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. The demise of the cell thus most often occurs within the context of the simultaneous demise of the whole organism.
Organelles and cellular subtypes also exhibit a differential susceptibility to stress during aging. This preference can result in the consistent advent and spreading of disease across particular subsets and even subcompartments of the cells. Thus age-onset diseases often begin in one distinct tissue before signs of dysfunction spread infectiously along reproducible networks, affecting the physiology of distal tissues in distinct but foreseable patterns.
We are trying to understand how the small and canonically-autonomous parts of a cell – the suborganelles and subcompartments – communicate both with each other and with the organism as a whole in response to aging. 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. We hope that a better understanding of the patterns, mechanisms, and consequences of endocrine-based stress responses will allow us to productively target the source and signal causing the distal effects seen in many age-onset disease.
The Communication of Mitochondrial Proteotoxic Stress
Mitochondrial dysfunction has been reported as a cause or as a consequence of nearly every single age-onset human disease. Recent work within our lab suggests that mitochondria potentially communicate or actively signal to regulate one another's activity between tissues. We have found that a tissue-specific mitochondrial stress can be sensed and transmitted to distal cells, invoking a cell non-autonomous mitochondrial stress response that extends life span. We are now working towardunderstanding the source and nature of this signal and the functional and morphological consequences of its signaling.
The Communication of Endoplasmic Reticulum Stress
The endoplasmic reticulum (ER) is responsible for the folding and maturation of up to as many as 13 million proteins per minute. Challenges to the ER folding environment can have a multitude of consequences on an organism’s viability: defects in ER function are strongly associated with a large number of metabolic and age-onset disorders. We wish to understand how ER stress is signaled and perceived throughout the organism as it ages, and the extent to which such signaling is conserved in vertebrates.
The Function of Cytoplasmic Heat Shock Response in Aging
We have an additional team within the lab working on stress responses of the cytoplasm. The idea behind this work is to understand how the cytoplasmic stress responses might affect proteome maintenance and the rate of aging of the entire organism. The master regulator of the cytoplasmic stress response is the transcription factor HSF-1. We have isolated a hypermorphic variant of HSF-1 that can dramatically extend the life span of the nematode and increase thermotolerance. Paradoxically, it does not result in a canonical upregulation of the downstream chaperone network typically ascribed to the achievement of these phenotypes. Recently, we have created a mouse model in which HSF-1 is constitutively activated in the CNS, and we are actively working to understand HSF-1’s effects on proteotoxic stress in this background. Importantly, this body of work may reveal novel aspects of heat shock regulation, conserved from worms to mice, that function independently of chaperone induction.
Stem Cells, Nutrient Availability and the Aging Process
The extreme pressure that evolution places on reproductive success has long suggested that resources will be allocated differently across cell types: for example, to ensure that the germline retains a pristine health that assures the survival of the organism’s progeny, resources required for a heightened maintenance of cellular defenses must be upregulated. Elimination of reproduction would conversely signal the upregulation of defense mechanisms in somatic tissue, and dietary restriction is likewise thought to re-appropriate resources from reproduction towards somatic cell defenses. We thus hypothesize that germline cells (such as human embryonic stem cells) or nutrient-deprived cells might exhibit a heightened capacity to ensure proteostasis and thereby avoid protein damage. Accordingly, we have invested a considerable amount of effort in understanding how the proteome of stem and germ cells can remain pristine. Our work has focused on the functional consequences of the upregulation of the proteasome found in these cells.
In parallel projects, we have found that genetic manipulation of specific receptors in olfactory neurons in both mice and worms is sufficient to increase health span and longevity, and are actively working to uncover the genetic signaling pathway underlying this response. Our lab has also discovered a highly conserved transcription factor, PHA-4, required for dietary restriction in C. elegans. We believe that this protein forms a core-signaling pathway that responds to and integrates an organism's response to reduced caloric intake. We are thus working toward understanding the molecular mechanism by which this pathway perceives and interprets the environmental signals that ultimately result in increased longevity.
Understanding the Effects of Aging on the Translatome
We are actively working on applying emergent technologies to manipulate and analyze the workings of the translational apparatus throughout the whole organism and within specific tissues. Significantly, this includes the establishment of ribosome profiling methodologies in worms and in stem cells. These techniques will allow us to dissect translation at a nucleotide resolution as it occurs, and will provide fundamental insights into the effects of aging on the rate, pausing, and non-coding start sites of translation. This system will allow us the capacity to both temporally and spatially disect apart the contributions of stress responses to changes in the translatome.