The Effect of Aging on Combinatorial Signal Integration

Assistant Professor Yoni Savir

As our life expectancy increases, the chances of getting protein folding diseases like Alzheimer’s, Parkinson’s, or diabetes also increases.  When proteins fail to fold, their function is impaired, and the consequences can be devastating for patients. Under normal circumstances, the cell has a quality control mechanism to prevent proteins from folding incorrectly, as well as to get rid of misfolded proteins. This mechanism is known as the unfolded protein response. The unfolded protein response is activated in response to an accumulation of unfolded or misfolded proteins in the protein factory of the cell (the endoplasmic reticulum). A major challenge is understating is how and why the response that copes with protein aggregation is failing with age; It is braking as the cell age? Is it working properly but overloaded with aggregates as the cells age? Answering these questions will advance our understating of cellular aging and will promote our ability to find new treatments for age-related diseases.

We use imaging in microfluidic devices together with an automated flow-cytometry system to characterize, at the single-cell level, the ability of cells to regulate their UPR as a function of age. We develop a mathematical framework using failure theory to decipher the mechanism behind UPR deterioration as the cell ages. We also study how genetic perturbations affect the ability of cells to operate the UPR as they age and their age-dependent response to amyloid-β and tau protein toxicity.

We take an interdisciplinary approach and use tools from experimental biology (high throughput setups, microfluidics, genetics), Biophysics and applied math (stochastic processes, mathematical biology) and Engineering (signal processing, deep learning).Yoni Savir