Research projects in the lab are currently focused on the following specific areas:
The Functional Biology of HDL Particles in Alzheimer’s Disease
Alzheimer’s is a debilitating neurodegenerative disease that is growing in prevalence despite decades of investment in the research and development of diagnostics and therapeutics.
In this project we are studying how changes in the composition and structure of HDL particles reduce the functional capacity of HDL particles in Alzheimer’s patients, and how APOE genotype mediates the relationship between HDL and cognitive function. We are particularly interested in how glycosylation – a post-translational modification that affects a wide range of critical functions including protein folding, cell-cell recognition, and binding – is altered in Alzheimer’s Disease. The ultimate goal of this project is to develop new ways to diagnose Alzheimer’s earlier, and to develop interventions that improve HDL functionality to reduce the risk of Alzheimer’s Disease. We have examined the effects of eggs, the Mediterranean diet, and studies are under way to assess the effects of prebiotics, vitamin D, prolonged fasting, and fasting mimetics on the ability of HDL particles to perform cholesterol efflux and mediate immunomodulatory effects on innate immune cells including macrophages and microglia.
Effects of Prolonged Fasting and Fasting Mimetics
We are what we eat. But we are also what we don’t eat, when we eat, how much we eat, how often we eat, how we prepare our food, where our food comes from, how active we are, how clean the air we breathe is, how much we travel, whether we have pets, and all of the rest of the details of each individual’s relationship with their environment. In this context, we are particularly intrigued by prolonged fasting (>24 hours) because of the convincing evidence that fasting is the single most powerful tool we have to extend lifespan, and more importantly, healthspan. But how much fasting is the right amount? And how often? It is not just about weight loss, fasting also confers a number of beneficial effects on metabolism and immune function, and we are interested in measuring the response to fasting in different individuals, and how fasting approaches may be useful for preventing disease, improving health, and extending healthspan. We are also developing molecular approaches to mimic the beneficial effects of fasting because fasting is not for everyone, particularly vulnerable populations like the elderly and individuals with underlying conditions.
Development of Methods to Isolate and Characterize HDL
Not only are HDL protective against vascular diseases, neurological diseases including Alzheimer’s Disease, and several other chronic, inflammatory, diet-mediated diseases, HDL are also associated with protection from infectious and auto-immune disease, and they are linked with extreme longevity. HDL affect nearly every aspect of health. Yet, we do not know how to improve HDL. In the Zivkovic Lab we focus on isolating HDL and characterizing their composition and functionality in different disease conditions, and in response to different dietary interventions (for example fasting, fasting mimetics, eggs, Mediterranean diet, prebiotics, vitamin D). We incorporate clinical, biochemical, in vitro, ex vivo, metabolomic, lipidomic, proteomic, glycomic, genomic, and computational approaches in our work to understand how HDL do what they do.
HDL are very tricky to study. They are tiny (10 nm in diameter, as small as many proteins) yet compositionally and functionally diverse. In the Zivkovic Lab we are developing methods using high performance size exclusion chromatography with inline optical detectors, including light scattering and refractive index detectors, to measure HDL particle size, structure, and even particle count as they are fractionated for further downstream compositional analyses.