Approved Research

Regulation of age-related diseases by cellular metabolites

Lay summary

How the cells in our body metabolize energy changes as we age. These changes, such as having more difficulty burning glucose to generate energy, have a key role in making us susceptible to diseases of aging like Alzheimer's disease and heart disease. On the other hand, our bodies have the ability to generate ketone bodies from fat as a substitute for glucose, and which may provide resilience to Alzheimer's disease and heart disease. The fingerprints of the metabolism changes in our cells can be seen in the blood, called metabolomics. The UK Biobank is the best resource in the world for studying the relationship between metabolomics and diseases of aging, because it includes both comprehensive metabolomics data with hundreds of molecules, as well as highly detailed clinical data on diseases, cognitive and physical function, diet and exercise patterns, and much more. We will use this unique UK resource to better understand the role of ketone bodies in aging and chronic disease, and to create a "metabolomic clock" of aging.

While ketone bodies are famously associated with fasting or ketogenic diet, our bodies make a little of them all the time. They are being investigated as therapies for Alzheimer's disease and heart disease, but little is known about how our own production of ketone bodies changes with age or affects these diseases of aging. First, we will study how our ketone body production is controlled - who makes more or less ketone bodies all the time, based on age, diet, exercise, genetics, or medical conditions. Second, we will study how ketone bodies, and variations in the genes that control ketone bodies, predict vulnerability or resistance to many different chronic diseases. These analysis will tell us for which diseases ketone bodies may be a risk factor, or a potential therapy. Third, we will create a "metabolomic clock" by analyzing which among hundreds of metabolic molecules in the blood change with age. This clock could then be used to discover how diseases and conditions of age are affected by our cellular metabolism, to guide new therapies.