Article

Genetic variation in glia–neuron signalling modulates ageing rate

Received:
Accepted:
Published online:

Abstract

The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1-dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia–neuron signalling modulates the rate of ageing in C. elegans.

  • Subscribe to Nature for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , , , & The hallmarks of aging. Cell 153, 1194–1217 (2013)

  2. 2.

    et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001)

  3. 3.

    & Genetics of longevity in model organisms: debates and paradigm shifts. Annu. Rev. Physiol. 75, 621–644 (2013)

  4. 4.

    The genetics of ageing. Nature 464, 504–512 (2010)

  5. 5.

    et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419, 808–814 (2002)

  6. 6.

    , , , & Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006)

  7. 7.

    , , & Mutations that increase the life span of C. elegans inhibit tumor growth. Science 313, 971–975 (2006)

  8. 8.

    & Does longer lifespan mean longer healthspan? Trends Cell Biol. 26, 565–568 (2016)

  9. 9.

    , , , & Longevity manipulations differentially affect serotonin/dopamine level and behavioral deterioration in aging Caenorhabditis elegans. J. Neurosci. 34, 3947–3958 (2014)

  10. 10.

    et al. The Drosophila DCO mutation suppresses age-related memory impairment without affecting lifespan. Nat. Neurosci. 10, 478–484 (2007)

  11. 11.

    et al. Whole-genome sequencing of a healthy aging cohort. Cell 165, 1002–1011 (2016)

  12. 12.

    , , & Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc. Natl Acad. Sci. USA 112, E277–E286 (2015)

  13. 13.

    Aging research—where do we stand and where are we going? Cell 159, 15–19 (2014)

  14. 14.

    & Variation within and among species in gene expression: raw material for evolution. Mol. Ecol. 15, 1197–1211 (2006)

  15. 15.

    & Quantitative genetic analyses of complex behaviours in Drosophila. Nat. Rev. Genet. 5, 838–849 (2004)

  16. 16.

    & Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 94, 679–689 (1998)

  17. 17.

    , & Selection at linked sites shapes heritable phenotypic variation in C. elegans. Science 330, 372–376 (2010)

  18. 18.

    et al. Balancing selection shapes density-dependent foraging behaviour. Nature 539, 254–258 (2016)

  19. 19.

    & Genetic contributions to behavioural diversity at the gene-environment interface. Nat. Rev. Genet. 12, 809–820 (2011)

  20. 20.

    & npr-1 regulates foraging and dispersal strategies in Caenorhabditis elegans. Curr. Biol. 18, 1694–1699 (2008)

  21. 21.

    & Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans. J. Neurosci. 13, 5407–5417 (1993)

  22. 22.

    , & Peptide hormone precursor processing: getting sorted? Mol. Cell. Endocrinol. 156, 1–6 (1999)

  23. 23.

    & Genetic analysis of endocytosis in Caenorhabditis elegans: coelomocyte uptake defective mutants. Genetics 159, 133–145 (2001)

  24. 24.

    et al. Gα 16/z chimeras efficiently link a wide range of G protein-coupled receptors to calcium mobilization. J. Biomol. Screen. 8, 39–49 (2003)

  25. 25.

    & in WormBook (ed. The C. elegans Research Community) (Wormbook, 2006)

  26. 26.

    et al. Dramatic fertility decline in aging C. elegans males is associated with mating execution deficits rather than diminished sperm quality. Exp. Gerontol. 48, 1156–1166 (2013)

  27. 27.

    , , & . Behavioral decay in aging male C. elegans correlates with increased cell excitability. Neurobiol. Aging 33, 1483.e5–1483.e23 (2012)

  28. 28.

    , & Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000)

  29. 29.

    & Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001)

  30. 30.

    & SIR-2.1 integrates metabolic homeostasis with the reproductive neuromuscular excitability in early aging male Caenorhabditis elegans. eLife 3, e01730 (2014)

  31. 31.

    et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013)

  32. 32.

    & NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014)

  33. 33.

    & Mitochondrial dysfunction and longevity in animals: untangling the knot. Science 350, 1204–1207 (2015)

  34. 34.

    & Metabolism and the UPR(mt). Mol. Cell 61, 677–682 (2016)

  35. 35.

    et al. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J. Cell Sci. 117, 4055–4066 (2004)

  36. 36.

    , , , & Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Genetics 174, 229–239 (2006)

  37. 37.

    A new test for detecting recent positive selection that is free from the confounding impacts of demography. Mol. Biol. Evol. 28, 365–375 (2011)

  38. 38.

    et al. Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity. Nat. Genet. 44, 285–290 (2012)

  39. 39.

    Minimum mutation fits to a given tree. Biometrics 29, 53–65 (1973)

  40. 40.

    Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (1957)

  41. 41.

    , & Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 139, 1247–1259 (1995)

  42. 42.

    et al. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 150, 129–155 (1998)

  43. 43.

    ., . & Fitness cost of extended lifespan in Caenorhabditis elegans. Proc. R. Soc. Lond. B 271, 2523–2526 (2004)

  44. 44.

    , & Caenorhabditis elegans integrates food and reproductive signals in lifespan determination. Aging Cell 6, 715–721 (2007)

  45. 45.

    & Neuropeptide Y: an anti-aging player? Trends Neurosci. 38, 701–711 (2015)

  46. 46.

    et al. Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proc. Natl Acad. Sci. USA 112, E1642–E1651 (2015)

  47. 47.

    et al. Altered intracellular processing and release of neuropeptide Y due to leucine 7 to proline 7 polymorphism in the signal peptide of preproneuropeptide Y in humans. FASEB J. 15, 1242–1244 (2001)

  48. 48.

