Open AccessReduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle‐age period
Author(s) -
Corenblum Mandi J.,
Ray Sneha,
Remley Quentin W.,
Long Min,
Harder Bryan,
Zhang Donna D.,
Barnes Carol A.,
Madhavan Lalitha
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12482
Subject(s) - biology , progenitor cell , regeneration (biology) , neural stem cell , subventricular zone , microbiology and biotechnology , neurogenesis , progenitor , stem cell , function (biology) , period (music) , andrology , immunology , medicine , physics , acoustics
Summary Although it is known that the regenerative function of neural stem/progenitor cells ( NSPC s) declines with age, causal mechanisms underlying this phenomenon are not understood. Here, we systematically analyze subventricular zone ( SVZ ) NSPC s, 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 NSPC s. When Nrf2 expression was suppressed in ‘young’ NSPC s, using short interfering RNA s, the survival and regeneration of the NSPC s was significantly compromised and mirrored ‘old’ NSPC s. Conversely, Nrf2 overexpression in ‘old’ NSPC s rendered them similar to ‘young’ NSPC s, and they showed increased survival and regeneration. Furthermore, examination of newborn Nrf2 knockout (Nrf2 −/−) mice revealed a lower number of SVZ NSPC s in these animals, when compared to wild‐type controls. In addition, the proliferative and neurogenic potential of the NSPC s 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.