Periodic Reporting for period 1 - MeLiLoN (Metabolic Networks that Link Longevity to Reproduction in Response to Nutrition)
Berichtszeitraum: 2015-10-01 bis 2017-03-31
In most western countries, life expectancy is increasing by 3 months a year. As the average age of the population increases, so too does the prevalence of age-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegenerative disorders. An essential component of ageing research is to understand at the cellular and molecular levels the biological mechanisms that contribute to the ageing process. This has major implications not only for the treatment of age-associated diseases but also for the promotion of healthy ageing.
Studies of experimental animals and observations in humans have identified an array of genes and nutritional conditions that increase lifespan. However, these manipulations (genetic or nutritional) often have detrimental effects on other biological processes; for example, reproduction, metabolism, immunity or growth. This is an area of ageing research that has largely been ignored but that is critical to the success of strategies intended to slow ageing and thus the onset of disease.
The goal of this research proposal is to understand how lifespan extension is linked to reproduction. We will use the nematode Caenorhabditis elegans as a model organism to identify novel conserved genes, molecules, and metabolic networks that link reproduction and longevity through nutrition. The proposed study is based on a unique set of preliminary data that identifies the first clear molecular links between these traits: a steroid hormone receptor that is essential for, and a reproduction-responsive lipase that is limiting for, lifespan extension achieved through changes in nutrition.
Understanding the regulation and function of these genes and pathways will clarify at the molecular level how reproduction is linked to longevity. Our ultimate goal is to design interventions that optimize metabolic activity to promote healthy ageing.
Studies of experimental animals and observations in humans have identified an array of genes and nutritional conditions that increase lifespan. However, these manipulations (genetic or nutritional) often have detrimental effects on other biological processes; for example, reproduction, metabolism, immunity or growth. This is an area of ageing research that has largely been ignored but that is critical to the success of strategies intended to slow ageing and thus the onset of disease.
The goal of this research proposal is to understand how lifespan extension is linked to reproduction. We will use the nematode Caenorhabditis elegans as a model organism to identify novel conserved genes, molecules, and metabolic networks that link reproduction and longevity through nutrition. The proposed study is based on a unique set of preliminary data that identifies the first clear molecular links between these traits: a steroid hormone receptor that is essential for, and a reproduction-responsive lipase that is limiting for, lifespan extension achieved through changes in nutrition.
Understanding the regulation and function of these genes and pathways will clarify at the molecular level how reproduction is linked to longevity. Our ultimate goal is to design interventions that optimize metabolic activity to promote healthy ageing.
Dietary restriction, defined as diminished food intake without reaching malnutrition, is known to extend lifespan modestly (20%–40%) but significantly in a range of species. Dietary restriction also delays reproduction and decreases fecundity and, in turn, changes in reproductive capacity affect energy metabolism and triacylglycerol (TAG) stores. For example, pathological or physiological cessation of reproductive ability in humans is often associated with increased fat storage and elevated levels of circulating free fatty acids, TAGs, and LDL-cholesterol. In animal husbandry, gonadectomy is widely used to increase fattening of animals to the detriment of lean meat production. Similarly, mutations in the nematode C. elegans and fruit fly D. melanogaster that compromise fertility also induce accumulation of TAGs. The disposable soma theory of aging has offered a simple framework to explain the links between reproduction, energy metabolism, and longevity by proposing the existence of a trade-off between energy expenditure on reproduction and on somatic maintenance. However, experiments in Drosophila and worms have challenged the notion that DR-induced lifespan extension must come at the expense of fecundity. The molecular nature of the connections between these 3 traits thus appears to be more complex than anticipated.
The extent to which fat metabolism contributes to DR-induced lifespan extension and how this may be linked to reproduction remains unclear. The lipase LIPL-4 is required for lifespan extension though ablation of the germline in C. elegans, but its involvement is independent of changes in fat storage and its action is probably restricted to lysosomes. Fatty acid desaturation has also been shown to mediate lifespan extension in germline-less animals. Recent work has shown that the lipases LIPL-1 and LIPL-3 are induced by starvation, and their overexpression increases lifespan under normal nutritional conditions. However, this occurs independently of DR-induced lifespan extension.
