Siegfried Hekimi, McGill University
Biology
Professor
Montreal, Quebec
siegfried.hekimi@mcgill.ca
Office:
(514) 398-6440
Expert In
Bio/Research
The work of the laboratory is mostly concerned with the elucidation of the cellular and molecular mechanisms that determine the physiological features of animals, including their lifespan. For this, we use an invertebrate model system, the nematode worm Caenorhabditis elegans, but we are also tra...
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Bio/Research
The work of the laboratory is mostly concerned with the elucidation of the cellular and molecular mechanisms that determine the physiological features of animals, including their lifespan. For this, we use an invertebrate model system, the nematode worm Caenorhabditis elegans, but we are also translating and extending our findings to vertebrates by using mice and cultured mouse and human cells, as well as known and novel drugs. The use of C. elegans allows us to carry out forward and reverse genetic screens to identify gene that are important in determining physiological features, including longevity. Identifying genes in which loss of activity increases lifespan is particularly powerful for understanding aging as it is an unassailable conclusion that when a loss-of-function change in a gene leads to increased longevity, then the normal function of the gene limits lifespan in normal animals.
In addition to aging, we are interested in the genetics and pharmacology of lipid and lipoprotein metabolism, which we study using C. elegans mutants with altered quantitative behavioural traits, such as slow peristalsis, that we know to be linked to the metabolism of cholesterol and of a type of lipoproteins that resembles the Low Density Lipoproteins (LDL) that are important in human health, especially during aging. We are interested in discovering and understanding new protein players in this process, as well as new drugs and their targets.
Using this approach we have genetically and molecularly identified and characterized several classes of genes, including 'clock' genes (clk; e.g. clk-1), which affect a variety of functions, genes encoding subunits of mitochondrial respiratory complexes (e.g. isp-1 and nuo-6), and various classes of suppressors of clk-1 (e.g. dsc genes, of which a subclass is involved in lipoprotein metabolism) that we now also study in vertebrates. We have been able to show that a reduction in the level of Mclk1, the mouse homologue of clk-1, leads to a remarkable (15-30%) increase in mouse lifespan. The evolutionary conservation of the effect of clk-1/Mclk1 suggests that we might be dealing with basic mechanisms of aging. The lifespan genes that we are studying mostly encode proteins that function in the mitochondria, and our work now is also deeply involved in understanding their exact function in mitochondrial physiology, and in the physiology of intact animals, which we study by indirect calorimetry and other non-invasive methods.
It is possible that “aging” is but the name we give to a particular pattern of age-dependent diseases, and that there is no aging process that is mechanistically distinct from the processes that underlie the development of each age-dependent disease. We are attempting to consider these questions experimentally by studying age-associated pathologies in mice mutants of Mclk1 (mouse clk-1) and of Risp1 (mouse isp-1), as well as by studying the effect of mutations in these genes on genetic backgrounds that are susceptible to particular age-dependent diseases, such as LDLr -/- and ApoE -/- (atherosclerosis), p53 -/- and v-Ha-Ras TG (cancer), Sod1 -/- (liver cancer), Sod2 -/- (mitochondrial oxidative stress), and others.
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In addition to aging, we are interested in the genetics and pharmacology of lipid and lipoprotein metabolism, which we study using C. elegans mutants with altered quantitative behavioural traits, such as slow peristalsis, that we know to be linked to the metabolism of cholesterol and of a type of lipoproteins that resembles the Low Density Lipoproteins (LDL) that are important in human health, especially during aging. We are interested in discovering and understanding new protein players in this process, as well as new drugs and their targets.
Using this approach we have genetically and molecularly identified and characterized several classes of genes, including 'clock' genes (clk; e.g. clk-1), which affect a variety of functions, genes encoding subunits of mitochondrial respiratory complexes (e.g. isp-1 and nuo-6), and various classes of suppressors of clk-1 (e.g. dsc genes, of which a subclass is involved in lipoprotein metabolism) that we now also study in vertebrates. We have been able to show that a reduction in the level of Mclk1, the mouse homologue of clk-1, leads to a remarkable (15-30%) increase in mouse lifespan. The evolutionary conservation of the effect of clk-1/Mclk1 suggests that we might be dealing with basic mechanisms of aging. The lifespan genes that we are studying mostly encode proteins that function in the mitochondria, and our work now is also deeply involved in understanding their exact function in mitochondrial physiology, and in the physiology of intact animals, which we study by indirect calorimetry and other non-invasive methods.
It is possible that “aging” is but the name we give to a particular pattern of age-dependent diseases, and that there is no aging process that is mechanistically distinct from the processes that underlie the development of each age-dependent disease. We are attempting to consider these questions experimentally by studying age-associated pathologies in mice mutants of Mclk1 (mouse clk-1) and of Risp1 (mouse isp-1), as well as by studying the effect of mutations in these genes on genetic backgrounds that are susceptible to particular age-dependent diseases, such as LDLr -/- and ApoE -/- (atherosclerosis), p53 -/- and v-Ha-Ras TG (cancer), Sod1 -/- (liver cancer), Sod2 -/- (mitochondrial oxidative stress), and others.
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