Enhanced NRF2 expression mitigates the decline in neural stem cell function during aging. Issue 6 (15th June 2021)

• Record Type: Journal Article
• Authors: Anandhan, Annadurai; Kirwan, Konner R.; Corenblum, Mandi J.; Madhavan, Lalitha
• Is Part Of: Aging cell. Volume 20:Issue 6(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-06-15
• Subjects: aging -- neural stem cells -- NRF2 -- redox -- subventricular zone; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13385
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: Although it is known that aging affects neural stem progenitor cell (NSPC) biology in fundamental ways, the underlying dynamics of this process are not fully understood. Our previous work identified a specific critical period (CP) of decline in NSPC activity and function during middle age (13–15 months), and revealed the reduced expression of the redox‐sensitive transcription factor, NRF2, as a key mediator of this process. Here, we investigated whether augmenting NRF2 expression could potentially mitigate the NSPC decline across the identified CP. NRF2 expression in subventricular zone (SVZ) NSPCs was upregulated via GFP tagged recombinant adeno‐associated viral vectors (AAV‐NRF2‐eGFP), and its cellular and behavioral effects compared to animals that received control vectors (AAV‐eGFP). The vectors were administered into the SVZs of aging rats, at time points either before or after the CP. Results indicate that animals that had received AAV‐NRF2‐eGFP, prior to the CP (11 months of age), exhibited substantially improved behavioral function (fine olfactory discrimination and motor tasks) in comparison to those receiving control viruses. Further analysis revealed that NSPC proliferation, self‐renewal, neurogenesis, and migration to the olfactory bulb had significantly increased upon NRF2 upregulation. On the other hand, increasing NRF2 after the CP (at 20 months of age) produced no notable changes in NSPC activity at either cellular or behavioral levels. These results, for the first time, indicate NRF2 pathway modulation as a means to support NSPC function with age and highlight a critical time‐dependency for activating NRF2 to enhance NSPC function. Abstract : The current work reveals that amplifying intrinsic levels of the redox transcription factor, NRF2, before a certain critical period (CP) of aging (13–15 months), can rescue the age‐related decline in neural stem cell function in rats. This finding has fundamental implications for not only understanding neural stem cell biology, but also advantageously modulating neural stem cell function with age.