Longer living through chemistry: Serotonin signaling and CR mimesis in the worm

A large-scale screen in C. elegans has identified two antidepressant medications that extend lifespan in biogerontologists’ favorite nematode. Petrascheck, Ye and Buck (that’s this Buck, not that Buck) report that mianserin and mirtazapine boost worm longevity by ~30%. In both cases, drug efficacy requires an intact serotonergic signaling pathway, implying that they act by influencing neuronal signaling (as they do in humans) rather than some other process.

Based on their studies of these compounds in long- and short-lived mutants as well as dietarily restricted animals, the authors conclude that the mechanism of longevity enhancement is similar to that of calorie restriction (CR). They favor a model in which the worm is being tricked into “thinking” that it’s undergoing CR without actually limiting food intake:

It may be that these two neurotransmitters exist in a dynamic equilibrium that is tipped in the direction of a starvation response by mianserin, possibly because of the greater inhibitory effect of mianserin on SER-4 than SER-3. In this way, mianserin might potentially create a ‘perceived’ state of starvation that, despite adequate food intake, would activate mechanisms of lifespan extension downstream of dietary restriction.

If the authors’ interpretation is correct, the results bolster the emerging view that perception about food availability (rather than its actual availability, or for that matter the organism’s actual food intake) is critical to the benefits of CR. We already know of two neurons that are essential for CR efficacy in the worm, and that in flies olfactory information about food can by itself regulate lifespan. With the discovery of these two compounds’ effect on aging, we’re starting to close in on the specific neural mechanisms by which information about food is translated into a pro-longevity response.

The role of serotonergic signaling in human longevity and CR effects remains unclear — but I must share this intriguing tidbit: One of the reasons that mianserin is an unpopular treatment for depression is its side effects, which include (drum roll) increased appetite and weight gain. Anyone who has seen a dietarily restricted mouse tear desperately into its 60% ration of daily chow knows that CR can dramatically affect food-related behavior — and if one were engaging in these CR-related behaviors without actually restricting food intake, it’s easy to see how weight gain would result. It’s tempting to speculate that mianserin’s appetite- and weight-related side effects might be the consequence of some type of CR mimesis. (This should be in no way construed as a suggestion that anyone give it a try; serotonergically normal people who screw with that particular neurochemical axis place themselves at risk of psychosis, not to mention a very bad case of dry mouth).

This isn’t the first time we’ve discussed a connection between CR and depression: two separate studies have shown that CR induces anxiety and depression in rats, probably via downregulation of serotonin synthesis and serotonergic receptors in the brain. This actually makes a certain amount of sense from an evolutionary point of view: if the environment is empty of food, it’s adaptive to just stay in the burrow and wait for better times, and depression is one path to that behavior. That’s quite a different story than the paper we’re discussing today: the rat studies showed that CR causes some aspects of depression, whereas the worm studies showed that drugs that alleviate depression (in humans) mimic some aspects of CR (in worms). I’m not sure how to integrate those results with these, or whether it’s worthwhile to try, but I’d love to see someone put these pieces together somehow.

One final note: There are other ongoing chemical biology screens for lifespan extension compounds currently underway; I mentioned one of them in my review of Gordon Lithgow’s talk at the 2007 Hillblom Foundation meeting (that one is being run at this Buck). Likely due to differences in the initial libraries of compounds screened, as well as idiosyncrasies in the screening protocols, the preliminary hits from the Buck Institute screen are nonoverlapping with the ones reported by Petrascheck et al. — so before long, we’ll have another crop of longevity-enhancing compounds to puzzle over.


One comment

  1. I am not sure if I agree with all of what ouroboros has said. Weight gain by these drugs is mediated by 5-ht2c blockade. My take is that by blocking this receptor the organism still feels starved hence releasing such CR chemicals, rather than the other way around. Modulation of serotonin usually doesn’t produce dry mouth, and blockade of the 5-ht2 system doesn’t produce psychosis, rather it alleviates it, hence 5-ht2 blocade by atypical antipsychotics. I also disagree with CR producing depression. CR reduces apoptosis, and increases hippocampal proliferation. It also increases BDNF which trophs serotonergic neurons. Fasting also induces a subsensitivity of inhibitory 5-ht1b receptors which leads to enhanced seronin release. CR can also produces anticonvulsant effects which may reduce anxiety. Here is a study of CR reducing anxiety in rats. http://www.nature.com/npp/journal/v28/n7/full/1300168a.html I wouldn’t try to link the many divergent effects of various serotonin receptors. It can quel anxiety in certain brain regions, and cause it in others.

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