| Invertebrate Molecular Genetics Unit |
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| Catherine A. Wolkow, Ph.D., Head Investigator |
| Overview: Longevity is affected by many factors, including metabolism, stress resistance and disease susceptibility. In addition, genetics can have a significant influence upon lifespan. For example, mutations that enhance stress resistance or increase metabolic efficiency can increase lifespan. There may also be other strategies, currently unknown, for enhancing longevity. The goal of the Invertebrate Molecular Genetics Unit (IMGU) is to identify factors influencing longevity and to determine the mechanisms behind their effects. |
| Insulin-like pathways control lifespan in C. elegans and other species. |
| C. elegans lifespan is controlled by an insulin-like pathway that includes an insulin/IGF-I receptor-like protein (DAF-2), a PI3K p110 catalytic subunit (AGE-1) and a FOXO transcription factor (DAF-16). Mutations that weaken signaling through this pathway, such as loss-of-function mutations in daf-2 or age-1, significantly extend the worm's adult lifespan. Signaling by DAF-2 and AGE-1 antagonizes the activity of DAF-16. In the absence of DAF-2 and AGE-1 signaling, DAF-16 may activate the expression of target genes required for long life. |
| Hormonal pathways also control lifespan in other species. Lifespan in Drosophila is lengthened by mutations in the genes insulin-like receptor (InR) or chico, a homolog of human IRS. Mouse mutants defective in growth hormone signaling also have extended lifespans. Growth hormone controls the production of several hormones, including IGF-I. Thus, it is possible that the control of lifespan by insulin-like pathways has been evolutionarily conserved. |
| The daf-2 pathway functions in neurons to control lifespan. Restoring daf-2 or age-1 activity to the neurons of daf-2 or age-1 mutants rescues the long lifespan phenotype. Conversely, long lifespan is not rescued by restoring daf-2 pathway activity to non-neuronal cell types, such as muscle. Neurons have also been shown to control lifespan in Drosophila, where neuronal expression of human SOD1 extends lifespan. Recent studies of daf-16 in C. elegans and its ortholog in Drosophila indicate that fat and intestinal cells are also important tissues controlling longevity. An important goal is to identify which neurons control lifespan via age-1 activity. Is lifespan controlled by a specific subset of neurons, or is this a general feature of all neurons? Transgenic approaches and genetic screens are in progress to answer this question. |
| Discovering causes of aging-related physical declines in C. elegans. |
| One ubiquitous feature of aging is gradual physical decline. Some species, including humans, also exhibit aging-associated cognitive declines. These declines are progressive with increasing age. In C. elegans, aging-related declines can be observed in behavioral responses that depend upon locomotion. In addition, these animals exhibit declines in feeding behavior with increasing age. One cause for lomotory decline during aging might be losses in muscle tissue integrity. If this is the case, then how do these changes in muscle cells affect neuromuscular signaling? Members of the IMGU are working to identify cellular changes that occur commonly with aging and to develop strategies that enable the aging body to maintain a high functionality. |
| Using C. elegans to identify new strategies for modifying longevity. |
| One strategy for increasing the health of people as they age is to identify compounds that can enhance longevity and/or healthspan. C. elegans is a remarkably useful organism for identifying and characterizing longevity-promoting compounds for its relatively short lifespan and amenibility to genetic analysis. Compounds with beneficial effects on longevity or healthspan are being characterized in the IMGU with the goal of determining the mechanisms by which these compounds act. By identifying the cellular processes that are affected by these compounds, we hope to devise addition, novel strategies for enhancing lifespan. |
| Members of the IMGU. |
| Cathy Wolkow, Ph.D. - Tenure Track Investigator Mark Wilson, M.S. - Biologist - Identification of new genes and compounds that enhance C. elegans lifespan. Minaxi Gami, Ph.D. - Visting Fellow - Genetic analysis of the age-1/PI 3-kinase signaling pathway. David Chow - Postbac IRTA Fellow - Mechanisms behind aging-related feeding decline. Keaton Hanselman - Postbac IRTA Fellow - Genetic analysis of age-1/PI 3-kinase signaling pathway. Wendy Iser - Postbac IRTA Fellow - Genetics and cell biology of stress-response pathways in C. elegans. |
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