Antidepressants of the Serotonin-Antagonist Type Increase Body Fat and Decrease Lifespan of Adult Caenorhabditis elegans

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

The MDT-15 Subunit of Mediator Interacts with Dietary Restriction to Modulate Longevity and Fluoranthene Toxicity in Caenorhabditis elegans

Dietary restriction (DR), the limitation of calorie intake while maintaining proper nutrition, has been found to extend life span and delay the onset of age-associated disease in a wide range of species. Previous studies have suggested that DR can reduce the lethality of environmental toxins. To further examine the role of DR in toxin response, we measured life spans of the nematode Caenorhabditis elegans treated with the mutagenic polyaromatic hydrocarbon, fluoranthene (FLA). FLA is a direct byproduct of combustion, and is one of U.S. Environmental Protection Agency's sixteen priority environmental toxins. Treatment with 5 µg/ml FLA shortened the life spans of ad libitum fed nematodes, and DR resulted in increased sensitivity to FLA. To determine the role of detoxifying enzymes in the toxicity of FLA, we tested nematodes with mutations in the gene encoding the MDT-15 subunit of mediator, a transcriptional coactivator that regulates genes involved in fatty acid metabolism and detoxification. Mutation of mdt-15 increased the life span of FLA treated animals compared to wild-type animals with no difference observed between DR and ad libitum fed mdt-15 animals. We also examined mutants with altered insulin-IGF-1-like signaling (IIS), which is known to modulate life span and stress resistance in C. elegans independently of DR. Mutation of the genes coding for the insulin-like receptor DAF-2 or the FOXO-family transcription factor DAF16 did not alter the animals' susceptibility to FLA compared to wild type. Taken together, our results suggest that certain compounds have increased toxicity when combined with a DR regimen through increased metabolic activation. This increased metabolic activation appears to be mediated through the MDT-15 transcription factor and is independent of the IIS pathway

Mechanical properties measured by Atomic Force Microscopy define health biomarkers in ageing C. elegans

Genetic and environmental factors are key drivers regulating organismal lifespan but how these impact healthspan is less well understood. Techniques capturing biomechanical properties of tissues on a nano-scale level are providing new insights into disease mechanisms. Here, we apply Atomic Force Microscopy (AFM) to quantitatively measure the change in biomechanical properties associated with ageing Caenorhabditis elegans in addition to capturing high-resolution topographical images of cuticle senescence. We show that distinct dietary restriction regimes and genetic pathways that increase lifespan lead to radically different healthspan outcomes. Hence, our data support the view that prolonged lifespan does not always coincide with extended healthspan. Importantly, we identify the insulin signalling pathway in C. elegans and interventions altering bacterial physiology as increasing both lifespan and healthspan. Overall, AFM provides a highly sensitive technique to measure organismal biomechanical fitness and delivers an approach to screen for health-improving conditions, an essential step towards healthy ageing

Evaluation of Current and Historical 10-inute-count screens at the Tracy Fish Collection Facility, Tracy, California

The U.S. Department of the Interior, Bureau of Reclamation\u27s Tracy Fish Collection Facilities (TFCF) 10-minute-count screen is a critical tool used to acquire sub-samples and provide an estimate of fish entering the facility. The introduction of a new screen in 1999, prior to fish screen retention comparisons, could possibly have altered TFCF salvage estimates. Three experiments were conducted during 2003 and 2004 to evaluate the retention efficiencies of the current and historical screens for juvenile delta smelt (Hypomesus transpacificus): (1) Wild Juvenile Delta Smelt Retention Comparison, (2) Evaluation of Bead Loss, and (3) Cultured Juvenile Delta Smelt Retention Comparison. In experiment No. 1 there was no significant difference between the mean number of juvenile delta smelt (20 to 30.5 mm in fork length [FL]) retained using the current (40.1 percent +/- 7.4; mean +/- standard error [SE], n = 6) and historical (34.5 percent +/- 7.9; n = 8) screens (p = 0.70). However, delta smelt with a greater maximum body depth than the maximum hole width were recovered outside of both screens. Experiment No. 2 was conducted to determine where, aside from screen holes, these fish may have been lost. The lowest success rate for retention of beads was achieved when no seal was used (8.6 percent for 4 mm, 41 percent for 10 mm). Retention of particles was highest (100 percent for beads \u3e 5 mm) when seals were used on the top and bottom of the screen, demonstrating that loss was occurring at both locations. In experiment No. 3 eight conditions were tested, using the two screen types. Retention was evaluated with and without seals with two class sizes of delta smelt (small, 20 to 25 mm in FL and large, 25 to 30 mm in FL). Retention of the small class size was significantly lower using the current screen with seals, compared to all three other treatment types (current + seal, 3 percent; current, 18 percent; historical + seal, 13 percent; historical, 15 percent, P = 0.002). However, no significant differences were detected among treatments of the large class size (current + seal, 23 percent; current, 33 percent; historical + seal, 59 percent; historical, 44 percent, P = 0.06). Experiments Nos. 1 and 3 support the hypothesis that there is no difference in retention between current and historical screens when seals are not used. SInce seals were not used historically, we conclude that the current and historical salvage data sets are comparable

Sir2 deletion prevents lifespan extension in 32 long-lived mutants

Activation of Sir2 orthologs is proposed to increase lifespan downstream of dietary restriction. Here, we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of DR on replicative lifespan (RLS) in the short-lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe lifespan extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.link_to_subscribed_fulltex

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging