The systemic environment: at the interface of aging and adult neurogenesis.

Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms

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

Restoring 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

Platelets Give a Running Start to Adult Hippocampal Neurogenesis

Exercise boosts neural stem and progenitor cell proliferation and differentiation in the dentate gyrus region of the hippocampus. In this issue of Stem Cell Reports, Leiter et al. (2019) identify acute exercise-induced platelet activation and platelet factor-4 as novel systemic mediators of adult hippocampal neurogenesis. : Exercise boosts neural stem and progenitor cell proliferation and differentiation in the dentate gyrus region of the hippocampus. In this issue of Stem Cell Reports, Leiter et al. (2019) identify acute exercise-induced platelet activation and platelet factor-4 as novel systemic mediators of adult hippocampal neurogenesis

The systemic environment: at the interface of aging and adult neurogenesis.

Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms

Innovative approaches in cognitive aging

Novel approaches to address cognitive aging and to delay or prevent cognitive decline in older individuals will require a better understanding of the biological and environmental factors that contribute to it. Studies in animal models-in particular, animals whose cognitive trajectory across their life span closely tracks that of humans-can provide important insights into the factors that contribute to the accumulation of reserve and ways in which it is preserved or depleted. A better understanding of the molecular processes that underlie these elements would enhance and guide not only research but also treatment approaches to these issues. These treatment approaches may include noninvasive brain stimulation and drug treatments to promote youthfulness or combat the aging process. It is important to realize, however, that these processes occur in the context of the human experience, and studies of them must consider the complexity and individuality of each person's life

Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration

Abstract Background Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer’s disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo. Methods Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus. Results We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo. Conclusions Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration

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

Restoring 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

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation

Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch