Effects of lifespan-extending interventions on cognitive healthspan.

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals.

Neurogenesis in aging and age-related neurodegenerative diseases.

Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aß, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.

Within-Trial Persistence of Learned Behavior as a Dissociable Behavioral Component in Hippocampus-Dependent Memory Tasks: A Potential Postlearning Role of Immature Neurons in the Adult Dentate Gyrus.

The term "memory strength" generally refers to how well one remembers something. But more precisely it contains multiple modalities, such as how easily, how accurately, how confidently and how vividly we remember it. In human, these modalities of memory strength are dissociable. In this study, we asked whether we can isolate a behavioral component that is dissociable from others in hippocampus-dependent memory tasks in mice, which potentially reflect a modality of memory strength. Using a virus-mediated inducible method, we ablated immature neurons in the dentate gyrus in mice after we trained the mice with hippocampus-dependent memory tasks normally. In memory retrieval tests, these ablated mice initially showed intact performance. However, the ablated mice ceased learned behavior prematurely within a trial compared with control mice. In addition, the ablated mice showed shorter duration of individual episodes of learned behavior. Both affected behavioral measurements point to persistence of learned behavior. Thus, the effect of the postlearning manipulation showed dissociation between initial performance and persistence of learned behavior. These two behavioral components are likely to reflect different brain functions and be mediated by separate mechanisms, which might represent different modalities of memory strength. These simple dissociable measurements in widely used behavioral paradigms would be useful to understand detailed mechanisms underlying the expression of learned behavior and potentially different modalities of memory strength in mice. We also discuss a potential role that immature neurons in the dentate gyrus may play in persistence of learned behavior.

Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress.

Major depression is hypothesized to be associated with dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis.

Anxiety-like behavior and cognitive flexibility in adult rats perinatally exposed to increased serotonin concentrations.

Serotonin (5-hydroxytryptamine, 5HT) is a biologically active amine that regulates the development of 5HT neurons and target tissues during neurogenesis, while later it assumes the function of a neurotransmitter. Serotonin mediates many essential behaviors common to all mammals, and is held responsible for anxiety-like behavior and cognitive rigidity. Proper serotonin levels, controlled through 5HT synthesis and metabolism, are crucial for normal brain development. In this study we investigated anxiety-like behavior and cognitive flexibility in adult animals after exposing their developing brains to increased 5HT concentrations. Wistar rats were treated subcutaneously from gestational day 12 to post-natal day 21 with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25mg/kg), a non-selective MAO inhibitor tranylcypromine (TCP, 2mg/kg), or saline. After reaching adulthood, animals were tested for anxiety-like behavior (exploratory behavior, thigmotactic behavior, social contact, and reaction to stressful stimulus) and cognitive flexibility (ability for reversal learning). Results of the behavioral studies corresponded with our previous neurochemical findings. Treatment with 5HTP, which has induced mild reduction in cortical 5HT concentrations, caused reduction in only one aspect of anxiety-like behavior (increased exploratory activity). Treatment with TCP, which lead to drastic reduction in 5HT concentration/function, resulted in a highly anxiolytic phenotype (reduced thigmotaxis, reaction to stress, and social anxiety) with improved cognitive flexibility. Although further neurochemical, anatomical and gene-expression studies are needed to elucidate the mechanisms underlying the observed behavior, we hope that our results will contribute to the understanding of the role of serotonin in anxiety-like behavior and cognitive rigidity.