ll Review Aging and Rejuvenation of Neural Stem Cells and Their Niches Paloma Navarro Negredo,1,3 Robin W. Yeo,1,3 and Anne Brunet1,2,* 1Department of Genetics, Stanford University, Stanford, CA 94305, USA 2Glenn Laboratories for the Biology of Aging, Stanford, CA 94305, USA 3These authors contributed equally *Correspondence: [email protected] https://doi.org/10.1016/j.stem.2020.07.002 Aging has a profound and devastating effect on the brain. Old age is accompanied by declining cognitive function and enhanced risk of brain diseases, including cancer and neurodegenerative disorders. A key ques- tion is whether cells with regenerative potential contribute to brain health and even brain ‘‘rejuvenation.’’ This review discusses mechanisms that regulate neural stem cells (NSCs) during aging, focusing on the effect of metabolism, genetic regulation, and the surrounding niche. We also explore emerging rejuvenating strategies for old NSCs. Finally, we consider how new technologies may help harness NSCs’ potential to restore healthy brain function during physiological and pathological aging. Introduction ability to give rise to glia (oligodendrocytes versus astrocytes; More than any other organ, the brain feels central to us for its Bonaguidi et al., 2011; Ortega et al., 2013), and their contribution ability to coordinate higher-order cognitive functions. But brain to brain function (Aimone et al., 2014; Corsini et al., 2009; Dupret function deteriorates with age. In parallel, neurodegenerative et al., 2008; Gao et al., 2018; Gheusi et al., 2000). disorders (e.g., Alzheimer’s and Parkinson’s diseases) and brain In the SVZ, NSCs are located within ‘‘pinwheel’’ structures and cancers (e.g., gliomas) surge in the elderly population. Although contact the brain’s vasculature and the cerebrospinal fluid (CSF) all cell types in the brain are affected during aging and could in the lateral ventricle (Mirzadeh et al., 2008; Shen et al., 2008; contribute to physiological decline and disease, resident neural Tavazoie et al., 2008). SVZ NSCs produce neuroblasts that stem cells (NSCs) in the adult brain have the potential to generate migrate along the rostral migratory stream and generate new new neurons (neurogenesis) and regenerate aspects of brain neurons in the olfactory bulb in rodents (Doetsch et al., 1997; function. Thus, maintaining a healthy stem cell pool in the brain Mizrahi et al., 2006) or incorporate into the striatum in humans throughout aging could be critical to improve overall brain health (Ernst et al., 2014). SVZ neurogenesis is important for various and reduce the incidence of neurodegenerative diseases and olfactory functions in rodents, such as odor discrimination and cancer. olfactory learning and memory (Bragado Alonso et al., 2019; The adult mammalian brain contains two primary reservoirs of Gheusi et al., 2000; Sakamoto et al., 2011). Interestingly, SVZ regenerative NSCs (known as ‘‘neurogenic niches’’): the subven- NSCs can also be activated upon injury (e.g., stroke) to generate tricular zone (SVZ) of the lateral ventricles and the dentate gyrus newborn neurons and astrocytes that can help to repair brain (DG) of the hippocampus (Figure 1; Bond et al., 2015; Silva-Var- injury in mice (Benner et al., 2013; Faiz et al., 2015; Li gas et al., 2013). A third pool of NSCs has been reported more et al., 2010a). recently in the hypothalamus (Bolborea and Dale, 2013; Pelle- In the hippocampal niche, NSCs are located at the border of grino et al., 2018). This review will primarily focus on the SVZ the inner granule cell layer in the DG, and they generate neuro- and hippocampal neurogenic niches but will also discuss spe- blasts, which migrate along the subgranular zone to produce cific results from NSCs in the hypothalamus. Neurogenic niches granule neurons (Gage, 2002; Ming and Song, 2011; Sun et al., are specialized microenvironments comprising a variety of 2015). Hippocampal neurogenesis contributes to learning and different cell types, including cells from the NSC lineage, but memory formation (Corsini et al., 2009; Dupret et al., 2008; also endothelial cells (blood vessels) and microglia (Aimone Gao et al., 2018; Guo et al., 2018) and stress resilience in mice et al., 2014). The head of the NSC lineage consists of quiescent (Anacker et al., 2018; Levone et al., 2014). In humans, the level NSCs (qNSCs), which are normally dormant but can be activated and duration of hippocampal neurogenesis have been subject to generate proliferating NSCs. Activated NSCs (aNSCs), in turn, to debate, but neurogenic regions with regenerative potential give rise to neural progenitor cells (NPCs), which have the poten- are likely present in adulthood in humans (Boldrini et al., 2018; tial to differentiate primarily into new neurons, and, in smaller Moreno-Jime´ nez et al., 2019; Sorrells et al., 2018; Tobin proportions, into astrocytes and oligodendrocytes (Bond et al., et al., 2019). 