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). 11/2000; 290(5489):147-50.
Source: PubMed


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.

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    • "Dauer pathway is an altered pathway of development of C. Elegans, and Dauer individuals have prolonged lifespans. Dauer pathway was found to be induced by an environment change and be mediated by insulin-like signaling pathway (Wolkow et al, 2000). Hormones and hormone-related genes were then thought to be important in regulating aging process apart from regulating development (de Magalhaes et al, 2005). "
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    ABSTRACT: Many theories have been proposed to answer two questions on aging: "Why do we age?" and "How do we age?" Among them, evolutionary theories are proposed to interpret the evolutionary advantage of aging, and "saving resources for group benefit" is thought to be the purpose of aging. However for saving resources, a more economic strategy should be to make a rapid death to the individuals who are over the reproduction age rather than to make them aging. Biological theories are proposed to identify the causes and the biological processes of aging. However, some theories including cell senescence/telomere theory, gene-controlling theory, and developmental theory, have unfortunately ignored the influence of damage on aging. Free-radical theory suggests that free radicals by causing intrinsic damage are the main cause of aging. However, even if intracellular free radicals cause injuries, they could be only associated with some but not all of the aging changes. Damage (fault)-accumulation theory predicts that faults as intrinsic damage can accumulate and lead to aging. However, in fact an unrepaired fault could not possibly remain in a living organism, since it can destroy the integrity of tissue structure and cause rapid failure of the organism. These traditional theories are all incomplete on interpreting aging phenomena. Nevertheless, developmental theory and damage (fault)-accumulation theory are more useful, because they have recognized the importance of damage and development process in aging. Some physical theories are useful, because they point out the common characteristics of aging changes, including loss of complexity, consequence of increase of entropy, and failure of information-transmission. An advanced theory, which can include all of these useful ideas in traditional theories, is needed.
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    • "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.
    Development 03/2014; 141(8). DOI:10.1242/dev.103846 · 6.46 Impact Factor
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    • "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 [30]. "
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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.
    Aging 03/2014; 6(2). · 6.43 Impact Factor
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