As an organism ages, its proteins face an increasing severity in the challenges they receive from extrinsic and intrinsic environmental perturbations (1, 2). Chaperones become dysregulated, while the degradation machineries stop working properly. The protein accumulates damage and starts to misfold. At this point, the cell needs to mount a response to restore its homeostasis; however, the stress response machinery that it typically relies upon when faced with such challenges has lost its capacity to function (1, 2).
This breakdown, however, does not lead to complete disorder. As the 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 (3, 4). The demise of the cell thus most often occurs within the context of the simultaneous 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 suborganelles and subcompartments – such that we can take a larger step back to ask how those smaller portions can communicate both with each other and with the organism as a whole. Our approaches have required us to diversify the contexts in which we ask questions: we work on model systems ranging from stem cells and 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 effect the physiology of the whole of the organism.
In our research, we have found that the stress response pathways that ensure proteome maintenance are not restricted to cell autonomous events, but can be communicated across an organism. We have reported that this is found for the unfolded protein response of the mitochondria (UPRMT), and now find distinct signaling events for the UPR of the endoplasmic reticulum (UPRER) and the cytosolic heat shock response (HSR). Collectively, we have discovered at least three distinct signaling events that report upon proteome form and function across an organism (Fig. 1). Our evidence strongly suggests that intracellular and even organelle-specific stress can be communicated extracellularly via a regulated, endocrine-like process to impinge on the aging process and health.
- Aging in C. elegans
- Human embryonic stem cell identity
Awards and Honors:
- Siebel Distinguished Chair in Stem Cell Biology (2013)
- Nathan Shock Award (2012)
- NIH/NIA MERIT Award (2012-2022)
- Vincent Cristofalo Award (2010)
- Glenn Foundation for Medical Research Award (2007-2009)
- McKnight Neuroscience of Brain Disorders Award (2007-2010)