Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition

Abstract

Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Accumulation of NK cells in the dentate gyrus of normal aged human brains.
Fig. 2: NK cells in the brain and peripheral organs of young and aged mice.
Fig. 3: Single-cell profiling identifies increased activation and cytotoxicity of NK cells in the aged dentate gyrus.
Fig. 4: Fate mapping of NK cells reveals that local proliferation contributes to NK cell accumulation in the aged dentate gyrus.
Fig. 5: IL-27 derived from aged neuroblasts supports NK cells.
Fig. 6: Aged dentate gyrus neuroblasts express cellular senescence signatures and produce SASP factors.
Fig. 7: NK cells eliminate aged neuroblasts.
Fig. 8: Altered expression of MHC class I molecules in aged neuroblasts and effects of NK cell removal on cognitive function in aged mice.

Data availability

Data were uploaded to Mendeley Dataset: https://doi.org/10.17632/bbzd4mwt8r.1. Bulk-RNA and single-cell RNA-sequencing data have been deposited in the NCBI Gene Expression Omnibus with the accession number GSE157772. Other information that supports the findings of this study is available from the corresponding author upon request. Source data are provided with this paper.

References

  1. 1.

    Dorshkind, K., Montecino-Rodriguez, E. & Signer, R. A. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 9, 57–62 (2009).

    CAS  PubMed  Google Scholar 

  2. 2.

    Gabuzda, D. & Yankner, B. A. Physiology: inflammation links ageing to the brain. Nature 497, 197–198 (2013).

    CAS  PubMed  Google Scholar 

  3. 3.

    Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Gardener, H., Wright, C. B., Rundek, T. & Sacco, R. L. Brain health and shared risk factors for dementia and stroke. Nat. Rev. Neurol. 11, 651–657 (2015).

    CAS  PubMed  Google Scholar 

  7. 7.

    Bauernfeind, F., Niepmann, S., Knolle, P. A. & Hornung, V. Aging-associated TNF production primes inflammasome activation and NLRP3-related metabolic disturbances. J. Immunol. 197, 2900–2908 (2016).

    CAS  PubMed  Google Scholar 

  8. 8.

    Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Kerur, N. et al. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat. Med. 24, 50–61 (2018).

    CAS  PubMed  Google Scholar 

  10. 10.

    Ritzel, R. M. et al. Age-associated resident memory CD8 T cells in the central nervous system are primed to potentiate inflammation after ischemic brain injury. J. Immunol. 196, 3318–3330 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Stichel, C. C. & Luebbert, H. Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol. Aging 28, 1507–1521 (2007).

    CAS  PubMed  Google Scholar 

  12. 12.

    Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Radjavi, A., Smirnov, I., Derecki, N. & Kipnis, J. Dynamics of the meningeal CD4+ T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol. Psychiatry 19, 531–533 (2014).

    CAS  PubMed  Google Scholar 

  14. 14.

    Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275 (2006).

    CAS  PubMed  Google Scholar 

  15. 15.

    Ahmed, R. M. et al. Physiological changes in neurodegeneration—mechanistic insights and clinical utility. Nat. Rev. Neurol. 14, 259–271 (2018).

    CAS  PubMed  Google Scholar 

  16. 16.

    Long, E. O., Kim, H. S., Liu, D., Peterson, M. E. & Rajagopalan, S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol. 31, 227–258 (2013).

    CAS  PubMed  Google Scholar 

  17. 17.

    Shi, F. D., Ljunggren, H. G., La Cava, A. & Van Kaer, L. Organ-specific features of natural killer cells. Nat. Rev. Immunol. 11, 658–671 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Yokoyama, W. M., Kim, S. & French, A. R. The dynamic life of natural killer cells. Annu. Rev. Immunol. 22, 405–429 (2004).

    CAS  PubMed  Google Scholar 

  19. 19.

    Sojka, D. K. et al. Cutting edge: local proliferation of uterine tissue-resident NK cells during decidualization in mice. J. Immunol. 201, 2551–2556 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Souza-Fonseca-Guimaraes, F., Cursons, J. & Huntington, N. D. The emergence of natural killer cells as a major target in cancer immunotherapy. Trends Immunol. 40, 142–158 (2019).

    CAS  PubMed  Google Scholar 

  21. 21.

