Today's open access paper is a review of potential approaches that might be used as a basis for therapies to restore a more youthful level of neurogenesis in the aging mammalian brain. Neurogenesis is the process by which new neurons are created by neural stem cell populations and then integrated into neural networks. In adults, neurogenesis is essential to memory, learning, and the limited degree of regeneration that the brain is capable of enacting. Unfortunately, the supply of new neurons declines with age as the underlying stem cells become ever less active. Beyond making the aging brain more resilient, methods of increasing neurogenesis may prove to be enhancement therapies capable of improving cognitive function even in young people.
Any discussion of adult neurogenesis must note the present debate over whether or not it in fact does take place in humans in the same way as it does in mice. It was only in the 1990s that neurogenesis was discovered to take place in some portions of the adult mouse brain, and since then near all work on neurogenesis in general, as well on changes in neurogenesis with age, has focused on mice, given the costs and difficulties inherent in studying human brains and brain tissue. This became a growing concern, careful human studies were undertaken, and in the past few years rigorous evidence has been presented on both sides of the question of adult human neurogenesis, both ruling it out, and demonstrating that it does take place. Considerable debate has taken place over the technical details of these studies and the underlying processes of neurogenesis. Insofar as there is a present weight of evidence, it appears to lean towards the conclusion that humans do in fact exhibit adult neurogenesis.
Adult neurogenesis is the generation of new neurons from neural stem cells (NSCs). NSCs are known for their hallmark characteristics of long-term self-renewal and differentiation into neurons and glia. While many noncanonical sites of neurogenesis have been observed in the mammalian brain, the two main stem cell niches studied are the subventricular zone (SVZ) located along the walls of the lateral ventricles (LV) and subgranular zone (SGZ) in the hippocampus. The largest pool of NSCs in rodents lies in the SVZ, where the majority of NSCs are quiescent (qNSCs). These qNSCs undergo activation (aNSC) and proliferate to produce transit amplifying cells (TACs). TACs rapidly proliferate and then differentiate into neuroblasts that migrate in chains along the rostral migratory stream (RMS) to the olfactory bulb (OB) and become synaptically integrated into the existing circuitry.
Neurogenesis in the SVZ results in the functional integration of neurons in the OB. This has been shown to be important in olfactory behavior such as memory and scent/pheromone discrimination. In addition, brain injury, in the form of ischemic stroke, induces NSC proliferation and production of neuroblasts (NBs). These NBs migrate to the site of injury to differentiate into astrocytes and neurons that synaptically integrate into the peri-infarct cortex. Blockade of neuroblast migration results in increased lesion size and worsened behavioral outcomes as SVZ-derived neurons with synaptic function are critical to stroke recovery. Additionally, post-stroke neurogenesis is plastic and can be increased and directed by overuse behavior that mimics current human neurorehabilitation therapies. During aging, neurogenesis is reduced, which contributes to declines in olfactory memory and repair.
Multiple strategies to rejuvenate neurogenesis have come from experiments utilizing blood/plasma exchange between young and aged rodents. Landmark studies utilizing heterochronic parabiosis, where a young and aged mouse are connected surgically to share circulation, showed that young circulating factors can rejuvenate neurogenesis in aged mice vice versa with old circulating factors young mice. The field has since made further progress by identification of circulating rejuvenation factors of NSCs in the SVZ and hippocampus that include GDF11 and TIMP2, as well as the pro-aging factors CCL11, β2-microglobulin, TGF-β, and recently VCAM1.
The dietary interventions caloric restriction (CR) (10-40% reduction in caloric intake) and the fasting mimicking diet (FMD) (50-90% reduction in caloric intake for 4 days twice a month) are perhaps the most robust, pleiotropic, and conserved methods of longevity extension and rejuvenation. In a mouse model of caloric restriction starting at 14-weeks of age, the number of NB and new neurons in the OB were preserved in the aged (12-months to 18-months) and comparable to levels of ad libitum fed young (six-month) mice. This preservation of neurogenesis resulted in olfactory memory in aged mice that was similar to young (six-month) mice.
The two top drugs that have emerged from CR research are rapamycin and metformin, which act primarily through inhibition of the mTOR and activation of the AMPK (downstream inhibition of mTOR) pathways. However, other studies suggest that mTOR signaling is a mediator of TAC proliferation since rapamycin treatment decreases the number of TACs in two-month old mice and mTOR activation decreases with age, concomitant with proliferation. Metformin has been shown to enhance proliferation in the young (three-month) SVZ, but despite interest in using metformin to ameliorate aging phenotypes, research with this drug in the aging SVZ is lacking.
Multiple lines of evidence now point towards an increased age-dependent inflammatory environment within the SVZ. A major source of this inflammation originates from aged microglia and should be a central target for inflammation reduction in future studies. Having identified the neurogenic-inhibiting contribution of aged microglia to NSC proliferation, researchers fed 8-month old mice the anti-inflammatory drug HCT1026. This treatment restored redox/inflammatory balance to the niche, and substantially increased neurogenesis. Increase in senescent cell burden in the aging SVZ has been found in 12-18 month old mice. Avoidance of the senescence program was achieved with p16INK41-/- mice aged to 15-19 months that partially rescued OB neurogenesis. A recent study showed that obesity is associated with increased senescence and reduced neuroblasts in the SVZ of middle-aged (10-13 months) mice and clearance of senescent cells partially rescued the number of neural precursors. Thus, removal of senescent cells in elderly mice, especially using treatments such as Dasatinib + Quercetin that have been used in clinical trials, appear to be favorable routes to rejuvenate neurogenesis but are in need of further study in aged animals to determine long term effects.
The studies gathered here present compelling evidence that aging of the SVZ niche is not a one-way street. Instead, the aging process is not only delayable through early interventions such as CR, but is also reversible by way of systemic interventions started late in life. The possibility of rejuvenation not only sheds light on the mechanisms of NSC aging, but is also an appealing therapeutic avenue for the rapidly increasing elderly human population.