Insulin/IGF‐1‐mediated longevity is marked by reduced protein metabolism (original) (raw)
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Nature genetics, 2001
The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells. In both cases, li...
Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling
ed or-independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organ-ismal " healthspan " has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans.
PLOS Genetics, 2005
Most of our knowledge about the regulation of aging comes from mutants originally isolated for other phenotypes. To ask whether our current view of aging has been affected by selection bias, and to deepen our understanding of known longevity pathways, we screened a genomic Caenorhabditis elegans RNAi library for clones that extend lifespan. We identified 23 new longevity genes affecting signal transduction, the stress response, gene expression, and metabolism and assigned these genes to specific longevity pathways. Our most important findings are (i) that dietary restriction extends C. elegans' lifespan by down-regulating expression of key genes, including a gene required for methylation of many macromolecules, (ii) that integrin signaling is likely to play a general, evolutionarily conserved role in lifespan regulation, and (iii) that specific lipophilic hormones may influence lifespan in a DAF-16/FOXO-dependent fashion. Surprisingly, of the new genes that have conserved sequence domains, only one could not be associated with a known longevity pathway. Thus, our current view of the genetics of aging has probably not been distorted substantially by selection bias. Citation: Hansen M, Hsu AL, Dillin A, Kenyon C (2005) New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 1(1): e17.
Reduced signaling through the C. elegans insulin/insulinlike growth factor-1-like tyrosine kinase receptor daf-2 and dietary restriction via bacterial dilution are two wellcharacterized lifespan-extending interventions that operate in parallel or through (partially) independent mechanisms. Using accurate mass and time tag LC-MS/MS quantitative proteomics, we detected that the abundance of a large number of ribosomal subunits is decreased in response to dietary restriction, as well as in the daf-2(e1370) insulin/insulin-like growth factor-1-receptor mutant. In addition, general protein synthesis levels in these long-lived worms are repressed. Surprisingly, ribosomal transcript levels were not correlated to actual protein abundance, suggesting that post-transcriptional regulation determines ribosome content. Proteomics also revealed the increased presence of many structural muscle cell components in long-lived worms, which appeared to result from the prioritized preservation of muscle cell volume in nutrient-poor conditions or low insulin-like signaling. Activation of DAF-16, but not diet restriction, stimulates mRNA expression of muscle-related genes to prevent muscle atrophy. Important daf-2-specific proteome changes include overexpression of aerobic metabolism enzymes and general activation of stress-responsive and immune defense systems, whereas the increased abundance of many protein subunits of the proteasome core complex is a dietaryrestriction-specific characteristic. Molecular & Cellular
Protein Synthesis Is a Novel Determinant of Aging in Caenorhabditis elegans
Annals of the New York Academy of Sciences, 2007
Protein synthesis is a tightly regulated cellular process that affects growth, reproduction, and survival in response to both intrinsic and extrinsic cues, such as nutrient availability and energy levels. A pronounced, age-related decline of the total protein synthesis rate has been observed in many organisms, including humans. The molecular mechanisms underlying this decline and their role in the aging process remain unclear. A series of recent studies in the nematode, Caenorhabditis elegans, have revealed a novel link between protein synthesis and aging. Remarkably, these research findings, in their totality, converge to indicate that reduction of mRNA translation prolongs life in worms. Signal transduction cascades implicated in aging, such as the insulin/insulin growth factor-1 pathway, interface with mechanisms regulating protein synthesis via a battery of key mRNA translation factors. Are the effects of these pathways on aging mediated, in part, by alterations in protein synthesis? This is an intriguing possibility in light of the latest discoveries. Whether attenuation of protein synthesis promotes longevity across different phyla is an additional important matter. Here, we survey work associating protein synthesis with aging and discuss the basis of life-span extension under conditions that attenuate protein synthesis.
Biogerontology, 2014
Nuclear envelope (NE) architecture and aging have been associated since the discovery that certain human progeria diseases are due to perturbations in processing of lamin A protein, generating alterations in NE morphology. However, whether changes in the NE are a causal effect of normal and premature aging is still controversial. Caenorhabditis elegans is a model organism where observations supporting both, dependent and independent roles of nuclear architecture in the aging process, have been reported. Using this model organism, we found that the long-lived glp-1 mutant and dietary restriction delayed age-associated nuclear morphology changes. In addition, we observed that the long-lived mutant of the insulin/IGF receptor daf-2 delayed the agedependent changes of nuclear architecture at 25ºC, as previously described. However, when daf-2 animals were incubated at 20ºC they remained long-lived, but nuclear appearance changed at similar rate as in the wild type. This supports the idea that both phenotypes, longevity and maintenance of nuclear architecture are tightly associated but can be separated and argues that nuclear morphology deterioration is not a cause of the natural aging process.
Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression
Genome Research, 2005
We have identified longevity-associated genes in a long-lived Caenorhabditis elegans daf-2 (insulin/IGF receptor) mutant using serial analysis of gene expression (SAGE), a method that efficiently quantifies large numbers of mRNA transcripts by sequencing short tags. Reduction of daf-2 signaling in these mutant worms leads to a doubling in mean lifespan. We prepared C. elegans SAGE libraries from 1, 6, and 10-d-old adult daf-2 and from 1 and 6-d-old control adults. Differences in gene expression between daf-2 libraries representing different ages and between daf-2 versus control libraries identified not only single genes, but whole gene families that were differentially regulated. These gene families are part of major metabolic pathways including lipid, protein, and energy metabolism, stress response, and cell structure. Similar expression patterns of closely related family members emphasize the importance of these genes in aging-related processes. Global analysis of metabolism-associated genes showed hypometabolic features in mid-life daf-2 mutants that diminish with advanced age. Comparison of our results to recent microarray studies highlights sets of overlapping genes that are highly conserved throughout evolution and thus represent strong candidate genes that control aging and longevity.
Molecular metabolism, 2019
Objective: Animal lifespan is controlled through genetic pathways that are conserved from nematodes to humans. Lifespan-promoting conditions in nematodes include fasting and a reduction of insulin/IGF signaling. Here we aimed to investigate the input of the Caenorhabditis elegans homologue of the mammalian rate-limiting lipolytic enzyme Adipose Triglyceride Lipase, ATGL-1, in longevity control. Methods: We used a combination of genetic and biochemical approaches to determine the role of ATGL-1 in accumulation of triglycerides and regulation of longevity. Results: We found that expression of ATGL is increased in the insulin receptor homologue mutant daf-2 in a FoxO/DAF-16-dependent manner. ATGL-1 is also up-regulated by fasting and in the eat-2 loss-of-function mutant strain. Overexpression of ATGL-1 increases basal and maximal oxygen consumption rate and extends lifespan in C. elegans. Reduction of ATGL-1 function suppresses longevity of the long-lived mutants eat-2 and daf-2. Conclusion: Our results demonstrate that ATGL is required for extended lifespan downstream of both dietary restriction and reduced insulin/IGF signaling.