A Genetic Program Promotes C. elegans Longevity at Cold Temperatures via a Thermosensitive TRP Channel

Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension. However, the underlying mechanisms remain unclear. One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging. This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process. Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures. We find that TRPA-1, a cold-sensitive TRP channel, detects temperature drop in the environment to extend lifespan. This effect requires cold-induced, TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO. Human TRPA1 can functionally substitute for worm TRPA-1 in promoting longevity. Our results reveal a previously unrecognized function for TRP channels, link calcium signaling to longevity, and, importantly, demonstrate that genetic programs contribute to lifespan extension at cold temperatures.

[1]  W. Schafer,et al.  Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors , 2010, Nature Neuroscience.

[2]  Yuqing Dong,et al.  Caenorhabditis elegans HCF-1 Functions in Longevity Maintenance as a DAF-16 Regulator , 2008, PLoS biology.

[3]  T. Johnson,et al.  daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans , 2001, Current Biology.

[4]  Cori Bargmann,et al.  Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans , 2003, Nature.

[5]  C. Kenyon,et al.  daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. , 1997, Science.

[6]  B. Nilius,et al.  TRP channels. , 2012, Comprehensive Physiology.

[7]  G. Ruvkun,et al.  The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans , 1997, Nature.

[8]  H. Aguilaniu,et al.  PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans , 2007, Nature.

[9]  M. Ohkura,et al.  A high signal-to-noise Ca2+ probe composed of a single green fluorescent protein , 2001, Nature Biotechnology.

[10]  T. Hunter,et al.  SMK-1, an Essential Regulator of DAF-16-Mediated Longevity , 2006, Cell.

[11]  Jennifer M. A. Tullet,et al.  Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans , 2008, Cell.

[12]  P. Sternberg,et al.  A C. elegans stretch receptor neuron revealed by a mechanosensitive TRP channel homologue , 2006, Nature.

[13]  J. Apfeld,et al.  Regulation of lifespan by sensory perception in Caenorhabditis elegans , 1999, Nature.

[14]  J. Freedman,et al.  Structure and Expression of the Caenorhabditis elegans Protein Kinase C2 Gene , 1997, The Journal of Biological Chemistry.

[15]  Peter G. Schultz,et al.  Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines , 2007, Nature.

[16]  G. Ruvkun,et al.  Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. , 1998, Genes & development.

[17]  X. Z. S. Xu,et al.  Function and regulation of TRP family channels in C. elegans , 2009, Pflügers Archiv - European Journal of Physiology.

[18]  C. Kenyon,et al.  Tissue-Specific Activities of C. elegans DAF-16 in the Regulation of Lifespan , 2003, Cell.

[19]  P. Sternberg,et al.  Inositol Trisphosphate Mediates a RAS-Independent Response to LET-23 Receptor Tyrosine Kinase Activation in C. elegans , 1998, Cell.

[20]  Kaveh Ashrafi,et al.  A TRPV Channel Modulates C. elegans Neurosecretion, Larval Starvation Survival, and Adult Lifespan , 2008, PLoS genetics.

[21]  Albert-László Barabási,et al.  Genome-scale analysis of in vivo spatiotemporal promoter activity in Caenorhabditis elegans , 2007, Nature Biotechnology.

[22]  Peter McIntyre,et al.  ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures , 2003, Cell.

[23]  A. Fleig,et al.  TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD. , 2006, Cellular signalling.

[24]  Donald L Riddle,et al.  DAF-9, a cytochrome P450 regulating C. elegans larval development and adult longevity. , 2002, Development.

[25]  Michael R. Green,et al.  Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation , 2006, Nature Genetics.

[26]  R. Vennekens,et al.  TRPA1 acts as a cold sensor in vitro and in vivo , 2009, Proceedings of the National Academy of Sciences.

[27]  Charles S. Zuker,et al.  The Coding of Temperature in the Drosophila Brain , 2011, Cell.

[28]  D. McKemy,et al.  The Nociceptor Ion Channel TRPA1 Is Potentiated and Inactivated by Permeating Calcium Ions* , 2008, Journal of Biological Chemistry.

