Aging is accompanied by a variety of molecular changes. These changes increase phenotypic heterogeneity among cells, which can have detrimental consequences. Indeed, aging is the main risk factor for a large number of maladies, including (neuro)degenerative diseases, cardiovascular diseases and cancer.
We are interested in elucidating how changes in the protein folding landscape contribute to phenotypic heterogeneity during aging, how these changes contribute to the aging process itself, and how aged cells can give rise to rejuvenated progeny. We employ the budding yeast (Saccharomyces cerevisiae) model, which has a finite replicative life span of approximately 25 division cycles. Remarkably, through asymmetric cell division, the aged cells give rise to daughter cells with a restored lifespan potential. Thus, this organism provides a powerful system to study the consequences of aging at the molecular level, their phenotypic effect, and how such age-related changes are spatially regulated.
Proteins are responsible for almost all cellular phenotypes. To carry out their proper function, proteins need to fold into a particular structure. This is facilitated by factors, such as chaperones, that maintain protein quality control. Failures in proteostasis can lead to protein misfolding and aggregation – phenomena frequently associated with aging and age-related diseases. Intriguingly, a number of proteins have an intrinsic propensity to alternate between different conformational states and to transition between soluble and assembled states. However, little is known about how these dynamic transitions are shielded form misfolding and how they contribute to the phenotypic landscape of cells and organisms.
In collaboration with the Picotti lab (ETH Zurich), we have recently surveyed the yeast proteome to identify proteins that undergo structural rearrangements in response to aging. Using this dataset as our roadmap, we are currently elucidating how aging leads to structural rearrangements in proteins regulating translation, metabolism, and proteostasis, and how these changes contribute to known and novel aging phenotypes. We are also interested elucidating how cells are able to coordinate the retention of such phenotypes during cell division in order to give rise to rejuvenated progeny.