Cell Stress Resistance
Does a central mechanism that increases resistance to many kinds of cellular injury ("cell stress") control the rate of aging?
Mutations that extend lifespan in the nematode worm C. elegans
typically make the worms resistant to many forms of stress, including heavy metals, heat, UV light, and oxidation. The implication is that the mutation slows aging and extends lifespan because it turns on a whole set of defense programs, each one specific for a different variety of cellular injury.
Our lab extended this idea to mammals in two directions. First, we found that skin fibroblast cell lines from long-lived mutant mice (Ames, Snell, GHRKO) were resistant to a wide variety of cellular stresses. Second, we showed that evolution of long-lived species of rodents, birds, primates, and other mammals endows these animals with stress-resistant cells as well. The implication is that when evolution needs to lengthen lifespan of specific birds and mammals, boosting up resistance to many kinds of stress is a major part of the package, and that at least some mutations that slow aging in mice use the same control system. For a review of this topic, check out this link.
Our current and recent work in this area has focused on testing specific biochemical ideas about the molecular basis for the stress resistance associated with slower aging in mutant and drug-treated mice. (Parallel work on long-lived species is described here.) Projects have involved studies of:
● Chaperone-mediated autophagy
● mTORC1 and mTORC2 structure and function
● Cap-independent translation mediated by m6A tags
● Implications of elevated ATF4
● Mitochondrial stress, biogenesis, and redox control
● mTORC1 and mTORC2 structure and function
● Cap-independent translation mediated by m6A tags
● Implications of elevated ATF4
● Mitochondrial stress, biogenesis, and redox control
A list of selected papers is included here.
