This post is related to the idea of "Optimizing resource use by outsourcing of lifespan research" to pet owners and zoos.

What should we study? We're clueless!
We don't understand aging very well. That's the reason why we need to perform both naive screens with novel chemical matter (more on that below) as well as large, high-throughput screens with drugs that target plausible pathways. But what are the plausible pathways if we are clueless?

Well, it's not quite as bad as you may think, since we do have some basic paradigms in aging research. Bluntly put, there's for instance "anti-growth" as well as "mimic CR/dwarfism" (= which usually amounts to an "anti-growth" paradigm). The idea that diminished signalling through a multitude of growth pathways extends longevity has been shown to be true in scores of studies (just recently, ref. 1, 2).

Preclinical studies: how about worms and flies?
Preclinical safety studies presently include cell culture work in human cells as well as rodent models (usually rat) and non-rodent models. The latter often includes dogs and primates (5). From a basic science perspective, we should consider mandating chronic "safety" testing in invertebrates. This would be very useful to biogerontologists, as we can expect to find a reasonable number of life extending drugs by pure chance. On the other hand, it is not clear if such "safety" testing has any meaning for human toxicity. An alternative would be to compel companies to give out the drugs (in a blinded fashion to prevent IP problems) and for the government to perform lifespan testing. This method would work particularly well to test the already available drug libraries. (As of today no free market based incentive exists to develop anti-aging therapies. We won't consider the details here.)

Indeed thousands of failed drug candidates must exist and represent a large untapped source for biogerontology. Modern cancer drugs are particularly promising since they target various growth-related pathways. In 2015 "According to the Pharmaceutical Research and Manufacturers of America (PhRMA), 771 new drugs and vaccines are in development by US companies" just to treat cancer (6). It is difficult to find high quality lists with advanced drugs, but there's one up to date list for lung cancer (7). These lists may come in handy for "smaller" projects like the NIA's ITP. It might also be helpful to think in terms of drug targets and then prioritize the most plausible targets and drugs (8).