Fight Aging!

Today's open access paper provides an interesting example of a mechanism that slows a facet of aging only in middle age, when tested in mice. Researchers found that upregulation of NRF2 expression in the brain via gene therapy had meaningful positive effects on neural stem cell function in middle age only. We might consider that any given aspect of cell behavior is governed by multiple overlapping regulatory networks, and thus it is quite possible to see a particular point of intervention work under some circumstances but not under others, depending on the state of the cell, its environment, and which regulatory systems are dominant as a consequence.

Neural stem cells provide a supply of new neurons to the brain, which is very important for tissue maintenance, recovery from injury, and the workings of memory, among other processes. These stem cell populations, like all others elsewhere in the body, decline in activity with age. Much of this is a reaction to the molecular damage of aging throughout the body and consequent changes in the signaling environment, rather than any critical inherent damage to the stem cells themselves. Thus a broad range of strategies in medical research aim to force stem cells into greater, more youthful levels of activity, overriding their controlling mechanisms in order to do so. It remains to be seen as to the degree that the risk of cancer, due to increased cell activity in an environment of increased cell damage, is a problem that will significantly limit the use of this approach in any given case.

Enhanced NRF2 expression mitigates the decline in neural stem cell function during aging

Adult neural stem progenitor cells (NSPCs) are characterized by the ability to self-renew and differentiate into neuronal and glial cell types in the mature nervous system. This cell-level plasticity is not fixed, but rather a dynamic and highly modulated process. NSPC activity can be influenced by a range of factors, such as physical exercise, environmental enrichment, stress, and nutrition, but also importantly aging. In fact, aging contracts NSPC niches in the brain and significantly alters their function. Given the pivotal role of stem cells in tissues with lifelong regenerative capacity such as the brain, understanding stem cell aging will be important if we are to understand aging at the organ level. More broadly, comprehending stem cell aging will also support the development of interventions that could improve both health and lifespan.

In this context, our previous studies, conducted in naturally aging rodents, identified a specific temporal pattern of change in NSPC dynamics during aging. In particular, the studies highlighted a critical time during middle age (13-15 months), when the regenerative function of NSPCs showed a striking decline. The studies also determined the reduced expression of nuclear factor (erythroid-derived 2) like 2 (or NRF2), as a key mechanism mediating this phenomenon. As such, this work provided first evidence of an important regulatory role for NRF2 in NSPC aging.

NRF2 is a redox-sensitive transcription factor known to be essential to the cell's homeostatic mechanism. NRF2 is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, inflammatory agents, and excessive nutrient/metabolite supply. In particular, NRF2 can up-regulate a range of classical ARE (antioxidant response element)-driven genes, encoding major antioxidants and other detoxification enzymes. In addition to its classical function in regulating the stress response, NRF2 has been linked to cell growth, proliferation, mitochondrial and trophic functions, protein quality control, and increased lifespan.

Given that NRF2 loss accentuates NSPC aging, in this study, we investigated whether increasing NRF2 levels could boost NSPC function with age. In particular, we studied whether inducing high intrinsic NRF2 expression can potentially mitigate the decline in NSPC regeneration during the critical middle-age period between 13 and 15 months, identified in our previous work. NRF2 was delivered to rat subventricular zone (SVZ) NSPCs through recombinant adeno-associated viral (AAV) vectors injected either before (at 11 months of age) or well after the critical aging period (at 20 months of age). We find that the administration of AAV-NRF2-eGFP vectors before the initiation of the critical period substantially improved SVZ NSPC regeneration and associated behavioral function, as compared to controls (AAV-eGFP delivery). On the other hand, application of AAV-NRF2-eGFP after the conclusion of the critical period failed to significantly promote NSPC activity and function. This data establishes a major governing role for NRF2 in NSPCs and support targeting the NRF2 pathway as a potential approach to advantageously modulate NSPC function with age.