Study of cellular aging processes

Most prevalent non-infectious diseases that affect people in the developed and developing world are associated with age, yet the mechanism by which these diseases dramatically increase as humans age is unclear. Studies in model systems have generated a number of intellectually attractive hypotheses to explain age-associated decline, and while there is a general consensus that accumulation of cellular damage is the basis for this decline, a molecular mechanism for what actually causes aging in any organism remains elusive.

The budding yeast Saccharomyces cerevisiae is an important model system for studying the aging process in eukaryotic cells; its replicative life span is extended by genetic and environmental processes that also extend life in metazoans. However, compared to its contributions to the study of other complex biological problems, its use in aging has been somewhat limited, in large part because of the difficulty in isolating replicatively aged cells. We have recently overcome this limitation by development of the Mother Enrichment Program (MEP), and can now isolate and examine large populations of synchronously aged cells. The MEP permits us to identify and characterize aging phenotypes and the underlying molecular mechanisms to a level of detail that is difficult to perform in any other organism at this time.

With use of the MEP, we are currently applying the full set of resources available in S. cerevisiae to the study of aging. As an example, we screened a collection of GFP-tagged marker proteins corresponding to most organelles and subcellular structures and discovered that the morphologies of several organelles changed in an age-dependent manner.

We are applying biochemical and genetic tools to understand these age-associated changes further. For instance, focusing on an age-associated mitochondrial morphology change, we found that mitochondrial membrane fusion is defective, and that mitochondrial membrane potential is lost.

We applied the power of yeast genetics to identify a causal link between age-associated changes in vacuolar function and the mitochondrial changes.

These examples highlight our continuing interest in defining the molecular events that define are the cause of cellular aging. Importantly, the processes identified in our studies of aging in S. cerevisiae are conserved among eukaryotes. Thus, our work may allow us to identify fundamental aspects of the aging process at the cellular level.