    , , & Engineering the Caenorhabditis elegans genome using Cas9-triggered homologous recombination. Nat. Methods 10, 1028–1034 (2013)

  49. 49.

    et al. Improving brightness and photostability of green and red fluorescent proteins for live cell imaging and FRET reporting. Sci. Rep. 6, 20889 (2016)

  50. 50.

    C. elegans: A Practical Approach (Oxford Univ. Press, 1999)

  51. 51.

    , , , & mls-2 and vab-3 control glia development, hlh-17/Olig expression and glia-dependent neurite extension in C. elegans. Development 135, 2263–2275 (2008)

  52. 52.

    , , , & PROS-1/Prospero is a major regulator of the glia-specific secretome controlling sensory-neuron shape and function in C. elegans. Cell Reports 15, 550–562 (2016)

  53. 53.

    , , & Direct conversion of C. elegans germ cells into specific neuron types. Science 331, 304–308 (2011)

  54. 54.

    et al. A gut-to-pharynx/tail switch in embryonic expression of the Caenorhabditis elegans ges-1 gene centers on two GATA sequences. Dev. Biol. 170, 397–419 (1995)

  55. 55.

    , , & Mechanosensory signalling in C. elegans mediated by the GLR-1 glutamate receptor. Nature 378, 78–81 (1995)

  56. 56.

    , , , & Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403, 560–564 (2000)

  57. 57.

    , , & Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 3264–3269 (2002)

  58. 58.

    , , , & C. elegans mutant identification with a one-step whole-genome-sequencing and SNP mapping strategy. PLoS One 5, e15435 (2010)

  59. 59.

    et al. Single-copy insertion of transgenes in Caenorhabditis elegans. Nat. Genet. 40, 1375–1383 (2008)

  60. 60.

    et al. Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior. Science 338, 540–543 (2012)

  61. 61.

    , , , & Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate. J. Neurosci. 24, 7427–7434 (2004)

  62. 62.

    et al. Approaches to identify endogenous peptides in the soil nematode Caenorhabditis elegans. Methods Mol. Biol. 615, 29–47 (2010)

  63. 63.

    & Temporal control of cell-specific transgene expression in Caenorhabditis elegans. Genetics 176, 2651–2655 (2007)

  64. 64.

    et al. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165, 1209–1223 (2016)

  65. 65.

    , , , & Enhanced neuronal RNAi in C. elegans using SID-1. Nat. Methods 7, 554–559 (2010)

  66. 66.

    et al. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000)

  67. 67.

    & . Numerical Taxonomy; The Principles and Practice of Numerical Classification (W. H. Freeman, 1973)

  68. 68.

    , & Prospects for inferring very large phylogenies by using the neighbor-joining method. Proc. Natl Acad. Sci. USA 101, 11030–11035 (2004)

  69. 69.

    & The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425 (1987)

  70. 70.

    , & Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol. Bioinform. Online 1, 47–50 (2007)

  71. 71.

    Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123, 585–595 (1989)

Download references

Acknowledgements

We thank M.-M. Poo, X. Yu and D. Chen for critical reading of the manuscript; H.-W. Zhu and L.-S. Wang for mass spectrometry analysis; Y. H. Wong and J. Chu for providing the Gα16 and mRuby3 plasmids, respectively; Z. Chen and X. Bai for experimental assistance; and the Caenorhabditis Genetics Center for providing strains. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB 13000000) and the National Natural Science Foundation of China (31471149 and 81527901).

Author information

Author notes

    • Jiang-An Yin
    •  & Ge Gao

    These authors contributed equally to this work.

Affiliations

  1. Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    • Jiang-An Yin
    • , Ge Gao
    • , Xi-Juan Liu
    • , Kai Li
    • , Xin-Lei Kang
    •  & Shi-Qing Cai
  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    • Ge Gao
    •  & Zi-Qian Hao
  3. CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    • Zi-Qian Hao
    •  & Hai-Peng Li
  4. Core Facility of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China

    • Hong Li
  5. Core Facility Center of the Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China

    • Yuan-Hong Shan
    •  & Wen-Li Hu

Authors

  1. Search for Jiang-An Yin in:

  2. Search for Ge Gao in:

  3. Search for Xi-Juan Liu in:

  4. Search for Zi-Qian Hao in:

  5. Search for Kai Li in:

  6. Search for Xin-Lei Kang in:

  7. Search for Hong Li in:

  8. Search for Yuan-Hong Shan in:

  9. Search for Wen-Li Hu in:

  10. Search for Hai-Peng Li in:

  11. Search for Shi-Qing Cai in:

Contributions

J.-A.Y. and G.G. performed most of the experiments. X.-J.L. performed male mating, locomotion and male retention assays. Z.-Q.H. and H.-P.L. performed population genetic analysis. K.L. carried out the endoplasmic reticulum fractionation assay. X.-L.K. conducted the male retention assay and helped to determine RGBA-1-2b. H.L., Y.-H.S., and W.-L.H. helped to conduct HPLC and mass spectrometry analysis of neuropeptides. S.-Q.C., J.-A.Y., and G.G. designed the study. S.-Q.C., J.-A.Y., G.G., and H.-P.L. analysed data and wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shi-Qing Cai.

Reviewer Information Nature thanks L. Bianchi, P. McGrath and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Statistical Test Results, Table and Figure Sample Sizes, Sequences for npr-28 RNAi and ubl-5 RNAi and Supplementary Figure 1, the uncropped blots.

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Data

    This file contains Supplementary Table 1.