[29]  Koutarou D. Kimura,et al.  daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. , 1997, Science.

[30]  Piotr Mikolajczyk,et al.  A+A+C , 1964 .

[31]  G. Ruvkun,et al.  Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. , 2009, Genes & development.

[32]  James H. Thomas,et al.  Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM Kinase II , 1999, Nature.

[33]  C. Kenyon,et al.  Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling , 2001, Nature Genetics.

[34]  M. Klass,et al.  Aging in the nematode Caenorhabditis elegans: Major biological and environmental factors influencing life span , 1977, Mechanisms of Ageing and Development.

[35]  W. Ryu,et al.  The CMK-1 CaMKI and the TAX-4 Cyclic Nucleotide-Gated Channel Regulate Thermosensory Neuron Gene Expression and Function in C. elegans , 2004, Current Biology.

[36]  L. Guarente,et al.  Two neurons mediate diet-restriction-induced longevity in C. elegans , 2007, Nature.

[37]  Zhaoyang Feng,et al.  Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans , 2009, Neurobiology of Aging.

[38]  C. Kenyon.  The genetics of ageing , 2010, Nature.

[39]  Raphaelle Winsky-Sommerer,et al.  Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span , 2006, Science.

[40]  D. Julius,et al.  TRP channel activation by reversible covalent modification , 2006, Proceedings of the National Academy of Sciences.

[41]  O. Hobert,et al.  A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans. , 2001, Development.

[42]  Cynthia Kenyon,et al.  Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor , 2003, Science.

[43]  D. McKemy,et al.  Identification of a cold receptor reveals a general role for TRP channels in thermosensation , 2002, Nature.

[44]  W. Schafer,et al.  Caenorhabditis elegans TRPA-1 functions in mechanosensation , 2007, Nature Neuroscience.

[45]  B. Conti,et al.  Considerations on Temperature, Longevity and Aging , 2008, Cellular and Molecular Life Sciences.

[46]  Gary Ruvkun,et al.  DAF-16 Target Genes That Control C. elegans Life-Span and Metabolism , 2003, Science.

[47]  Matthias Blüher,et al.  Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue , 2003, Science.

[48]  S. Mitani,et al.  EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity. , 2010, Cell metabolism.

[49]  R. Baumeister,et al.  C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. , 2004, Developmental cell.

[50]  J. Barry,et al.  cis regulatory requirements for hypodermal cell-specific expression of the Caenorhabditis elegans cuticle collagen gene dpy-7 , 1997, Molecular and cellular biology.

[51]  Wei Li,et al.  A C. elegans Model of Nicotine-Dependent Behavior: Regulation by TRP-Family Channels , 2006, Cell.

[52]  D L Riddle,et al.  daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. , 2000, Genes & development.

[53]  J. Loeb,et al.  Is There a Temperature Coefficient for the Duration of Life? , 1916, Proceedings of the National Academy of Sciences of the United States of America.

[54]  D. McKemy,et al.  Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 , 2004, Nature.

[55]  Linda Partridge,et al.  Extending Healthy Life Span—From Yeast to Humans , 2010, Science.

[56]  J. McGhee,et al.  Spatial control of gut-specific gene expression during Caenorhabditis elegans development. , 1991, Science.

[57]  R. Waterston,et al.  Proper expression of myosin genes in transgenic nematodes. , 1989, The EMBO journal.

[58]  A. Patapoutian,et al.  Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin , 2004, Neuron.

[59]  P. McIntyre,et al.  A TRP Channel that Senses Cold Stimuli and Menthol , 2002, Cell.

[60]  S. Earley,et al.  Endothelium-Dependent Cerebral Artery Dilation Mediated by TRPA1 and Ca2+-Activated K+ Channels , 2009, Circulation research.

[61]  J. Cypser,et al.  Mortality shifts in Caenorhabditis elegans: remembrance of conditions past , 2009, Aging cell.

[62]  S. W. Oh,et al.  JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. , 2005, Proceedings of the National Academy of Sciences of the United States of America.