    Gan, Y. et al. Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc. Natl Acad. Sci. USA 111, 2704–2709 (2014).

    CAS  PubMed  Google Scholar 

  22. 22.

    Liu, Q. et al. Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations. Immunity 46, 474–487 (2017).

    CAS  PubMed  Google Scholar 

  23. 23.

    Liu, Q. et al. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat. Neurosci. 19, 243–252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Chapple, R. H. et al. Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis. Blood Adv. 2, 1220–1228 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gazit, R. et al. Fgd5 identifies hematopoietic stem cells in the murine bone marrow. J. Exp. Med. 211, 1315–1331 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Chong, W. P. et al. NK–DC crosstalk controls the autopathogenic Th17 response through an innate IFN-ɣ–IL-27 axis. J. Exp. Med. 212, 1739–1752 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Liu, L. et al. IL-27-mediated activation of natural killer cells and inflammation produced antitumour effects for human oesophageal carcinoma cells. Scand. J. Immunol. 68, 22–29 (2008).

    CAS  PubMed  Google Scholar 

  28. 28.

    Matsui, M. et al. Interleukin-27 activates natural killer cells and suppresses NK-resistant head and neck squamous cell carcinoma through inducing antibody-dependent cellular cytotoxicity. Cancer Res. 69, 2523–2530 (2009).

    CAS  PubMed  Google Scholar 

  29. 29.

    Liu, J. et al. Prospective separation and transcriptome analyses of cortical projection neurons and interneurons based on lineage tracing by Tbr2 (Eomes)-GFP/Dcx-mRFP reporters. Dev. Neurobiol. 76, 587–599 (2016).

    CAS  PubMed  Google Scholar 

  30. 30.

    Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

    CAS  Google Scholar 

  34. 34.

    Maynard, S., Fang, E. F., Scheibye-Knudsen, M., Croteau, D. L. & Bohr, V. A. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb. Perspect. Med. 5, a025130 (2015).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35 (2011).

    CAS  PubMed  Google Scholar 

  37. 37.

    Fan, X., Wheatley, E. G. & Villeda, S. A. Mechanisms of hippocampal aging and the potential for rejuvenation. Annu. Rev. Neurosci. 40, 251–272 (2017).

    CAS  PubMed  Google Scholar 

  38. 38.

    Kronenberg, G. et al. Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol. Aging 27, 1505–1513 (2006).

    PubMed  Google Scholar 

  39. 39.

    Chow, C. L., Guo, W., Trivedi, P., Zhao, X. & Gubbels, S. P. Characterization of a unique cell population marked by transgene expression in the adult cochlea of nestin-CreERT2/tdTomato-reporter mice. J. Comp. Neurol. 523, 1474–1487 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Franco, S. J. et al. Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337, 746–749 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Bernardini, G. et al. CCL3 and CXCL12 regulate trafficking of mouse bone marrow NK cell subsets. Blood 111, 3626–3634 (2008).

    CAS  PubMed  Google Scholar 

  44. 44.

    Ma, A., Koka, R. & Burkett, P. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu. Rev. Immunol. 24, 657–679 (2006).

    CAS  PubMed  Google Scholar 

  45. 45.

    Raulet, D. H. Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. 3, 781–790 (2003).

    CAS  PubMed  Google Scholar 

  46. 46.

    Glynn, M. W. et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat. Neurosci. 14, 442–451 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Goddard, C. A., Butts, D. A. & Shatz, C. J. Regulation of CNS synapses by neuronal MHC class I. Proc. Natl Acad. Sci. USA 104, 6828–6833 (2007).

    PubMed  Google Scholar 

  48. 48.

    Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Pape, K., Tamouza, R., Leboyer, M. & Zipp, F. Immunoneuropsychiatry—novel perspectives on brain disorders. Nat. Rev. Neurol. 15, 317–328 (2019).

    PubMed  Google Scholar 

  50. 50.

    Chapple, R. H. et al. Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis. Blood Adv. 2, 1220–1228 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Gan, Y. et al. Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc. Natl Acad. Sci. USA 111, 2704–2709 (2014).

    CAS  PubMed  Google Scholar 

  52. 52.

    Liu, Q. et al. Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations. Immunity 46, 474–487 (2017).

    CAS  PubMed  Google Scholar 

  53. 53.

