Anders Olsen

Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans

Protein synthesis is a regulated cellular process that links nutrients in the environment to organismal growth and development. Here we examine the role of genes that regulate mRNA translation in determining growth, reproduction, stress resistance and lifespan. Translational control of protein synthesis by regulators such as the cap‐binding complex and S6 kinase play an important role during growth. We observe that inhibition of various genes in the translation initiation complex including ifg‐1, the worm homologue of eIF4G, which is a scaffold protein in the cap‐binding complex; and rsks‐1, the worm homologue of S6 kinase, results in lifespan extension in Caenorhabditis elegans. Inhibition of ifg‐1 or rsks‐1 also slows development, reduces fecundity and increases resistance to starvation. A reduction in ifg‐1 expression in dauers was also observed, suggesting an inhibition of protein translation during the dauer state. Thus, mRNA translation exerts pleiotropic effects on growth, reproduction, stress resistance and lifespan in C. elegans.

An automated high-throughput assay for survival of the nematode Caenorhabditis elegans

Many genetic or environmental manipulations that extend life span in the nematode Caenorhabditis elegans (C. elegans) also enhance survival following acute stresses such as oxidative damage and thermal stress. This coupling of stress response and aging mechanisms has proved a useful tool in identifying new genes that affect the aging process without the need for performing lengthy life span analyses. Therefore, it is likely that this approach may also be applied to the identification of pharmacological agents that extend life span through enhanced resistance to oxygen radicals or other stressors. To facilitate high-throughput drug screens in the nematode, we have developed a microtitre plate survival assay that uses uptake of the fluorescent dye SYTOX green as a marker of nematode death. An increase in throughput compared with the conventional survival assay was achieved by combining automated worm-handling technology with automated real-time fluorescence detection. We have validated this assay by examining survival during acute heat stress and protection against oxidative stress with the superoxide dismutase/catalase mimetic Euk-134. We propose that this novel method of survival analysis will accelerate the discovery of new pharmacological interventions in aging and oxidative stress.

Oxidative stress in Caenorhabditis elegans: protective effects of superoxide dismutase/catalase mimetics

The lifespan of Caenorhabditis elegans can be extended by the administration of synthetic superoxide dismutase/catalase mimetics (SCMs) without any effects on development or fertility. Here we demonstrate that the mimetics, Euk‐134 and Euk‐8, confer resistance to the oxidative stress‐inducing agent, paraquat and to thermal stress. The protective effects of the compounds are apparent with treatments either during development or during adulthood and are independent of an insulin/IGF‐I‐like signalling pathway also known to affect thermal and oxidative stress resistance. Worms exposed to the compounds do not induce a cellular stress response and no detrimental effects are observed.

Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments

Mild hormetic heat treatments early in life can significantly increase the lifespan of the nematode C. elegans. We have examined the effects of heat treatments at different ages and show that treatments early in life cause the largest increases in lifespan. We also find that repeated mild heat treatments throughout life have a larger effect on lifespan compared to a single mild heat treatment early in life. We hypothesize that the magnitude of the hormetic effect is related to the levels of heat shock protein expression. Following heat treatment young worms show a dramatic increase in the levels of the small heat shock protein HSP-16 whereas old worms are a 100-fold less responsive. The levels of the heat shock proteins HSP-4 and HSP-16 correlate well with the effects on lifespan by the hormetic treatments.

Compounds that Confer Thermal Stress Resistance and Extended Lifespan

The observation that long-lived and relatively healthy animals can be obtained by simple genetic manipulation prompts the search for chemical compounds that have similar effects. Since aging is the most important risk factor for many socially and economically important diseases, the discovery of a wide range of chemical modulators of aging in model organisms could prompt new strategies for attacking age-related disease such as diabetes, cancer and neurodegenerative disorders [Collins, J.J., Evason, K., Kornfeld, K., 2006. Pharmacology of delayed aging and extended lifespan of Caenorhabditis elegans. Exp. Gerontol.; Floyd, R.A., 2006. Nitrones as therapeutics in age-related diseases. Aging Cell 5, 51-57; Gill, M.S., 2006. Endocrine targets for pharmacological intervention in aging in Caenorhabditis elegans. Aging Cell 5, 23-30; Hefti, F.F., Bales, R., 2006. Regulatory issues in aging pharmacology. Aging Cell 5, 3-8]. Resistance to multiple types of stress is a common trait in long-lived genetic variants of a number of species; therefore, we have tested compounds that act as stress response mimetics. We have focused on compounds with antioxidant properties and identified those that confer thermal stress resistance in the nematode Caenorhabditis elegans. Some of these compounds (lipoic acid, propyl gallate, trolox and taxifolin) also extend the normal lifespan of this simple invertebrate, consistent with the general model that enhanced stress resistance slows aging.

Using Caenorhabditis elegans as a model for aging and age-related diseases.

Abstract:  During the last three decades the soil nematode C. elegans has become a prominent model organism for studying aging. Initially research in the C. elegans aging field was focused on the genetics of aging and single gene mutations that dramatically increased the life span of the worm. Undoubtedly, the existence of such mutations is one of the main reasons for the popularity of the worm as model system for studying aging. However, today many different approaches are being used in the C. elegans aging field in addition to genetic manipulations that influence life span. For example, environmental manipulations such as caloric restriction and hormetic treatments, evolutionary studies, population studies, models of age‐related diseases, and drug screening for compounds that extend life span are now being investigated using this nematode. This review will focus on the most recent developments in C. elegans aging research with the aim of illustrating the diversity of the field.

Checkpoint Proteins Control Survival of the Postmitotic Cells in Caenorhabditis elegans

Checkpoints are evolutionarily conserved signaling mechanisms that arrest cell division and alter cellular stress resistance in response to DNA damage or stalled replication forks. To study the consequences of loss of checkpoint functions in whole animals, checkpoint genes were inactivated in the nematode C. elegans. We show that checkpoint proteins are not only essential for normal development but also determine adult somatic maintenance. Checkpoint proteins play a role in the survival of postmitotic adult cells.

Pharmacological intervention in invertebrate aging

Prompted by successful genetic interventions in aging we now consider the utility of pharmacological interventions. A few clear cases of lifespan extension resulting from exposure to compounds suggest that aging can be slowed and that the pharmacology of lifespan extension is a feasible area for research. Compounds that slow aging may prompt the rational design of therapeutics against age-related diseases. Here we evaluate invertebrate models for drug discovery in aging and outline how the field may develop from these simple first steps.

Aging in C. elegans

In the last decade of the 20th century one model organism has received more attention from gerontologists than any other, namely the free-living soil nematode Caenorhabditis elegans (C. elegans). We owe much of our general view of the genetic determination of lifespan to this organism. C. elegans became a popular organism for the analysis of complex biological problems following the pioneering work of Sidney Brenner and Sir John Sulston who determined the developmental cellular fate map [1]. It is also noted for the early work of Robert Horvitz and colleagues who used the cell lineage map to begin a genetic dissection of programmed cell death [2].