Saul A. Villeda - US grants

DESCRIPTION (provided by applicant): Aging in mammals is associated with a decline in the function and regenerative capacity of tissue specific stem cells. In the adult central nervous the age-related decline of these functional stem/progenitor cells (NSC), and subsequently neurogenesis, is correlated with impairments in olfaction and cognitive functions such as learning and memory. Interestingly, changes to the systemic milieu of an organism, such as those induced through increased exercise and dietary restriction, have been shown to partially mitigate this cellular decline, as well as enhance learning and memory. Recent pioneering work has examined intrinsic molecular mechanisms that underlie NSC aging at the cellular level, however a gap still exists in elucidating how age-dependent NSC function is impaired by changes in the systemic molecular environment during aging. The purpose of this proposal is therefore to begin to elucidate how systemic changes in an aging organism alters the functionality of NSC in the adult brain. Specifically, my hypothesis is that age-dependent changes in the systemic molecular environment regulate the maintenance and potential rejuvenation of adult NSC in the aging brain. I will address this hypothesis in three aims: 1. To identify a systemic molecular profile of soluble signaling proteins that correlate with age-dependent decline in NSC maintenance and neural regeneration, 2. To determine how molecular changes in the young and old systemic environments affect age-dependent NSC function in vivo, and 3. To determine how individual changes in the aging molecular profile alter NSC function in vitro. These studies will ultimately provide insight into mechanisms by which the aging process impairs NSC function and may identify novel therapeutic targets for combating impaired neural repair. Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and the amelioration of organ dysfunction due to normal aging. The possibility of harnessing stem cells for therapeutics to combat age-related regenerative limitations raises the question as to how the aging process modulates tissue specific stem cell activity, as well as their inability to maintain both the structure and function of organs within an aging organism. In this context these experiments will provide insight into the effect of aging on NSC function in the brain which is of particular interest due to the associated onset of cognitive impairments and lack of neural repair in response to neurodegenerative diseases such as Alzheimer's disease.

DESCRIPTION (provided by applicant): Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and amelioration of age-related organ dysfunction. The possibility of harnessing stem cells to reverse normal aging raises the question as to how the aging process modulates tissue specific stem cell activity. In the central nervous system, investigating the effect of aging on neural stem/progenitor cell (NPC) function is of particular interest due to the associated onset of cognitive impairments, and lack of neural repair in response to neurodegenerative diseases, such as Alzheimer's disease. During my doctoral work, I discovered that molecular changes occurring in the aging systemic milieu negatively regulate NPC function and cognition. Furthermore, I identified a subset of systemic immune factors - ¿2-Microglobulin (B2M), CCL11 and CCL2 -, as potential regulators of neurogenesis and cognitive function. Interestingly, immune signaling has emerged as a key player in the negative regulation of adult neurogenesis. Thus, the goal of this application is to investigate how immune-related molecular changes in the aging systemic milieu regulate NPC function and associated cognitive processes. Specifically, my hypothesis is that systemic age-related immune factors impair neurogenesis, and cognitive processes, by both inhibiting NPC function directly and indirectly via resident immune cells. I will address this hypothesis in three aims: 1.To determine the direct versus indirect effect of systemic age-related immune factors on NPC function in vitro, 2. To examine the direct effect of systemic age-related immune factors on neurogenesis and cognitive function in vivo, 3. To explore the indirect effect of systemic age-related immune factors mediated by resident immune cells on neurogenesis and cognitive function in vivo. Ultimately, I hope that by investigating the cellular and molecular mechanisms underlying impairments in NPC function, we can better understand how to ameliorate age-related cognitive dysfunction by harnessing the latent plasticity remaining within the old brain.