    Liu, Q. et al. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat. Neurosci. 19, 243–252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank H. Li, Y. Feng, Y. Li, X. Yang, M. Yuan, Y. Xiu, J. Fan, Y. Zhang and H. Zhao for technical assistance. We thank S. X. Shi for editorial assistance. This study was supported in part by the National Science Foundation of China (91949208, 91642205, 81830038, 81971094 and 81771274); the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China; and the National Key Research and Development Program of China (2018YFC1312200).

Author information

Affiliations

Authors

Contributions

Q.L. and F.-D.S. formulated the concept and designed the studies. W.-N.J., K.S., W.H. and J.-H.S. performed the experiments. W.-N.J., K.S. and Q.L. analyzed the results. Q.L., W.-N.J., L.V.K. and F.-D.S. interpreted the results. Q.L., W.-N.J., L.V.K. and F.-D.S. wrote and edited the manuscript.

Corresponding author

Correspondence to Qiang Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Neuroscience thanks Valery Krizhanovsky, Hongjun Song, 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

Extended Data Fig. 1 NK cells reside within the parenchyma of aged human and mouse brains.

a, Immunofluorescence staining of aged human brain sections containing dentate gyrus shows that NK cells do not co-localize with endothelial cells (CD31+). Images are representative of 5 subjects (72 ± 6.7 years) with similar results. Scale bars: 40 µm (inset: 20 µm). b, Immunofluorescence staining of wild type male aged (18 months) mouse brain sections containing dentate gyrus shows that NK cells do not co-localize with endothelial cells (CD31+). Images are representative of 5 aged (18 months) mice. Scale bars: 40 µm (inset: 20 µm).

Extended Data Fig. 2 Single cell transcriptome analysis reveals increased NK cell activity in aged mouse brains.

CD45high immune cells were sorted by flow cytometry from spleen and dentate gyrus tissues of wild type male young (3 months) and aged (18 months) mice. Subsequently, single-cell RNA-sequencing was performed using the 10x Genomics Chromium platform. Unsupervised clustering and t-distributed stochastic neighbor embedding (tSNE) projections were performed on 6,422 cells from young spleen, 6,649 cells from young dentate gyrus, 5,521 cells from aged spleen, and 7,299 cells from aged dentate gyrus. a, Unsupervised hierarchical clustering was performed on CD45high cells obtained from aged spleen and aged dentate gyrus. Heatmap shows markedly altered gene expression in CD45high cells obtained from aged dentate gyrus versus aged spleen. b, Violin plots show the indicated immune cell subsets including NK cells in aged (18 months) dentate gyrus. c. Volcano plot shows that genes expressing NK cell signatures were enriched in the aged (18 months) dentate gyrus.

Extended Data Fig. 3 RNA sequencing reveals differentially expressed gene clusters in neuroblasts from young and aged dentate gyrus.

Single-cell suspensions were prepared from dissected dentate gyrus of male young (3 months) and aged (18 months) DCX-mRFP reporter mice. Thereafter, mRFP+ neuroblasts were sorted via flow cytometry. a, Heat map shows RNA transcriptomes of 1,101 differentially expressed genes from neuroblasts of young and aged dentate gyrus. The relative abundance of transcripts is indicated by the color (red, high; blue, low). b, Enrichment analysis was performed to measure the significance of altered gene expression by Gene Ontology annotations. The enrichment of pathways was analyzed by Fisher exact test. c, Real-time PCR analysis of selected genes that reflect neuroblast functions, such as cell growth and death, cell cycle, immune regulation, etc, in aged neuroblasts versus young neuroblasts. n = 3 per group. d, Bubble diagram displays enriched pathways based on function in the KEGG database. Pathway categories with FDR <0.05 were reported. e. KEGG database was used to build the network of differentially expressed genes of aged/young neuroblasts according to the relationship among mRNA, miRNA and proteins in the database. Error bars represent s.e.m.

