Relationship Between Resistance to Proteotoxic Stress and Longevity

by Lara Shamieh, Ph.D.

In humans, several age-related diseases are associated with aberrant protein folding or aggregation, including neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. Research on basic mechanisms of aging in invertebrate organisms has indicated that one important cause of aging may be loss of protein homeostasis and increasing proteotoxicity due to misfolding, oxidative damage, and protein aggregation. My project specifically uses the nematode Caenorhabditis elegans model system to study the relationship between resistance to proteotoxic stress and longevity. Others in the lab have recently reported that dietary restriction (DR) dramatically suppresses age-related paralysis in three transgenic nematode models of proteotoxicity.

Using C. elegans, I am investigating the hypothesis that DR slows aging and improves protein homeostasis through a mechanism that involves altered ubiquitin dynamics. My preliminary data demonstrates that the pool of ubiquitinated proteins (the "ubiquitome") in C. elegans is substantially depleted in response to DR by bacterial deprivation (BD). This depletion of the ubiquitome is likely to have profound effects on protein degradation by the ubiquitin-proteasomal system (UPS) as well as to result in altered function for many different mono-ubiquitinated proteins.