Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147-150
Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA. Science
(Impact Factor: 33.61).
An insulinlike signaling pathway controls Caenorhabditis elegans aging, metabolism, and development. Mutations in the daf-2 insulin receptor-like gene or the downstream age-1 phosphoinositide 3-kinase gene extend adult life-span by two- to threefold. To identify tissues where this pathway regulates aging and metabolism, we restored daf-2 pathway signaling to only neurons, muscle, or intestine. Insulinlike signaling in neurons alone was sufficient to specify wild-type life-span, but muscle or intestinal signaling was not. However, restoring daf-2 pathway signaling to muscle rescued metabolic defects, thus decoupling regulation of life-span and metabolism. These findings point to the nervous system as a central regulator of animal longevity.
Available from: Mei Zhen
- "Results from DAF-2 tissue-specific rescue experiments (Wolkow et al., 2000) led to consistent, but not unambiguous, conclusions: DAF-2 driven by two pan-neural promoters showed strong (Punc-14) or partial (Punc-119) rescue of daf-2 Daf-c, whereas DAF-2 driven by an intestinal promoter had no effect. The authors noted that Punc-14 exhibited leaky expression in the pharynx and/or intestine (footnote 23 in Wolkow et al., 2000). The requirement of DAF-16 was examined by both tissue-specific rescue experiments and mosaic analyses. "
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ABSTRACT: Adverse environmental conditions trigger C. elegans larvae to activate an alternative developmental program, termed dauer diapause, which renders them stress resistant. High-level insulin signaling prevents constitutive dauer formation. However, it is not fully understood how animals assess conditions to choose the optimal developmental program. Here, we show that insulin-like peptide (ILP)-mediated neuron-intestine communication plays a role in this developmental decision. Consistent with, and extending, previous findings, we show that the simultaneous removal of INS-4, INS-6 and DAF-28 leads to fully penetrant constitutive dauer formation, whereas the removal of INS-1 and INS-18 significantly inhibits constitutive dauer formation. These ligands are processed by the proprotein convertases PC1/KPC-1 and/or PC2/EGL-3. The agonistic and antagonistic ligands are expressed by, and function in, neurons to prevent or promote dauer formation. By contrast, the insulin receptor DAF-2 and its effector, the FOXO transcription factor DAF-16, function solely in the intestine to regulate the decision to enter diapause. These results suggest that the nervous system normally establishes an agonistic ILP-dominant paradigm to inhibit intestinal DAF-16 activation and allow reproductive development. Under adverse conditions, a switch in the agonistic-antagonistic ILP balance activates intestinal DAF-16, which commits animals to diapause.
Available from: Teppei Fujikawa
- "It is safe to say that the concept that neurons regulate lifespan is well-appreciated in other species as for example the worm Caenorhabditis elegans and the fly Drosophila melanogaster [27, 28]. Genetic manipulation of the insulin signaling in neurons extends the lifespan up to two or three folds in worms [29, 30]. Thus, it seems as neurons can govern aging process in an insulin-depend manner . "
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ABSTRACT: Diabetes afflicts hundreds of millions worldwide. People affected by type 1 diabetes mellitus (T1DM; the insulin-deficient form of diabetes) or type 2 diabetes mellitus (T2DM; the insulin-resistant form of diabetes) have significantly reduced life expectancy compared to normal individuals. This is due in part to the fact that (despite improvements) current anti-diabetic approaches are suboptimal. Indeed, severe morbidities (e.g.: cardiovascular disease, hypertension) are still too often associated with diabetes. Recent preclinical results indicate that different types of hypothalamic neurons are endowed with the ability to mediate the hyperglycemia-lowering action of the adipocyte-derived hormone leptin in an insulin-dependent and insulin-independent fashion. These results may pave the way for better anti-diabetic approaches and therefore positively impact on life expectancy of diabetic subjects.
Available from: Lifen Wang
- "The insulin signaling pathway is a central regulator of longevity in both invertebrates and vertebrates (Wolkow et al., 2000; Tatar et al., 2003; Kenyon, 2005; Greer and Brunet, 2008; Broughton and Partridge, 2009; Kenyon, 2010; Barzilai et al., 2012). Single-gene loss-of-function mutations in insulin signaling components extend lifespan in Caenorhabditis elegans and D. melanogaster, and loss of insulin signaling activity in specific tissues of mice can also promote longevity. "
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ABSTRACT: Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster. The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality. Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine.
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