The first Monday of each month, the Knight Initiative for Brain Resilience will host monthly seminars to bring together awardees, affiliated professors and students for a series of 'lab meeting' styled talks. Two speakers will discuss their brain resilience research, experiences in the field, and answer questions about their work.
Sylvie Dobrota, Stanford University
Mitochondrial DNA Sequence Variation and Cognitive Outcomes
Mitochondrial dysfunction is a hallmark of aging that manifests in numerous age-associated disorder. However, the impact of mitochondrial DNA (mtDNA) genetic sequence variation on neurocognitive outcomes remains poorly understood. Mitochondrial bioenergetics, which are impacted by mtDNA mutations, can impact a human’s resilience to aging and response to physiologic stressors. A stroke represents a major physiologic stressor to the brain, and subsequent cognitive impairment and dementia are common – estimates of post-stroke cognitive impairment range from 20-80%, depending on the population studied. No prior research has evaluated the role of mtDNA in the brain’s resilience to a stroke event, and whether it could modulate the resulting cognitive impairment that is commonly observed. This talk will describe our preliminary findings on the association between mtDNA sequence variants and cognitive outcomes in two studies: the LIFE (Lifestyle Interventions and Independence for Elders) and Health ABC (Health Aging and Body Composition). We will also detail ongoing work in additional populations including the StrokeCog study at Stanford, a cohort study of stroke survivors. The identification of novel pathologic mtDNA variants has the potential to advance our understanding of the biologic mechanisms of cognitive decline and inform novel interventions to reduce cognitive impairment after stroke.
Paloma Navarro, Stanford University
Neuro-immune interactions in the aging brain
Aging has a profound and devastating effect on the brain. A fundamental question is how immune cells and inflammation contribute to the aging process in the brain. The subventricular zone (SVZ) provides a great paradigm to address this question. This brain region brain is infiltrated by T cells, shows increased inflammation and exhibits clear functional decline during aging in both mouse and humans. We systematically characterized age-related changes in this region with a specific focus on immune cell populations. We found that T cells show an exhaustion phenotype and that microglia, the resident immune cells of brain, showed both an increase in pro-inflammatory signaling and a decrease in anti-inflammatory signaling during aging. Based on these molecular signatures, we used protein engineering to specifically manipulate different immune cells in the old brain. We found that activating a very small population of T cells, even in the presence of an anti-inflammatory agent, seems to be detrimental for the old brain. This suggests that T cells could be drivers of aging in the brain and that removing them or preventing their inflammatory effects could be potential immunotherapies to counter brain aging.