Pharmacology Lags Behind Genetic Engineering and Environmental Causes of Longevity

This is a somewhat obvious point, but seems worth making once or twice. The primary methods of extending life in laboratory animals involve genetic engineering and environmental line items such as calorie restriction - these are how new metabolic states that lead to increased longevity are discovered in the research mainstream. The process of then developing drugs to try to recapture some of these effects inevitably lags behind in effectiveness: it's a complex process with many dead ends and only partial successes, whereas testing new genetic alterations in lower animals proceeds fairly rapidly these days. This recent paper illustrates the point:

The regulation of animal longevity shows remarkable plasticity, in that a variety of genetic lesions are able to extend lifespan by as much as 10-fold. Such studies have implicated several key signaling pathways that must normally limit longevity, since their disruption prolongs life. Little is known, however, about the proximal effectors of aging on which these pathways are presumed to converge, and to date, no pharmacologic agents even approach the life-extending effects of genetic mutation.

In the present study, we have sought to define the downstream consequences of age-1 nonsense mutations, which confer 10-fold life extension to the nematode Caenorhabditis elegans - the largest effect documented for any single mutation. Such mutations insert a premature stop codon upstream of the catalytic domain of the AGE-1/p110α subunit of class-I PI3K. As expected, we do not detect class-I PI3K, [nor] do we find any PI3K activity as judged by immunodetection of phosphorylated AKT, which strongly requires PIP3 for activation by upstream kinases, or immunodetection of its product, PIP3.

We tested a variety of commercially available PI3K inhibitors, as well as three phosphatidylinositol analogs (PIAs) that are most active in inhibiting AKT activation, for effects on longevity and survival of oxidative stress. Of these, GDC-0941, PIA6, and PIA24 [extended] lifespan by 7-14%, while PIAs 6, 12, and 24 (at 1 or 10 μM) increased survival time [under oxidative stress] by 12-52%. These effects may have been conferred by insulinlike signaling.



What is your opinion - will we have anti-anging drugs on the merket in the next 10 years? I mean drugs that add 3-5 years to life expectancy. And how they are going to measure their effectiveness?

Posted by: futurama at April 2nd, 2013 6:50 AM

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