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: 31.48). 11/2000; 290(5489):147-50.
Source: PubMed

ABSTRACT 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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    • "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.
    Journal of Experimental Biology 01/2014; 217(Pt 1):109-18. DOI:10.1242/jeb.089920 · 3.00 Impact Factor
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    • "The IIS pathway plays an endocrine role to modulate lifespan in a cell-nonautonomous manner. Genetic mosaics lacking daf-2 in neuronal precursor cells are long-lived (Apfeld and Kenyon, 1998), and neuronal expression of daf-2 rescues the daf-2 mutant-mediated lifespan extension (Wolkow et al., 2000). However , the essential IIS downstream transcription factor DAF-16 functions mainly in the intestine to modulate longevity (Libina et al., 2003). "
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    ABSTRACT: Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.
    Cell Reports 12/2013; 5(6). DOI:10.1016/j.celrep.2013.11.018 · 8.36 Impact Factor
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