Although it is known that the regenerative function of neural stem/progenitor cells (NSPCs) declines with age, causal mechanisms underlying this phenomenon are not understood. Here, we systematically analyze subventricular zone (SVZ) NSPCs, in various groups of rats across the aging spectrum, using in vitro and in vivo histological and behavioral techniques. These studies indicate that although NSPC function continuously declines with advancing age, there is a critical time period during middle age (13-15 months) when a striking reduction in NSPC survival and regeneration (proliferation and neuronal differentiation) occurs. The studies also indicate that this specific temporal pattern of NSPC deterioration is functionally relevant at a behavioral level and correlates with the decreasing expression of the redox-sensitive transcription factor, Nrf2, in the NSPCs. When Nrf2 expression was suppressed in 'young' NSPCs, using short interfering RNAs, the survival and regeneration of the NSPCs was significantly compromised and mirrored 'old' NSPCs. Conversely, Nrf2 overexpression in 'old' NSPCs rendered them similar to 'young' NSPCs, and they showed increased survival and regeneration. Furthermore, examination of newborn Nrf2 knockout (Nrf2-/-) mice revealed a lower number of SVZ NSPCs in these animals, when compared to wild-type controls. In addition, the proliferative and neurogenic potential of the NSPCs was also compromised in the Nrf2-/- mice. These results identify a novel regulatory role for Nrf2 in NSPC function during aging and have important implications for developing NSPC-based strategies to support healthy aging and to treat age-related neurodegenerative disorders.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/622598 |
| Date | 08 1900 |
| Creators | Corenblum, Mandi J., Ray, Sneha, Remley, Quentin W., Long, Min, Harder, Bryan, Zhang, Donna D., Barnes, Carol A., Madhavan, Lalitha |
| Contributors | Univ Arizona, Dept Neurol, Univ Arizona, Neurosci & Cognit Sci Undergrad Program, Undergrad Biol Res Program, Univ Arizona, Pharmacol & Toxicol, Univ Arizona, Dept Psychol, Univ Arizona, Dept Neurosci, Univ Arizona, Evelyn F McKnight Brain Inst, Department of Neurology; University of Arizona; Tucson AZ USA, Department of Neurology; University of Arizona; Tucson AZ USA, Department of Neurology; University of Arizona; Tucson AZ USA, Pharmacology and Toxicology; University of Arizona; Tucson AZ USA, Pharmacology and Toxicology; University of Arizona; Tucson AZ USA, Pharmacology and Toxicology; University of Arizona; Tucson AZ USA, Department of Neurology; University of Arizona; Tucson AZ USA, Department of Neurology; University of Arizona; Tucson AZ USA |
| Publisher | WILEY-BLACKWELL |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License. |
| Relation | http://doi.wiley.com/10.1111/acel.12482 |
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