How can insulin resistance cause weight gain? (3) AD-9308

This is a random, throw away post. A one-liner, don't laugh. I happened on this paper following a link in a link to a link during my 4-HNE reading:

 Disruption of the mGsta4 Gene Increases Life Span of C57BL Mice

This sort of comment makes me sit up and take notice

"Surprisingly, the opposite was true."

as in

"We expected that disruption of mGsta4, a murine gene encoding a major antielectrophilic enzyme, will parallel the effect of a similar intervention in C. elegans and curtail the life span of the knockout mice. Surprisingly, the opposite was true. In the present article, we report this observation and provide a possible explanation for this unexpected effect."

The enzyme from the gene mGsta4 is a membrane associated glutathione-S transferase which is important (like ALDH2 in previous posts) for the detoxification of ROS-derived substances such as 4-HNE (amongst others). The best explanation for the findings in the study is that 4-HNE accumulates in tissues of mGsta4 null mice which activates extra defence mechanisms against electrophilic molecules. The end result is near-normalisation of tissue 4-HNE combined with an extended lifespan. At least in Bl/6 mice. But not in C elegans, here it does the opposite. Choose your model wisely before tinkering with your metabolism.


Apart from the somewhat amusing concept that reducing the detoxification of 4-HNE might be a longevity ploy, it made me wonder about the ALDH2 mutations in the East Asian human populations. Full introduction of this mutated gene in mice exposed to an high linoleic acid plus high sucrose diet leads to supplementary obesity. This is unlikely to be quite so problematic on a more species appropriate diet for either mice or humans. The ALDH2 modified mice were normal weight on chow.

For a mutation to persist there has to be an advantage to the individual carrying that mutation which increases their probability of reproductive success. Null mGsta4 mice show no change to their maximum life span but have a 10% increase in median life span and have a marked increase of 36% in lifespan at the 10th percentile, ie during the peak reproductive period of life.

Does the same happen with the reduced efficacy gene for ALDH2 in people as happens in the null mGsta4 gene in Bl/6 mice? Would this show as an increased healthspan but without increased peak longevity? Provided you don't live on fudge made from sucrose and corn oil of course. I tend to think median lifespan extension probably correlates with increased healthspan but that peak longevity might be more of a luck-based failure to die. Hmmmm...

So the law of unintended consequences makes me think long and hard about ALDH2 activation using a drug such as AD-9308. You could use it to reduce 4-HNE from an obesogenic 1.0~ishμM to almost nothing and so reverse whatever benefit has been preserved by the ALDH2 down regulatory mutation in humans. After all 560 million East Asians carry the gene which appears to have been designed to make us fat and insulin resistant when fed a high linoleic acid, high sucrose diet. But not if eating real food. So lets develop a drug for all East Asians to be able to eat junk food without getting fat! Might this simply result in looking good in your coffin?

Evolution is not stupid. It leaves that to drug developers.

Peter