Research Paper Volume 11, Issue 16 pp 6175—6198
Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy
- 1 Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, UNAM, Mexico City 04510, México
- 2 Departamento de Neuropatología, División de Neurociencias, Instituto de Fisiología Celular, UNAM, Mexico City 04510, México
- 3 Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Mexico City 09340, México
Received: March 12, 2019 Accepted: August 9, 2019 Published: August 30, 2019https://doi.org/10.18632/aging.102181
How to Cite
Copyright © 2019 Moreno-Blas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY 3.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Senescent cells accumulate in various tissues and organs with aging altering surrounding tissue due to an active secretome, and at least in mice their elimination extends healthy lifespan and ameliorates several chronic diseases. Whether all cell types senesce, including post-mitotic cells, has been poorly described mainly because cellular senescence was defined as a permanent cell cycle arrest. Nevertheless, neurons with features of senescence have been described in old rodent and human brains. In this study we characterized an in vitro model useful to study the molecular basis of senescence of primary rat cortical cells that recapitulates senescent features described in brain aging. We found that in long-term cultures, rat primary cortical neurons displayed features of cellular senescence before glial cells did, and developed a functional senescence-associated secretory phenotype able to induce paracrine premature senescence of mouse embryonic fibroblasts but proliferation of rat glial cells. Functional autophagy seems to prevent neuronal senescence, as we observed an autophagic flux reduction in senescent neurons both in vitro and in vivo, and autophagy impairment induced cortical cell senescence while autophagy stimulation inhibited it. Our findings suggest that aging-associated dysfunctional autophagy contributes to senescence transition also in neuronal cells.
BECN1: Beclin 1; CQ: Cloroquine; DAPI: 4′,6-Diamidine-2′-phenylindole dihydrochloride; DDR: DNA Damage Response; DIV: Days in vitro; FM: Fresh medium; GFAP: Glial fibrillary acidic protein; IL6: Interleukin-6; LAMP: Lysosomal-associated membrane protein; MEFs: Mouse embryonic fibroblasts; mH2A: Histone macroH2A; mTOR: mechanistic target of rapamycin; N2A: Neuro 2A; PI3KC3: Phosphatidylinositol 3-kinase class 3; p38MAPK: p38 mitogen-activated protein kinase; SA-β-gal: Senescence-Associated β-galactosidase; SAHF: Senescence-associated heterochromatin foci; SAMP8: senescence-accelerated mice prone; SASP: Senescence-associated secretory phenotype; SBB: Sudan Black B; Spautin-1: Specific and potent autophagy inhibitor 1; SQSTM1: Sequestosome 1; TASCC: TOR-autophagy spatial coupling compartment; TGFβ: Transforming growth factor-beta; Tre: Trehalose; 53BP1: p53-binding protein 1; MCP-1: monocyte chemotactic protein 1, official name C-C motif chemokine 2; GATA4: GATA binding protein 4.