Age-related Decline In Neurogenesis Research Articles

Cell-Based Therapies for the Treatment of Traumatic Brain Injury: Promises and Trajectories

Traumatic Brain Injury (TBI) is a debilitating condition that poses a significant public health concern. Historically linked to motor vehicle accidents, the epidemiology of TBI has evolved. Falls now emerge as the predominant cause, particularly among older adults. Sport-related TBIs have also garnered increased attention due to concerns regarding long-term neurological sequelae. To date, therapeutic interventions remain limited and have yet to yield substantial clinical benefits. Cell-based therapies offer promising avenues for neural repair and regeneration: endogenous stem cell therapies capitalize on endogenous pools that can be triggered by the injury and further enhanced by therapeutic approaches. In contrast, exogenous cell therapies provide an exogenous source of cells. However, challenges such as age-related decline in neurogenesis, age-related inflammation, and the heterogeneity of TBI present significant hurdles to overcome. Moreover, translating stem cell research from the laboratory to clinical applications necessitates the adherence to good manufacturing practice standards, which presents distinct obstacles. Addressing these challenges requires a multifaceted approach, including careful patient selection in clinical trials, appropriate experimental models, and the optimization of therapeutic techniques. Ultimately, a combination of strategies is likely to yield the most promising outcomes in the pursuit of effective TBI therapies.

From Youthful Vigor to Aging Decline: Unravelling the Intrinsic and Extrinsic Determinants of Hippocampal Neural Stem Cell Aging.

Since Joseph Altman published his pioneering work demonstrating neurogenesis in the hippocampus of adult rats, the number of publications in this field increased exponentially. Today, we know that the adult hippocampus harbors a pool of adult neural stem cells (NSCs) that are the source of life-long neurogenesis and plasticity. The functions of these NSCs are regulated by extrinsic cues arising from neighboring cells and the systemic environment. However, this tight regulation is subject to imbalance with age, resulting in a decline in adult NSCs and neurogenesis, which contributes to the progressive deterioration of hippocampus-related cognitive functions. Despite extensive investigation, the mechanisms underlying this age-related decline in neurogenesis are only incompletely understood, but appear to include an increase in NSC quiescence, changes in differentiation patterns, and NSC exhaustion. In this review, we summarize recent work that has improved our knowledge of hippocampal NSC aging, focusing on NSC-intrinsic mechanisms as well as cellular and molecular changes in the niche and systemic environment that might be involved in the age-related decline in NSC functions. Additionally, we identify future directions that may advance our understanding of NSC aging and the concomitant loss of hippocampal neurogenesis and plasticity.

Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life

Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain’s endogenous reserve of neural stem cells.

Increasing Neural Stem Cell Division Asymmetry and Quiescence Are Predicted to Contribute to the Age-Related Decline in Neurogenesis

Adult murine neural stem cells (NSCs) generate neurons in drastically declining numbers with age. How cellular dynamics sustain neurogenesis and how alterations with age may result in this decline are unresolved issues. We therefore clonally traced NSC lineages using confetti reporters in young and middle-aged adult mice. To understand the underlying mechanisms, we derived mathematical models that explain observed clonal cell type abundances. The best models consistently show self-renewal of transit-amplifying progenitors and rapid neuroblast cell cycle exit. In middle-aged mice, we identified an increased probability of asymmetric stem cell divisions at the expense of symmetric differentiation, accompanied by an extended persistence of quiescence between activation phases. Our model explains existing longitudinal population data and identifies particular cellular properties underlying adult NSC homeostasis and the aging of this stem cell compartment.

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain

SUMMARYRestoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.

FGF Signaling Is Necessary for Neurogenesis in Young Mice and Sufficient to Reverse Its Decline in Old Mice.

Hippocampal deficits can result from trauma, neurodegeneration, or aging and can lead to loss of memory and mood control. The addition of new neurons to the hippocampus facilitates memory formation, but how this process is regulated and how we might manipulate it to reverse hippocampal dysfunction remains unclear. The FGF signaling pathway has been hypothesized to be important, but its role in generating new neurons had been poorly defined. Our study indicates that FGF signaling maintains and expands subsets of neural precursor cells. Moreover, in older mice, increasing FGF signaling is sufficient to reverse the decline in neuron production to levels found in young adults, providing a potential means of reversing age-related hippocampal deficits.

The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation

A decrease in neurogenesis in the aged brain has been correlated with cognitive decline. The molecular signaling that regulates age-related decline in neurogenesis is still not fully understood. We found that different subtypes of neural stem cells (NSCs) in the hippocampus were differentially impaired by aging. The quiescent NSCs decreased slowly, although the active NSCs exhibited a sharp and dramatic decline from the ages of 6–9 months and became more quiescent at an early stage during the aging process. The activity of the mammalian target of rapamycin (mTOR) signal pathway is compromised in the NSCs of the aged brain. Activating the mTOR signaling pathway increased NSC proliferation and promoted neurogenesis in aged mice. In contrast, inhibiting the mTOR signaling pathway decreased NSCs proliferation. These results indicate that an age-associated decline in neurogenesis is mainly because of the reduction in proliferation of active NSCs, at least partially because of the compromise in the mTOR signaling activity. Stimulating the mTOR signaling revitalizes the NSCs, restores their proliferation, and enhances neurogenesis in the hippocampus of the aged brain.

