Gordon J. Lithgow

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.

Geroscience: Linking Aging to Chronic Disease

Mammalian aging can be delayed with genetic, dietary, and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand geroscience research directed at extending human healthspan.

Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin‐like signals

Insulin‐like signalling is a key determinate of lifespan in diverse species including mammals but the mechanism by which this pathway influences the rate of aging is unknown. In the roundworm Caenorhabditis elegans, mutations in the insulin‐like signalling pathway extend adult lifespan and are associated with up‐regulation of stress response genes including those for heat shock proteins (HSPs). We tested the hypothesis that the C. elegans insulin‐like signalling pathway determines longevity through modulating HSP levels. We introduced extra copies of the gene encoding HSP‐16 and this conferred stress resistance and longevity both in a wildtype and a long‐lived mutant strain. The DAF‐16 transcription factor is essential for maximal hsp‐16 expression and for lifespan extension conferred by hsp‐16. This demonstrates that lifespan is determined in part by insulin‐like regulation of molecular chaperones.

Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan

Genetic studies indicate that protein homeostasis is a major contributor to metazoan longevity. Collapse of protein homeostasis results in protein misfolding cascades and the accumulation of insoluble protein fibrils and aggregates, such as amyloids. A group of small molecules, traditionally used in histopathology to stain amyloid in tissues, bind protein fibrils and slow aggregation in vitro and in cell culture. We proposed that treating animals with such compounds would promote protein homeostasis in vivo and increase longevity. Here we show that exposure of adult Caenorhabditis elegans to the amyloid-binding dye Thioflavin T (ThT) resulted in a profoundly extended lifespan and slowed ageing. ThT also suppressed pathological features of mutant metastable proteins and human β-amyloid-associated toxicity. These beneficial effects of ThT depend on the protein homeostasis network regulator heat shock factor 1 (HSF-1), the stress resistance and longevity transcription factor SKN-1, molecular chaperones, autophagy and proteosomal functions. Our results demonstrate that pharmacological maintenance of the protein homeostatic network has a profound impact on ageing rates, prompting the development of novel therapeutic interventions against ageing and age-related diseases.

Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans

In the nematode CAENORHABDITIS ELEGANS, dauer formation, stress resistance, and longevity are determined in part by DAF‐2 (insulin receptor‐like protein), AGE‐1 (phosphatidylinositol‐3‐OH kinase cat¬alytic subunit), and DAF‐16 (forkhead transcription factor). Mutations in DAF‐2 and AGE‐1 result in increased resistance to heat, oxidants, and UV. We have discov¬ered that DAF‐2 and AGE‐1 mutations result in increased Cd and Cu ion resistance in a 24 h toxicity assay. Lethal concentration (LC50) values for Cd and Cu ions in DAF‐2 and AGE‐1 mutants were significantly (P<0.001) higher than in wild‐type nematodes. However, LC50 values in DAF‐16;AGE‐1 mutants were not significantly different, implying that metal resistance is influenced by a DAF‐16‐related function. As metallothionein (MT) proteins play a major role in metal detoxification, we examined the expression of MT genes both under noninducing conditions and after exposure to sublethal and acute heavy metal stress. MT1 mRNA levels were significantly (P<0.05) higher in DAF‐2 mutants compared to AGE‐1 mutants and wild‐type C. ELEGANS under basal conditions. After 10 mM Cd treatment, induction of MT1 and MT2 mRNA was three‐ and twofold higher, respectively, in DAF‐2 mutant worms than in wild‐type. However, a sublethal concentration of Cd (0.1 mM) resulted in even higher (three‐ to sevenfold) levels of both MT mRNAs in all strains. Cu did not induce MT1 or MT2 mRNAs. These results are consistent with a model in which the insulin‐signaling pathway determines life span through regulation of stress protein genes.— Barsyte, D., Lovejoy, D. A., Lithgow, G. J. Longevity and heavy metal resistance in DAF‐2 and AGE‐1 long‐lived mutants of Caenorhabditis elegans. FASEB J. 15, 627‐634 (2001)

Stress resistance as a determinate of C. elegans lifespan.

It is difficult to exaggerate the progress that has been made in biogerontology over the last 15 years. As with all scientific revolutions, a few experiments in a small number of laboratories have changed the way in which we think about and design experiments. As a result of these experiments, there is much evidence to suggest that a rudimentary understanding of some of the processes that cause aging will be available in the next decade. One particular area of progress is the molecular genetics of lifespan. Although one may draw some distinctions between chronological lifespan and normal aging, extended lifespan remains one of the best indicators that an intervention in an aging process has been made. The isolation of a long-lived variant of a laboratory invertebrate is now essentially a trivial project but the information obtained from this approach is proving invaluable. As with most other biological problems, the most important experimental developments are coming from studying simple organisms in a reductionist fashion.

Evolution of lifespan in C. elegans.

It was proposed almost 50 years ago that ageing is non-adaptive and is the consequence of a decline in the force of natural selection with age. This led to the theory that ageing results from detrimental effects late in life of genes that act beneficially in early life, so any genetic alteration that increases lifespan might be expected to reduce fitness, for example. We show here that a mutation that greatly increases the lifespan of the nematode Caenorhabditis elegans does indeed exhibit a fitness cost, as demonstrated during starvation cycles that may mimic field conditions, thereby validating the pleiotropy theory of ageing.

Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans

Lithium (Li+) has been used to treat mood affect disorders, including bipolar, for decades. This drug is neuroprotective and has several identified molecular targets. However, it has a narrow therapeutic range and the one or more underlying mechanisms of its therapeutic action are not understood. Here we describe a pharmacogenetic study of Li+ in the nematode Caenorhabditis elegans. Exposure to Li+ at clinically relevant concentrations throughout adulthood increases survival during normal aging (up to 46% median increase). Longevity is extended via a novel mechanism with altered expression of genes encoding nucleosome-associated functions. Li+ treatment results in reduced expression of the worm ortholog of LSD-1 (T08D10.2), a histone demethylase; knockdown by RNA interference of T08D10.2 is sufficient to extend longevity (∼25% median increase), suggesting Li+ regulates survival by modulating histone methylation and chromatin structure.

Mechanisms and Evolution of Aging

In their Perspective, Lithgow and Kirkwood postulate that evolutionary theory predicts that the process of aging is not subject to selection in the same way as other physiological processes such as development. They then describe the genetics of aging in the worm Caenorhabditis elegans and how what we know about the functions of the genes that have been identified as controlling life-span support this notion.

Fitness cost of extended lifespan in Caenorhabditis elegans

An insulin/IGF–I–like signalling pathway determines the rate of aging of the adult nematode, Caenorhabditis elegans. Mutations in genes encoding this pathway can result in a doubling of lifespan. While such mutations may appear to have little effect on development or fertility, evolutionary theory predicts that large increases in lifespan will not be optimal for fitness. We demonstrate by laboratory natural selection that partial loss of function of the insulin receptor–like protein DAF–2 results in dramatically reduced fitness even under laboratory conditions. Despite long–lived mutants appearing healthy, they exhibit a heavy fitness cost consistent with an evolutionary theory of aging.