Mechanical Signaling and its Role in Cell Fate and Aging

Cells respond to the passive and active mechanics of their surrounding niche from the onset of fertilization through senescence. Their response is regulated by cell contractility but ultimately interpreted by a variety of nuclear- and adhesion-based mechanisms that convert biophysical information, e.g. niche stiffness, to biochemical cues. Here I will describe how age-associated expression and localization changes of one adhesion protein–vinculin–perturb the cytoskeleton to adversely affect heart relaxation and impair chamber filling in Drosophila melanogaster, the fruit fly, leading to diastolic dysfunction. In a second example, I will show how age-associate nuclear stiffness changes, caused by reduced Lamin A/C expression, drives the loss of cardiac identity and again results in diastolic dysfunction. In both examples, we observe conservation of mechanism with aged rats and rhesus macaques: progressive loss of Vinculin and Lamin A/C drive significant negative remodeling and loss on contractile function with age. I will also illustrate how our findings have influenced the translation of cell-based therapies and the identification of novel therapeutic targets in humans.