Persistent Loss of Hippocampal Neurogenesis and Increased Cell Death following Adolescent, but Not Adult, Chronic Ethanol Exposure

Although adolescence is a common age to initiate alcohol consumption, the long-term consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3-4 weeks after adolescent (postnatal day, PD28-48) or adult (PD70-90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if the effects of ethanol exposure were region specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol-exposed animals about 4 weeks after exposure when these animals were compared to control age-mates. The effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both the DG and the SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3-positive immunoreactivity observed in the adolescent ethanol group compared to controls, but no alterations in cell proliferation when indexed by Ki67. These results suggest that a history of adolescent ethanol exposure results in lowered levels of differentiating neurons, probably due at least in part to increased cell death of immature neurons. These effects were evident in adulthood, weeks following termination of the chronic exposure, and may contribute to previously reported behavioral deficits on hippocampal-related tasks after chronic ethanol exposure in adolescence.

Increased Re-Entry into Cell Cycle Mitigates Age-Related Neurogenic Decline in the Murine Subventricular Zone

Although new neurons are produced in the subventricular zone (SVZ) of the adult mammalian brain, fewer functional neurons are produced with increasing age. The age-related decline in neurogenesis has been attributed to a decreased pool of neural progenitor cells (NPCs), an increased rate of cell death, and an inability to undergo neuronal differentiation and develop functional synapses. The time between mitotic events has also been hypothesized to increase with age, but this has not been directly investigated. Studying primary-cultured NPCs from the young adult and aged mouse forebrain, we observe that fewer aged cells are dividing at a given time; however, the mitotic cells in aged cultures divide more frequently than mitotic cells in young cultures during a 48-hour period of live-cell time-lapse imaging. Double-thymidine-analog labeling also demonstrates that fewer aged cells are dividing at a given time, but those that do divide are significantly more likely to re-enter the cell cycle within a day, both in vitro and in vivo. Meanwhile, we observed that cellular survival is impaired in aged cultures. Using our live-cell imaging data, we developed a mathematical model describing cell cycle kinetics to predict the growth curves of cells over time in vitro and the labeling index over time in vivo. Together, these data surprisingly suggest that progenitor cells remaining in the aged SVZ are highly proliferative.

The role of omega-3 fatty acids in adult hippocampal neurogenesis

Neurogenesis occurs in limited areas of the adult mammalian brain, and has been reported in the hippocampus of rodents and man. Neurogenesis is enhanced in conditions associated with enhanced synaptic plasticity and following neuronal injury, suggesting a role for neurogenesis in cognition and brain repair. Omega-3 polyunsaturated fatty acids (PUFAs) have been shown to promote hippocampal neurogenesis in a variety of models. Importantly, recent work has shown that the fat-1 transgenic mouse, an animal model of endogenous omega-3 PUFA enrichment, exhibits enhanced neurogenesis, with concomitant improvements in spatial memory compared to wild type mice. During ageing, the rate of neurogenesis declines significantly and there is a strong correlation between memory impairment in hippocampal-dependent tasks and this decline. Interestingly, there is a strong correlation between omega-3 PUFA and hippocampal-dependent memory tasks, and we have recently shown that supplementation of aged rats with omega-3 PUFAs partially reverses the age-related decline in neurogenesis. Thus omega-3 PUFAs positively influence neurogenesis, and these effects may contribute to improved cognitive performance. However, the mechanisms by which omega-3 PUFAs regulate neurogenesis remain unclear, although a number or putative targets have been suggested. The aims of this paper are to review the role of omega-3 PUFA in hippocampal neurogenesis, and explore some of the potential mechanisms of action which may underlie the observed effects.

Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells

Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in the expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked whether a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in the gene expression of GFAP, VEGF, and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits NSC and progenitor cell maintenance and contributes to decreased neurogenesis.

Stem cell review series: role of neurogenesis in age-related memory disorders.

Neuroplasticity is characterized by growth and branching of dendrites, remodeling of synaptic contacts, and neurogenesis, thus allowing the brain to adapt to changes over time. It is maintained in adulthood but strongly repressed during aging. An age-related decline in neurogenesis is particularly pronounced in the two adult neurogenic areas, the subventricular zone and the dentate gyrus. This age-related decline seems to be attributable mainly to limited proliferation, associated with an age-dependent increase in quiescence and/or a lengthening of the cell cycle, and is closely dependent on environmental changes. Indeed, when triggered by appropriate signals, neurogenesis can be reactivated in senescent brains, thus confirming the idea that the age-related decrease in new neuron production is not an irreversible, cell-intrinsic process. The coevolution of neurogenesis and age-related memory deficits – especially regarding spatial memory – during senescence supports the idea that new neurons in the adult brain participate in memory processing, and that a reduction in the ability to generate new neurons contributes to the appearance of memory deficits with advanced age. Furthermore, the age-related changes in hippocampal plasticity and function are under environmental influences that can favor successful or pathological aging. A better understanding of the mechanisms that regulate neurogenesis is necessary to develop new therapeutic tools to cure or prevent the development of memory disorders that may appear during the course of aging in some individuals.