Extended Data Fig. 4 Aged neuroblasts express SASP and cell cycle arrest genes.

a, Single-cell suspensions were prepared from dissected young (3 months) and aged (18 months) dentate gyrus tissues of male wild type mice. Thereafter, several cell types in the aged dentate gyrus were identified by flow cytometry using antibodies to surface markers. Quantitative RT-PCR analysis of SASP and cell cycle gene expression in isolated cell types from young and aged dentate gyrus, including neurons (CD15CD29lowCD24hi), microglia (CD11b+CD45int), astrocytes (GLAST+), neural stem cells (GLAST+EGFR+CD24) and neuroblasts (GLASTEGFRCD24low). Neuroblasts are a major cell population that possess the most upregulated genes among SASP components and cell cycle arrest genes (outlined in green), as well as upregulated Il27 gene (outlined in green). b, Bar graph shows quantification of IL-27 mRNA levels in cells from young and aged dentate gyrus. **p<0.01 by two-tailed unpaired Student’s t-test. p=0.0023, t=6.934, df=4. c, Immunostaining shows IL-27-expressing neuroblasts in aged (18 months) dentate gyrus, but not in young (3 months) dentate gyrus. Scale bar: 40 µm. n = 8 per group. **p<0.01 by two-tailed unpaired Student’s t-test. p=0.002, t=3.777, df=14. Error bars represent s.e.m.

Extended Data Fig. 5 Aged neuroblasts induce NK cell expansion in vitro.

Single-cell suspensions were prepared from dissected young (3 months) and aged (18 months) dentate gyrus tissues of male wild type mice. NK cells were harvested from spleen of young (3 months) mice. Co-culture experiments were performed using NK cells and FACS-sorted dentate gyrus cell types including neurons (CD15-CD29lowCD24hi), microglia (CD11b+CD45int), astrocytes (GLAST+), neural stem cells (GLAST+EGFR+ CD24) and neuroblasts (GLASTEGFRCD24low). NK cell proliferation was assessed by measuring Ki67-expressing NK cells using flow cytometry. n = 4 per group. **p<0.01 by two-tailed unpaired Student’s t-test. p=0.0101, t=3.702, df=6. Error bars represent s.e.m.

Extended Data Fig. 6 Characterization of the senescence status of neuroblasts.

a, Immunostaining and quantification show expression of the senescence marker P16 in DCX+ cells of male young (3 months) and aged (18 months) mice. Scale bar: 20 µm. n = 6 per group. *p<0.05 by two-tailed unpaired Student’s t-test. p=0.0119, t=3.069, df=10. b, Immunostaining and quantification show BrdU incorporation in DCX+ cells of young and aged mice. Scale bar: 20 µm. n = 6 per group. *p<0.05 by two-tailed unpaired Student’s t-test. p=0.0103, t=3.153, df=10. c. The proportion of aged neuroblasts in the G1/G0, S and G2/M cell cycle phases of young and aged neuroblasts was measured by flow cytometry. n = 5 per group. *p<0.05 by two-tailed unpaired Student’s t-test. p=0.045, t=2.374, df=8. d, RNA-sequencing of aged neuroblasts reveals dysregulated expression of genes related to DNA damage response (DDR). e, KEGG database was used to build the network of differentially expressed DDR genes in aged (18 months) neuroblasts according to the relationship among mRNA, miRNA and proteins in the database. Data are representative of three independent experiments. Error bars represent s.e.m.

Extended Data Fig. 7 Senescence of aged neuroblasts increases NK cell number and activity.