PROJECT SUMMARY/ABSTRACT Cognitive decline continues to be one of greatest health threats affecting the elderly. In fact, aging remains the single most dominant risk factor for dementia-related neurodegenerative diseases, including Alzheimer's disease. When considering, the rate at which the human population is aging, it becomes imperative to identify means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. Presupposed dogma holds that the old brain is unable to combat the effects of aging due to a lack of inherent plasticity that facilitates permanent age-related functional impairments. We, and others, have begun to challenge such dogma by showing that systemic manipulations such as heterochronic parabiosis (in which the circulatory systems of young and old animals are connected) can enhance adult stem cell function in the aged brain. Moreover, my lab recently demonstrated that neuronal and cognitive rejuvenation is possible in the aged brain by systemic administration of young blood plasma, and identified the transcription factor Creb as a critical mediator of brain rejuvenation. While the burgeoning field of rejuvenation research is fast growing, the current focus thus far has been placed on identifying individual blood-borne factors in young blood. However, this approach has left fundamental questions unexplored: 1. How long lasting are the rejuvenating effects of young blood on the old brain? 2. What mechanistic changes does young blood elicit in the old brain to promote rejuvenation? 3. Do the beneficial effects of young blood on the aged brain extend to dementia-related neurodegenerative diseases such as Alzheimer's disease? The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of young blood on the aged brain. Specifically, our hypothesis is that systemic exposure to young blood elicits long lasting rejuvenation of synaptic and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with three Specific Aims: 1. Characterize the kinetics of brain rejuvenation following systemic exposure to young blood. 2. Identify molecular mechanisms downstream of Creb underlying brain rejuvenation by young blood. 3. Distinguish rejuvenating versus therapeutic effects of young blood in a model of accelerated aging and Alzheimer's disease. Ultimately, these studies will challenge traditional views of brain aging by using the rejuvenating effects of young blood to obtain a mechanistic understanding of the cellular events required for unleashing the latent plasticity within the old brain. The results will also have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.

PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. One exciting possibility is to harness the regenerative capacity of stem cells in the adult brain to reverse normal aging and ameliorate cognitive dysfunction by enhancing neurogenesis. We, and others, have shown that systemic manipulations such as heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) or young plasma administration can partially reverse age-related impairments in neural stem/progenitor cell (NPC) function and loss of cognitive faculties in the aged brain. Interestingly, heterochronic parabiosis studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that mitigating the effect of pro-aging factors may also provide an effective approach to rejuvenate aging phenotypes, however functional investigation of individual pro-aging factors is lacking. Recently my lab identified ?2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a systemic pro-aging factor that negatively regulates regenerative and cognitive functions in the adult hippocampus. The purpose of the proposed study is to gain mechanistic insight into the pro-aging effects of MHC I molecules on the aging brain, and ascertain the therapeutic potential of targeting these molecules at old age. Specifically, our hypothesis is that B2M in concert with classical MHC I molecules act as pro-aging factors driving age-related regenerative and cognitive impairments in the adult hippocampus. We will test this theory with Three Specific Aims: 1: Characterize age-related molecular mechanisms downstream of B2M and MHC I underlying regenerative and cognitive enhancements in the adult brain. 2: Determine effectiveness of reducing cell surface MHC I expression to ameliorate age-related regenerative and cognitive impairments. 3: Investigate classical MHC I molecules, H2-Kd and H2-Db, as pro-aging negative regulators of regenerative and cognitive function in the brain. Successful completion of these studies will have significant translational potential, identifying molecular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative disorders and their downstream consequences in terms of impaired regenerative and cognitive functions.

PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain increasing susceptibility to dementia- related neurodegenerative diseases, such as Alzheimer's disease, in healthy individuals. Evidence suggests that exercise can counter age-related decline in regenerative capacity and cognition in the aged brain. The ability to reverse brain aging through systemic interventions such as exercise could enable the mitigation of vulnerability to age-related neurodegenerative diseases, fulfilling an unmet need that is growing more pressing as the human population ages. Despite the evident benefit of exercise, its application is hindered in the elderly by technical barriers, with evidence that perception of physical frailty or poor health alone can decrease adherence. Therefore, it is critical to identify accessible therapeutic approaches that confer benefits of exercise while circumventing pre-existing limitations. We and others have previously shown that systemic manipulations, including heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, likewise enhance adult neurogenesis and cognition in aged mice1,3,13. The rejuvenating effects observed with exercise mirror those of a youthful circulation, raising the possibility that exercise similarly functions through blood factors to exert its beneficial effects. Indeed, preliminary data from our lab demonstrate that systemic administration of blood plasma derived from exercised mice reverses age-related impairments in adult neurogenesis and cognition in aged mice. The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of exercise-induced blood factors on the aged brain. Specifically, our hypothesis is that systemic exposure to exercise-induced blood factors elicits long lasting rejuvenation of regenerative and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with Three Specific Aims: 1: Characterize the kinetics of brain rejuvenation following systemic exposure to exercise-induced blood factors. 2: Investigate the role of the exercise-induced blood factor Gpld1 in rejuvenating the aged brain. 3: Determine the therapeutic potential of exercise-induced blood factors in a mouse model of Alzheimer's disease. Successful completion of these studies will have significant translational potential, identifying molecular and cellular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.