Doctoral Dissertations: Ellen Quarles

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Speaker

Ellen Quarles
MBD Program
Pathology
University of Washington

Faculty Sponsor

Peter Rabinovitch


Date & Time

November 17, 2017 at 3:30pm - 4:30pm

Location

Health Sciences Building, RR134

Calendar

Doctoral Dissertations

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Add to Calendar 11/17/2017 03:30 PM 11/17/2017 04:30 PM America/Los_Angeles Doctoral Dissertations: Ellen Quarles Doctoral Dissertations: Ellen Quarles

Ellen Quarles
MBD Program
Pathology
University of Washington
Even in the context of healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects are evident in the decline of diastolic function, increase in left ventricular hypertrophy, metabolic substrate shifts, and alterations to the cardiac proteome. Previous work from our lab indicated that short‐term (10‐week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. We now demonstrate that the improvement of diastolic function is highly persistent 8 weeks after cessation of an 8‐week treatment of rapamycin in both male and female 24+‐month‐old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after two further months without the drug. However, rapamycin treatment did lead to a persistent increase in abundance of electron transport chain (ETC) complex components, most of which belonged to Complex I. Although ETC protein abundance and Complex I activity were each differentially affected in males and females, the ratio of Complex I activity to Complex I protein abundance was equally reduced, and highly persistently, in both sexes. Thus rapamycin treatment in the aged mice persistently improves diastolic function, persistently alters the cardiac proteome in the absence of persistent metabolic changes, and leads to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy or other treatments that promote proteostasis for enhancement of healthspan may involve intermittent short term treatment.
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Description

Even in the context of healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects are evident in the decline of diastolic function, increase in left ventricular hypertrophy, metabolic substrate shifts, and alterations to the cardiac proteome. Previous work from our lab indicated that short‐term (10‐week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. We now demonstrate that the improvement of diastolic function is highly persistent 8 weeks after cessation of an 8‐week treatment of rapamycin in both male and female 24+‐month‐old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after two further months without the drug. However, rapamycin treatment did lead to a persistent increase in abundance of electron transport chain (ETC) complex components, most of which belonged to Complex I. Although ETC protein abundance and Complex I activity were each differentially affected in males and females, the ratio of Complex I activity to Complex I protein abundance was equally reduced, and highly persistently, in both sexes. Thus rapamycin treatment in the aged mice persistently improves diastolic function, persistently alters the cardiac proteome in the absence of persistent metabolic changes, and leads to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy or other treatments that promote proteostasis for enhancement of healthspan may involve intermittent short term treatment.