Effect of neural precursor proliferation level on neurogenesis in rat brain during aging and after focal ischemia

The observed age-related decline in neurogenesis may result from reduced proliferation or increased death rate of neuronal precursor cells (NPCs). We found that caspase-3, but not caspase-6, -7, or -9, was activated in NPCs in neurogenic regions of young, young-adult, middle-aged and aged rat brains. The number of capase-3-immunoreactive cells was highest in young and lowest in aged rats. Surprisingly, intraventricular administration of a caspase-3 inhibitor failed to restore the number of BrdU-positive cells in the aged dentate gyrus, suggesting that the age-related decline in neurogenesis may be attributable primarily to reduced proliferation. Additionally, we also found that NPCs in the subventricular zone of young-adult and aged rat brain were increased after focal cerebral ischemia, suggesting that the increase in neurogenesis induced by ischemia may result from an increase in the rate of NPC proliferation, but not from a decrease in NPC death. Thus, our results suggest that age-related and injury-induced changes in the rate of neurogenesis are controlled at the level of NPC proliferation. Furthermore, our results may imply that the mechanisms that maintain a stable population of NPCs in the normal adult and in the ischemic brain, which account for the observed age-dependent reduction or injury-induced increases in neurogenesis, impinge on the regulation of cell division at the NPC level.

Dynamics of neurogenesis in the dentate gyrus of adult rats

Hippocampal neurogenesis declines steadily over the first year of life in the rodent, but the process persists into senescence despite a dramatic drop in the number of neurons it produces. At this point though, the survival and development patterns exhibited by new granule cells in the aging brain remain unclear in relation to patterns observed in the younger brain. The present study was carried out in order to obtain a direct quantitative comparison of hippocampal neurogenesis in juvenile and middle-aged rats with a high degree of temporal resolution, and to compare the survival and differentiation of the new cells over time. Thirty-eight-day-old and 12-month-old, male Sprague–Dawley rats were injected with 5-bromo-2′-deoxyuridine (BrdU) in order to label cells dividing in the dentate gyrus over a 24-h period, and immunohistochemical labeling was performed in order to record cell production and survival at eight different time points over the following two-month period. Using a marker of neuronally committed precursors and immature neurons (doublecortin; DCX), as well as a marker of mature neurons (calbindin d-28 K; CaBP), the extent and timeline of neuronal differentiation, maturation, and migration of the new cells were also characterized. Results indicated that 12-month-old rats experienced a nearly 94% reduction in neurogenesis relative to juveniles, due almost entirely to a 92% drop in cell production. A largely preserved course of development and migration in the remaining newborn cells suggests treatments that enhance cell proliferation could be crucial in reversing the age-related decline in neurogenesis.

Lifelong corticosterone level determines age-related decline in neurogenesis and memory

Ageing is accompanied by an alteration of spatial memory, a decline in hippocampal neurogenesis and a dysregulation of the hypothalamic–pituitary axis (HPA) leading to elevated levels of circulating corticosterone. However, the role of the HPA axis in age-related decline in cognitive functions and in neurogenesis decline remains unclear. We found that suppression of glucocorticoids secretion from midlife to the rest of the animals’ life increases neurogenesis in old animals and prevents the emergence of age-related memory disorders. Reciprocally, aged rats with a chronic upregulation of the HPA axis exhibit not only spatial memory impairments but also very low levels of hippocampal cell proliferation and survival. Altogether, these results indicate that the extent of lifetime exposure to glucocorticoids determines the extent of age-related decline in hippocampal neurogenesis and consequently age-related cognitive dysfunctions.

Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice

Age-related changes in neurogenesis and its modulation by caloric restriction (CR) were studied in C57BL/6 mice. To this end, bromodeoxyuridine (BrdU) labeling was used to assess neuronal and glial precursor proliferation and survival in the granular cell layer (GCL) and the hilus of the dentate gyrus of 2-, 12-, 18-, and 24-month-old mice. For both regions, we found an age-dependent decrease in proliferation but not in survival of newborn cells. Interestingly, the reduction in proliferation occurred between 2 and 18 months of age with no additional decline between 18- and 24-month-old mice. Phenotyping of the newborn cells revealed a decrease in the neuron fraction in the GCL between 2 and 12 months of age but not thereafter. The majority of BrdU cells in the hilus colocalized with astrocytic but none with neuronal markers. CR from 3 to 11 months of age had no effect on neurogenesis in the GCL, but had a survival-promoting effect on newly generated glial cells in the hilus of the dentate gyrus. In conclusion, C57BL/6 mice reveal a substantial reduction in neurogenesis in the dentate gyrus until late adulthood with no further decline with aging. Long-term CR does not counteract this age-related decline in neurogenesis but promotes survival of hilar glial cells.