Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice.
BACKGROUND
Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging.


RESULTS
We analyzed age-associated changes in murine heart and the manner in which suppression of the p110alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart.


CONCLUSIONS
Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.
Inuzuka
Yasutaka
Y
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Okuda
Junji
J
Kawashima
Tsuneaki
T
Kato
Takao
T
Niizuma
Shinichiro
S
Tamaki
Yodo
Y
Iwanaga
Yoshitaka
Y
Yoshida
Yuki
Y
Kosugi
Rie
R
Watanabe-Maeda
Kayo
K
Machida
Yoji
Y
Tsuji
Shingo
S
Aburatani
Hiroyuki
H
Izumi
Tohru
T
Kita
Toru
T
Shioi
Tetsuo
T
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors
D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C484760:PIK3CA protein, human