Mitokine control of metabolism and longevity – supported by LIMNA

Abstract

As an organism ages, its proteins face an increasing severity in the challenges they receive from extrinsic and intrinsic environmental perturbations. Chaperones become dysregulated while the degradation machineries become ineffective. A protein accumulates damage and starts to misfold, at which point the cell needs to mount a response to restore its homeostasis. With age, however, the stress response machinery that it typically relies upon when faced with such challenges has lost its capacity to function.

This breakdown does not lead to complete disorder. As an organism ages it exhibits a degree of correlated, recognizable, and predictable changes to its physiology over time. These changes can occur synchronously across multiple tissues and organs. The phenotypic changes of aging occur in a type of concert rather than in isolation, suggesting the residual participation of the endocrine system in the onset of age-related phenotypes. The demise of the cell thus most often occurs within the context of the concurrent demise of the whole organism.

Our lab focuses on the questions of why an aging organism begins to lose control over the integrity of its proteome, and how this loss is communicated across its various tissues. We have taken the unique approach of breaking down a cell into its small and canonically-autonomous parts – its sub-organelles and sub-compartments – such that we can take a larger step back to ask how those smaller portions can communicate both with each other and throughout the organism as a whole. Our approaches have required us to diversify the context in which we ask questions: as such we work on model systems ranging from stem cells to nematodes to mice. We have developed and applied techniques that allow us to manipulate signaling pathways or proteins within a single tissue, cell, or an organelle within a single cell so that we can observe how that small perturbation might reverberate and affect the physiology of the whole organism.