Single-cell suspensions were prepared from dentate gyrus of male young (3 months) and aged (18 months) DCX-mRFP reporter mice. Thereafter, mRFP+ neuroblasts were sorted using flow cytometry and cultured in vitro. a, Real-time PCR and western blotting assessment of senescence markers (P16, P21 and P53) at mRNA and protein levels in cultured neuroblasts receiving treatment with mTOR inhibitor rapamycin or vehicle for 48 h. *p<0.05, **p<0.01 by two-tailed unpaired Student’s t-test. Left: n = 5 per group. P16: p=0.006, t=3.705, df=8; P21: p=0.0237, t=2.786, df=8; P53: p=0.0007, t=5.324, df=8. Right: n = 3 per group. P16: p=0.0324, t=3.217, df=4; P53: p=0.0073, t=5.037, df=4. b, Flow cytometry analysis of senescence-associated β-galactosidase (β-gal) expression in groups of cultured young (3 months) and aged (18 months) neuroblasts receiving indicated treatment for 48 h. n = 4 per group. **p<0.01 by one-way ANOVA. F2,9=20.01. Aged + vehicle vs. aged + rapamycin, p=0.002, q=7.012, df=9; aged + vehicle vs. aged + mTOR siRNA, p=0.0006, q=8.319, df=9. c, Flow cytometry analysis of IL-27 expression in groups of cultured young (3 months) and aged (18 months) neuroblasts receiving indicated treatment for 48 h. n = 8 per group. **p< 0.01 by one-way ANOVA. F2,21=11.0. Aged + vehicle vs. aged + rapamycin, p=0.0022, q=5.525, df=21; aged + vehicle vs. aged + mTOR siRNA, p=0.0011, q=5.976, df=21. d, Flow cytometry analysis of expression of NKG2D or Granzyme B in groups of NK cells after coculture with aged (18 months) neuroblasts receiving indicated treatment for 48 h. n = 8 per group. **p<0.01 by one-way ANOVA. NKG2D: F3,28=15.22. Aged + vehicle vs. aged + rapamycin, p=0.0045, q=5.276, df=28; aged + vehicle vs. aged + mTOR siRNA, p<0.001, q=7.413, df=28; aged + vehicle vs. aged + IL-27 siRNA, p<0.001, q=8.927, df=28. Granzyme B: F3,28=8.171. Aged + vehicle vs. aged + rapamycin, p=0.0094, q=4.865, df=28; aged + vehicle vs. aged + mTOR siRNA, p=0.0015, q=5.873, df=28; aged + vehicle vs. aged + IL-27 siRNA, p=0.001, q=6.106, df=28. Data are representative of three independent experiments. Error bars represent s.e.m.

Source data

Extended Data Fig. 8 Antibody depletion of NK cells in aged mice.

Anti-NK1.1 mAb (PK136) was used to deplete NK cells. 100 μg of anti-NK1.1 mAb was injected i.p. into each mouse every 5 days until the end of experiments. Single-cell suspensions were prepared from blood or brain tissues of male aged mice receiving anti-NK1.1 mAb or IgG control. a-b, Flow cytometry analysis of NK cell counts in blood (a) and brain (b) of aged (18 months) mice receiving anti-NK1.1 mAb or IgG control. n = 5 per group. **p<0.01 by two-tailed unpaired Student’s t-test. In a, p<0.0001, t=10.76, df=8. In b, p=0.0002, t=6.632, df=8. Data are representative of three independent experiments. Error bars represent s.e.m.

Extended Data Fig. 9 Absence of NKT cells does not affect neurogenesis and cognitive function in aged mice.

a, Immunostaining reveals the counts of Nestin+ neural stem cells and DCX+ neuroblasts in dentate gyrus tissues of male aged (18 months) wild type and CD1d-/- (devoid of NKT cells) mice. n = 6 per group. b, Spatial memory performance was measured in aged (18 months) wild type and CD1d-/- mice using Morris water maze. Bar graph shows swimming velocity in indicated groups of mice. n = 6 per group. c, Cumulative data plots show swimming distance of aged wild type and CD1d-/- mice. Swimming distance summary was from beginning to the end of each trial session from day 1 to 4. Images show swimming traces of indicated groups during the probe test at day 5. n = 14 per group. d-e, Quantification of time spent in the northeast quadrant during the probe test (d) and target-platform crossing times (e). In d-e, n = 14 mice per group. Data are representative of three independent experiments. Error bars represent s.e.m.

Extended Data Fig. 10 Reduced apoptosis of dentate gyrus neuroblasts in aged mice receiving anti-NK1.1-mAb.

a-b, Immunostaining (a) and quantification (b) show Caspase-3+DCX+cells in the aged (18 months) dentate gyrus of male wild type mice receiving one-month treatment of anti-NK1.1 mAb or IgG control. Scale bar: 40 µm. n = 6 mice per group. *p<0.05 by two-tailed unpaired Student’s t-test. p=0.0186, t=2.805, df=10. Data are representative of three independent experiments. Error bars represent s.e.m.

Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2 and Supplementary Table 1.

Reporting Summary

Supplementary Data

Antibody list.

Source data

Source Data Fig. 6

Unprocessed western blots of Fig. 6e.

Source Data Extended Data Fig. 7

Unprocessed western blots of Extended Fig. 7a.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jin, WN., Shi, K., He, W. et al. Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition. Nat Neurosci 24, 61–73 (2021). https://doi.org/10.1038/s41593-020-00745-w

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing