title: Increased gene dosage of Ink4/Arf and p53 delays age-associated central nervous system functional decline.
abstract: The impairment of the activity of the brain is a major feature of aging, which coincides with a decrease in the function of neural stem cells. We have previously shown that an extra copy of regulated Ink4/Arf and p53 activity, in s-Ink4/Arf/p53 mice, elongates lifespan and delays aging. In this work, we examined the physiology of the s-Ink4/Arf/p53 brain with aging, focusing on the neural stem cell (NSC) population. We show that cells derived from old s-Ink4/Arf/p53 mice display enhanced neurosphere formation and self-renewal activity compared with wt controls. This correlates with augmented expression of Sox2, Sox9, Glast, Ascl1, and Ars2 NSC markers in the subventricular zone (SVZ) and in the subgranular zone of the dentate gyrus (DG) niches. Furthermore, aged s-Ink4/Arf/p53 mice express higher levels of Doublecortin and PSA-NCAM (neuroblasts) and NeuN (neurons) in the olfactory bulbs (OB) and DG, indicating increased neurogenesis in vivo. Finally, aged s-Ink4/Arf/p53 mice present enhanced behavioral and neuromuscular coordination activity. Together, these findings demonstrate that increased but regulated Ink4/Arf and p53 activity ameliorates age-related deterioration of the central nervous system activity required to maintain the stem cell pool, providing a mechanism not only for the extended lifespan but also for the health span of these mice.
authors.affiliation: Neuro-Oncology Group, Biodonostia Institute, Paseo Dr. Beguiristain s/n, San Sebastian, 20014, Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: Carrasco-Garcia
authors.affiliation: Neuro-Oncology Group, Biodonostia Institute, Paseo Dr. Beguiristain s/n, San Sebastian, 20014, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Arrizabalaga
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernandez Almagro st, Madrid, 28029, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Francis Crick Institute, Mill Hill, London, NW7 1AA, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.affiliation: Neuro-Oncology Group, Biodonostia Institute, Paseo Dr. Beguiristain s/n, San Sebastian, 20014, Spain.|Francis Crick Institute, Mill Hill, London, NW7 1AA, UK.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000378:metabolism* / Q000473:pathology; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020823:ADP-Ribosylation Factor 1; D051792:Basic Helix-Loop-Helix Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D027341:Excitatory Amino Acid Transporter 1; D009687:Nuclear Proteins; D055758:SOX9 Transcription Factor; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C499317:Ascl1 protein, mouse; C493393:Slc1a3 protein, mouse; C527783:Sox2 protein, mouse; C527933:Sox9 protein, mouse; C527300:Srrt protein, mouse
keywords: Arf; Ink4a; aging; anti-aging; gerontogenes; neural stem cells; neuroscience; p53