2015). The SVZ and hippocampal neurogenic niches have simi- During aging, the ability of NSCs to proliferate and give rise to larities in their overall cellular composition and neurogenic po- new neurons decreases dramatically. In vivo labeling and micro- tential. However, these reservoirs also exhibit differences in their scopy revealed a decline in neurogenesis in SVZ and hippocam- turnover dynamics (symmetric versus asymmetric divisions; Cal- pal neurogenic niches during aging (Ben Abdallah et al., 2010; zolari et al., 2015; Encinas et al., 2011; Obernier et al., 2018), their Bondolfi et al., 2004; Enwere et al., 2004; Kuhn et al., 1996; 202 Cell Stem Cell 27, August 6, 2020 ª 2020 Elsevier Inc. ll Review Figure 1. Neurogenesis during Aging The ability of NSCs to proliferate and produce new neurons declines sharply after development and continues to decline during aging, whereas the incidence of neurodegeneration and age- related diseases increases (the diagram shows conceptual trajectories for neurogenesis and neu- rodegeneration). The adult mammalian brain con- tains two reservoirs of regenerative neural stem cells (NSCs): the DG of the hippocampus and the SVZ of the lateral ventricles (teal green). These niches contain qNSCs that can be activated to produce actively proliferating NSCs (aNSCs). aNSCs have the potential to differentiate into neu- rons, oligodendrocytes, or astrocytes. NSC aging at the molecular, niche, brain, and organismal levels and provide new av- enues to slow or potentially even reverse the age-dependent decline in neuro- genesis. Nutrient-Sensing Pathways, Metabolism, and Protein Homeostasis during NSC Aging Neurogenic niches are sensitive to changes in nutrient availability and signaling, including those occurring during aging. The various cell types in the niche have very different metabolic and protein Luo et al., 2006; Maslov et al., 2004). This decline likely involves a homeostasis needs, depending on their state (e.g., qNSCs number of cellular processes, including increased NSC versus actively proliferating NSCs). In this section, we review dormancy, decreased NSC self-renewal, a decline in neuronal recent evidence supporting the role of these processes in NSC fate commitment, and NSC death (Encinas et al., 2011; Obernier aging and rejuvenation. and Alvarez-Buylla, 2019; Urba´ n et al., 2016). The decrease in Nutrient-Sensing Pathways neurogenesis with age is accompanied by poorer performance Nutrient-sensing pathways, such as the insulin/insulin growth on learning and memory tasks and reduced olfactory discrimina- factor 1 (IGF1)-FOXO pathway, are key conserved regulators of tion (Enwere et al., 2004; Gage and Temple, 2013; McAvoy et al., aging (Chantranupong et al., 2015) and are also essential for 2016), suggesting that age-related NSC defects may have broad NSC maintenance and function in the SVZ and DG. For example, functional consequences. In humans, the decline in neurogene- early work revealed that loss of FOXO transcription factors sis in elderly individuals has been associated with cognitive (FOXOs), the downstream effectors of the insulin/IGF1 pathway, impairment and neurodegenerative diseases (Moreno-Jime´ nez leads to premature exhaustion of the NSC pool (Paik et al., 2009; et al., 2019; Tobin et al., 2019). Thus, key questions emerging Renault et al., 2009; Yeo et al., 2013). Consistently, loss of the in this field include the following. How do regenerative regions PTEN phosphatase (which is upstream of FOXO) also causes containing NSCs change over a lifespan? Do the various regen- NSC depletion (Bonaguidi et al., 2011), even when PTEN loss erative niches differ, or do they rely on similar mechanisms? Are initially triggers NSC proliferation (Gregorian et al., 2009). More the cells that divide in the old brain the same cells that had recent work has shown that suppression of IGF1 signaling in already divided and produced neurons in the younger brain? young NSCs via IGF1 receptor (IGF1R) conditional knockout How can the regenerative potential of NSCs be leveraged to pro- in vivo (which results in FOXO activation) improves neurogenesis mote brain homeostasis and repair? in the SVZ, increases spine density in newborn neurons, and en- In this review, we discuss recently discovered mechanisms hances olfactory learning (Chaker et al., 2015). Together, these leading to the age-related decline in neurogenesis in vertebrates, results indicate that suppressing insulin/IGF1 signaling (and, focusing on intrinsic factors (e.g., metabolism and genetic regu- subsequently, activating FOXO) is beneficial for long-term main- lation)