Aging and disease are characterized by dysfunction at the organismal, organ, tissue, and cellular levels. Plasma-based proteomic biomarkers have proven incredibly valuable for assessing disease status and therapeutic efficacy and have largely been based on markers of organ-level dysfunction or degeneration. However, early states of many disease processes are driven by cellular dysfunction that can take many months or years to manifest in measurable tissue or organ-level problems. Thus, plasma-based biomarkers of cellular dysfunction could result in earlier disease detection or identify prodromal states wherein treatment could prevent the subsequent development of disease.
Dysfunction in several cellular organelles, in particular, has been associated with aging and disease. As one prominent example, loss of proteostasis is a widely recognized hallmark of many disease processes and of aging in general, and is characterized by dysfunction in the endoplasmic reticulum (ER stress and unfolded protein response) and lysosome (accumulation of undigested protein substrates). We hypothesize that these and other organelle-specific problems would result in increases in organelle-derived proteins in blood, leading to unique biomarker signatures of cellular dysfunction. We aim to use UK biobank data to develop organelle-based biomarker clocks that can predict accelerated aging or the development of disease.