Antidepressants of the serotonin-antagonist type increase body fat and decrease lifespan of adult caenorhabditis elegans low blood glucose symptoms

It was recently suggested that specific antidepressants of the serotonin-antagonist type, namely mianserin and methiothepin, may exert anti-aging properties and specifically extend lifespan of the nematode C.elegans by causing a state of perceived calorie restriction (Petrascheck M, Ye X, Buck LB: An antidepressant that extends lifespan in adult Caenorhabditis elegans; Nature, Nov 22, 2007;450(7169):553–6, PMID 18033297). Using the same model organism, we instead observe a reduction of life expectancy when employing the commonly used, standardized agar-based solid-phase assay while applying the same or lower concentrations of the same antidepressants. Consistent with a well-known side-effect of these compounds in humans, antidepressants not only reduced lifespan but also increased body fat accumulation in C.

elegans reflecting the mammalian phenotype. Taken together and in conflict with previously published findings, we find that antidepressants of the serotonin-antagonist type not only promote obesity, but also decrease nematode lifespan.

In recent years, the nematorde Caenorhabditis elegans has become a well-established model organism to identify compounds that may be capable of extending lifespan not only in invertebrates, but also mammals. Accordingly, several research groups have published nematode-based findings on such compounds [1]– [30], whereas for most of these it is currently unknown whether they might exert similar effects in mammals, while for others this was proposed in regards to rodent lifespan [31] or at least in regards to reduction of aging-associated physiological alterations, whereas no extension of lifespan was observed [32].

Like numerous other psychoactive compounds, the antidepressant mianserin has been shown to increase appetite [33] as well as body mass [34] in humans. Conversely, obesity has been shown to decrease life span in humans [35] as well as C. elegans [25], while in both species serotonin signalling has been implicated in body fat accumulation [36]. In conflict with this evidence, recently published findings unexpectedly suggest that mianserin, and additional antidepressants of the serotonin antagonist type might extend C.elegans lifespan [24], which would surprisingly implicate that obesity promotes longevity.

While the latter study has employed liquid media to determine C. elegans lifespan, we have employed standardized and widely accepted agar-based assays aiming to replicate these findings, and unexpectedly observe a dose-dependent reduction of C.elegans lifespan, primarily suggesting that different assays to determine nematode lifespan generate opposing results.

Panel A: The antidepressant mianserin shortens C.elegans lifespan at concentrations of 50 µM (dark blue boxes; this concentration was shown extend lifespan in the original publication [ref. 24]), 5 µM (medium blue boxes), and 500 nM (light blue boxes). Untreated control nematodes are depicted by black circles. Panel B: The chemically and functionally related compound methiothepin similarly shortens C.elegans lifespan at concentrations of 10 µM (red boxes; this concentration was shown extend lifespan in the original publication [ref. 24]), 1 µM (orange boxes), and has no significant effect on lifespan at a lower concentration of 100 nM (yellow boxes). Untreated control nematodes are depicted by black circles.

Petrascheck and colleagues have used liquid media not only for 96-well based screening assays, but also for final determinations of lifespans [24]. These liquid media are not commonly used for definite lifespan determinations, since they have been repeatedly reported to potentially cause differences in life span when compared to the well-established, standard solid-phase media; the first report in fact was published more the 30 years ago [37]. Liquid media have caused opposing results when being applied by different laboratories using apparently identical protocols [3], [9]. Moreover and according to their Methods Summary section [24], Petraschek et al. have not only based their liquid media on recipes from a publication [3] that was fundamentally put into question [9], but also from another laboratory [38] that has previously published a striking lack of correlation between lifespan results obtained with liquid- versus solid-phase media [39]. Lastly and most importantly, Petrascheck and colleagues observe a mean life expectancy of at least 23.6 days in N2 nematodes using their liquid media [24], whereas we [25] and others [40], [41] consistently observe a significantly shorter mean lifespan when using solid-phase media. This suggests that nematodes maintained in liquid media are kept in an a priori state of calorie restriction known to extend lifespan per se, i.e. in the absence of life-extending compounds [42], which has been recently shown to alter multiple pathways of energy metabolism [43] as to be expected in a priori states of calorie restriction [44]– [46].

Accordingly, and to test whether solid phase media as used in our C.elegans experiments reflect the situation in humans, we have tried to replicate the fact that mianserin increases human body mass [34] by applying this compound to nematodes. Indeed, both compounds significantly increased body fat after ten days of incubation at the concentrations that have been used by Petrascheck and colleagues [24] ( Figs. 2a and 2b), whereas other pharmacological interventions known to extend C.elegans lifespan have been previously shown to decrease body fat content [25]. Nevertheless it should be noted that a specific genetic disruption that extends C.elegans lifespan, namely of the insulin-/IGF1-receptor signaling ( daf-2) [40] have been shown to increase C.elegans body fat [47].

Kampkotter A, Gombitang Nkwonkam C, Zurawski RF, Timpel C, Chovolou Y, et al. (2007) Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Arch Toxicol 81: 849–858.

Pinder RM, Blum A, Stulemeijer SM, Barres M, Molczadzki M, et al. (1980) A double-blind multicentre trial comparing the efficacy and side-effects of mianserin and chlorimipramine in depressed in- and outpatients. Int Pharmacopsychiatry 15: 218–227.

Castelein N, Hoogewijs D, De Vreese A, Braeckman BP, Vanfleteren JR (2008) Dietary restriction by growth in axenic medium induces discrete changes in the transcriptional output of genes involved in energy metabolism in Caenorhabditis elegans. Biotechnol J 3: 803–812.

Lenaerts I, Walker GA, Van Hoorebeke L, Gems D, Vanfleteren JR (2008) Dietary restriction of Caenorhabditis elegans by axenic culture reflects nutritional requirement for constituents provided by metabolically active microbes. J Gerontol A Biol Sci Med Sci 63: 242–252.