10779/crick.12631259.v1 Estefania Carrasco-Garcia Estefania Carrasco-Garcia Olatz Arrizabalaga Olatz Arrizabalaga Manuel Serrano Manuel Serrano Robin Lovell-Badge Robin Lovell-Badge Ander Matheu Ander Matheu Increased gene dosage of Ink4/Arf and p53 delays age-associated central nervous system functional decline The Francis Crick Institute 2020 Arf Ink4a aging anti-aging gerontogenes neural stem cells neuroscience p53 ADP-Ribosylation Factor 1 Aging Animals Basic Helix-Loop-Helix Transcription Factors Cell Proliferation Cyclin-Dependent Kinase Inhibitor p16 DNA-Binding Proteins Dentate Gyrus Excitatory Amino Acid Transporter 1 Gene Dosage Gene Expression Regulation Mice Mice, Transgenic Neural Stem Cells Neurogenesis Nuclear Proteins Olfactory Bulb Primary Cell Culture SOX9 Transcription Factor SOXB1 Transcription Factors Signal Transduction Spheroids, Cellular Transcription Factors Tumor Suppressor Protein p53 Lovell-Badge U117562207 11 Medical and Health Sciences 06 Biological Sciences Developmental Biology 2020-07-09 13:14:56 Journal contribution https://crick.figshare.com/articles/journal_contribution/Increased_gene_dosage_of_Ink4_Arf_and_p53_delays_age-associated_central_nervous_system_functional_decline/12631259 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.