During this period of our grant, we have examined the association between lifespan extension through nutritional challenge and fat catabolism in fertile and sterile C. elegans. We found that, in contrast to fertile animals, a number of sterile mutants fail to mobilize fat when subjected to harsh nutritional conditions; namely bacterial deprivation. Interestingly, these animals also exhibited enhanced lifespan extension upon food restriction. We show that these two phenotypes are linked through the lipase LIPL-5/LIPF. lipl-5 is induced by starvation in fertile, but not sterile, animals, and fertile lipl-5 mutants exhibit reduced intestinal TAG catabolism and enhanced BD-mediated lifespan extension. Consistent with these observations, overexpression of lipl-5 in sterile animals reverses their enhanced BD-associated lifespan extension and restores their capacity to catabolize TAGs. Moreover, manipulation of other processes that affect fat stores (other lipases insulin signaling and autophagy) do not alter lipl-5 expression and do not influence BD-induced lifespan extension, implying that the effect of LIPL-5 is not mediated solely by its contribution to metabolism. Thus, our data suggest that LIPL-5 induction results in signals that negatively affect survival upon starvation: in fertile animals, BD is accompanied by a rapid activation of LIPL-5–mediated lipolysis that limits lifespan; in contrast, sterile animals do not induce lipolysis and thus exhibit longer lifespans upon starvation. In addition, we found that LIPL-5 is strictly localize in coelomocytes that are liver like cells in the worm. Collectively, our data are consistent with the idea that – under harsh nutritional conditions – LIPL-5–mediated mobilization of TAG stores in wild type animals is limiting for lifespan extension, and that disruption of coelomocytes specific lipl-5 alone is sufficient to reverse this limitation. This work is ready to be published.
In addition, we have discovered that under certain conditions where the function of the germline is altered, addition of glucose ceases to be toxic for the animals. This is surprising because no links between germline function and glucose metabolism had never been reported before. In some specific conditions where reproduction is altered, glucose not only ceases to be toxic, but it actually increases substantially the lifespan and the health of the animals. We will investigate the mechanism at stake in this unusual lifespan and healthspan extension.
The extent to which fat metabolism contributes to DR-induced lifespan extension and how this may be linked to reproduction remains unclear. The lipase LIPL-4 is required for lifespan extension though ablation of the germline in C. elegans, but its involvement is independent of changes in fat storage and its action is probably restricted to lysosomes. Fatty acid desaturation has also been shown to mediate lifespan extension in germline-less animals. Recent work has shown that the lipases LIPL-1 and LIPL-3 are induced by starvation, and their overexpression increases lifespan under normal nutritional conditions. However, this occurs independently of DR-induced lifespan extension.
During this period of our grant, we have examined the association between lifespan extension through nutritional challenge and fat catabolism in fertile and sterile C. elegans. We found that, in contrast to fertile animals, a number of sterile mutants fail to mobilize fat when subjected to harsh nutritional conditions; namely bacterial deprivation. Interestingly, these animals also exhibited enhanced lifespan extension upon food restriction. We show that these two phenotypes are linked through the lipase LIPL-5/LIPF. lipl-5 is induced by starvation in fertile, but not sterile, animals, and fertile lipl-5 mutants exhibit reduced intestinal TAG catabolism and enhanced BD-mediated lifespan extension. Consistent with these observations, overexpression of lipl-5 in sterile animals reverses their enhanced BD-associated lifespan extension and restores their capacity to catabolize TAGs. Moreover, manipulation of other processes that affect fat stores (other lipases insulin signaling and autophagy) do not alter lipl-5 expression and do not influence BD-induced lifespan extension, implying that the effect of LIPL-5 is not mediated solely by its contribution to metabolism. Thus, our data suggest that LIPL-5 induction results in signals that negatively affect survival upon starvation: in fertile animals, BD is accompanied by a rapid activation of LIPL-5–mediated lipolysis that limits lifespan; in contrast, sterile animals do not induce lipolysis and thus exhibit longer lifespans upon starvation. In addition, we found that LIPL-5 is strictly localize in coelomocytes that are liver like cells in the worm. Collectively, our data are consistent with the idea that – under harsh nutritional conditions – LIPL-5–mediated mobilization of TAG stores in wild type animals is limiting for lifespan extension, and that disruption of coelomocytes specific lipl-5 alone is sufficient to reverse this limitation. This work is ready to be published.
In addition, we have discovered that under certain conditions where the function of the germline is altered, addition of glucose ceases to be toxic for the animals. This is surprising because no links between germline function and glucose metabolism had never been reported before. In some specific conditions where reproduction is altered, glucose not only ceases to be toxic, but it actually increases substantially the lifespan and the health of the animals. We will investigate the mechanism at stake in this unusual lifespan and healthspan extension.
Concerning our first finding (lipl-5), it will be important in the future to fund out is a similar lipase can have a similar impact in mammals. Interestingly, LIPL-5 is localized in cells that seem to be liver like cells. It would be extremely interesting to investigate hepatic lipase and their role in the dietary restriction response.
Our initial finding on the impact of glucose on lifespan and health can have profound implications. We first need to better understand the mechanisms at stake and to investigate whether we have found a way to lift the devastating effect of glucose on health over time.
Both of these works are completely new and will provide valuable knowledge on our understanding of the genetic and metabolic regulation of lifespan.
In sum, we are pleased to be able to provide significant results in such a short amount of time.
Our initial finding on the impact of glucose on lifespan and health can have profound implications. We first need to better understand the mechanisms at stake and to investigate whether we have found a way to lift the devastating effect of glucose on health over time.
Both of these works are completely new and will provide valuable knowledge on our understanding of the genetic and metabolic regulation of lifespan.
In sum, we are pleased to be able to provide significant results in such a short amount of time.