Ethosuximide treatment decreases the adult life span in <i>C. elegans</i> when UV-irradiated with the bacterial food source and NGM.

<p>(<b>A</b>) The ethosuximide (UV) treated N2 worms showed shortened life span as compared to untreated worms. (<b>B</b>) Wild-type and ethosuximide (UV) treated animals after 6 days from egg. Ethosuximide treated worms have severe defects and reduced viability. Several animals were selected, fixed onto a slide, and photographed. Images representative of the majority of animals were selected.</p

Chemosensory mutants resistant to high-dose ethosuximide do not show similar resistance to UV-treated ethosuximide.

<p>Eggs from N2, <i>osm-3(p802)</i>, <i>che-3(p801)</i>, and <i>che-3(am165)</i> worms were laid on plates containing topically added ethosuximide or UV-ethosuximide at 10, 30, 70, 80 or 85 mM, as indicated (volume matched water, control). Plates were scored for survival 5 days later.</p

Ethosuximide treatment without UV-exposure extends the adult life span in <i>C. elegans</i> in a temperature-dependent manner.

<p>NGM containing 10-type (N2) animals at (<b>A</b>) 15°C and (<b>B</b>) 20°C, but not at (<b>C</b>) 25°C. Irradiated ethosuximide showed similar toxicity at all three temperatures. (<b>D</b>) Dietary restriction further extended the life span of ethosuximide-treated worms, but failed to rescue the short life span of UV-ethosuximide treated worms.</p

Duration of UV treatment of ethosuximide affects toxicity, absorption spectrum, and longevity of <i>C. elegans</i>.

<p>(<b>A</b>) Ethosuximide was exposed to UV-light (254nm) for varying lengths of time. L4 worms were transferred to Amp/FUDR plates containing UV-treated ethosuximide added topically to a final concentration of 10 mM and were scored for life span. Increased length of UV-exposure, led to an increased toxicity, as measured by a shortened life span. (<b>B</b>) Ethosuximide was exposed to UV light for various lengths of time (shown in graph legend). An absorption spectrum over the ranges of 220nm to 400nm was collected for the untreated and UV-treated ethosuximide solutions. (<b>C</b>) Ethosuximide delays development in wild-type (N2) worms. Eggs were transferred to NGM plates with topical addition of water (control), 30 mM ethosuximide, or 30 mM UV-irradiated ethosuximide at 20°C. The developmental stage of each worm was determined after 1, 2, 4 and 6 days as L1/L2, L3 and L4 larvae and young adult/egg-laying adult nematodes. Data from two experiments (3 independent plates each experiment) were pooled.</p

Statistics for life span data presented in this study.

<p> The notation (UV) indicates that the ethosuximide was exposed to UV light and BD indicates that the animals were maintained in the absence of bacterial food during adulthood until death. Conc., concentration; Etho, Ethosuximide; N, number of worms in the experiment; BD, bacterial deprivation by removal of the bacterial food source during adulthood.</p><p>*p<0.05. p-values compare the experimental group with the control group of the upper row. Significant vales </p

Other anticonvulsants do not exhibit similar UV-mediated toxicity in <i>C. elegans</i>.

<p>(<b>A</b>) Structures of ethosuximide, trimethadione and succinimide. (<b>B</b>) Unlike ethosuximide, UV-irradiated trimethadione and UV-irradiate succinimide caused no detectable toxicity. (<b>C</b>) Heat-treated ethosuximide also did not cause toxicity similar to UV-treated ethosuximide toxicity. L4 worms were transferred to plates containing 5, 10, 50 or 100 mM heat-treated ethosuximide, 5, 10, 50 or 100 mM UV-treated ethosuximide, or ethosuximide (control). Plates were scored for the proportion of viable worms at day 7 of adulthood. The error bars represent variation of three independent experiments (mean ± SEM).</p

Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in <i>Caenorhabditis elegans</i>

<div><p>Mitochondrial dysfunction can increase oxidative stress and extend lifespan in <i>Caenorhabditis elegans</i>. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPR^mt) and extends lifespan. Here we report that transaldolase (<i>tald-1</i>) deficiency impairs mitochondrial function <i>in vivo</i>, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H₂O₂ levels. Lifespan extension from knockdown of <i>tald-1</i> is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (<i>fmo-2</i>). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.</p></div