TY - JOUR
T1 - Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
AU - Quarles, Ellen
AU - Basisty, Nathan
AU - Chiao, Ying Ann
AU - Merrihew, Gennifer
AU - Gu, Haiwei
AU - Sweetwyne, Mariya T.
AU - Fredrickson, Jeanne
AU - Nguyen, Ngoc Han
AU - Razumova, Maria
AU - Kooiker, Kristina
AU - Moussavi-Harami, Farid
AU - Regnier, Michael
AU - Quarles, Christopher
AU - MacCoss, Michael
AU - Rabinovitch, Peter S.
N1 - Funding Information:
Support was provided by NIH grants R01 AG038550, P01 AG001751, P30 AG013280, K08 HL128826, and T32 AG000057.
Publisher Copyright:
© 2019 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that short-term (10-week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age-related changes. In this report, we demonstrate that the rapamycin-dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8 weeks after cessation of an 8-week treatment of rapamycin in both male and female 22- to 24-month-old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after 8 further weeks without the drug. However, rapamycin 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 and persistently reduced after rapamycin treatment in both sexes. Thus, rapamycin treatment in the aged mice persistently improved diastolic function and myocardial stiffness, persistently altered the cardiac proteome in the absence of persistent metabolic changes, and led to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short-term treatments.
AB - Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that short-term (10-week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age-related changes. In this report, we demonstrate that the rapamycin-dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8 weeks after cessation of an 8-week treatment of rapamycin in both male and female 22- to 24-month-old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after 8 further weeks without the drug. However, rapamycin 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 and persistently reduced after rapamycin treatment in both sexes. Thus, rapamycin treatment in the aged mice persistently improved diastolic function and myocardial stiffness, persistently altered the cardiac proteome in the absence of persistent metabolic changes, and led to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short-term treatments.
KW - aging
KW - echocardiography
KW - heart
KW - persistence
KW - proteomics
KW - rapamycin
UR - http://www.scopus.com/inward/record.url?scp=85076343196&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076343196&partnerID=8YFLogxK
U2 - 10.1111/acel.13086
DO - 10.1111/acel.13086
M3 - Article
C2 - 31823466
AN - SCOPUS:85076343196
SN - 1474-9718
VL - 19
JO - Aging Cell
JF - Aging Cell
IS - 2
M1 - e13086
ER -