1. Pro-Aging Immune Factors in Old Blood.
Our lab investigates the effect of systemic pro-aging immune factors on the hippocampus. We identified ß2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a pro-aging factor that negatively regulates neurogenesis and cognitive function (Villeda et al. Nature 2011; Smith et al. Nature Med 2015; Lin et al. Plos Bio 2021). Excitingly, in old animals the absence of endogenous B2M expression resulted in improved cognitive function and enhanced neurogenesis (Smith et al. Nature Med 2015). Using a heterochronic hematopietic stem cell (HSC) transplantation model we identified the blood-derived cytokine Cyclophilin A (CyPA) as a pro-aging factor that impairs synaptic plasticity and cognition. Moreover, we demonstrated that inhibition circulating CyPA improves cognition in aged mice (Smith et al. Aging Cell 2020).
We are currently developing approaches to target pro-aging immune factors in blood to ameliorate age-related impairments in regenerative, synaptic, and cognitive function in old age.
2. Pro-Youthful Factors in Young Blood.
Heterochronic parabiosis studies have shown that blood-borne factors present in young blood can promote adult neural stem cell function and increase synaptic plasticity in the hippocampus of aged mice (Villeda et al. Nature 2011). Moreover, systemic administration of young blood plasma into aged mice reverses age-related cognitive impairments in learning and memory (Villeda et al. Nature Med 2014). Mechanistically, we identified cyclic AMP response element binding protein (Creb) as a critical mediator of young blood induced cognitive enhancements. Additionally, we identified platelet factors in young plasma - and chemokine CXCL4/platelet factor 4 (PF4) in particular - as pro-youthful blood factors that attenuate neuroinflammation, rejuvenate the aged peripheral immune system and rescue cognition in aging (Schroer et al. Nature 2023).
We are currently examining the molecular mechanisms by which individual pro-youthful factors in young blood rejuvenate the aged brain.
3. Exercise-Induced Rejuvenating Blood Factors.
Our lab is exploring the potential of blood factors to transfer the benefits of exercise on the aging brain. We demonstrated that systemic administration of plasma derived from blood of aged exercised mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice (Horowitz et al. Science 2020). Using a proteomic approach, we identified glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) as a liver-derived exercise-induced circulating blood factor in aged mice and humans with potential relevance to cognitive function in mice. Increasing systemic levels of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of glycosylphosphatidylinositol (GPI)-anchored substrate cleavage.
We are currently exploring a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.
4. Mechanisms of Cognitive Rejuvenation.
Our lab has identified molecular candidates intrinsic to the aging hippocampus that can be targeted to counteract functional decline. We identified the epigenetic regulator ten eleven translocation methylcytosine dioxygenase 2 (Tet2) - which catalyzes the production of 5-hydroxymethylcytosine (5hmC) - as a key epigenetic mechanism restoring adult neurogenesis (Gontier et al. Cell Reports 2018). Mimicking an aged condition by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis. In a heterochronic parabiosis rejuvenation model hippocampal Tet2 expression was restored, and increasing Tet2 in adult neural stem cells offset the precipitous age-related decline in adult neurogenesis.
We also identified the post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) as a key molecular mediator promoting neurogenic and cognitive rejuvenation. Mimicking an age-related decline in O-GlcNAcylation by targeting neural stem cell or neuronal O-GlcNAc transferase (OGT) recapitulated cellular and cognitive features of brain aging (Wheatley et al. Current Biology 2019; White et al. PNAS 2020).
Excitingly, increasing neuronal O-GlcNAcylation in aged mice by overexpressing OGT, or targeting neuronal Tet2, enhanced hippocampal-dependent learning and memory in adult and aged mice (Wheatley et al. Current Biology 2019; Pratt Cell Reports 2022). Our data indicate that epigenetic and post-translation modifications regulate age-related regenerative and cognitive decline in the aging brain, with functional implications for broad neurogenic rejuvenation.
We are currently leveraging unbiased transcirptomic and proteomic approaches to identify molecular drivers across broad hippocampal cell types that facilitate cognitive rejuvenation.
