Abstract 1411: Suppression of Insulin Signaling Attenuates Cardiac Aging in Mice
Aging is a major risk factor for heart failure. Suppression of the insulin signaling pathway increases the lifespan of model organisms. We tested whether the alteration of insulin signaling modifies the cardiac aging process. We analyzed young (12 week old) and aged (64 – 80 week old) wild type (WT) mice, and young and aged transgenic mice that expressed dominant-negative phosphoinositide-3-kinase (dnPI3K) in a heart-specific manner. PI3K is a major downstream effector of insulin. We analyzed heart function using cardiac catheterization under dobutamine infusion. Max dp/dt in aged dnPI3K mice was higher than that in aged WT mice, and heart rate was not different between aged WT and aged dnPI3K mice. The extent of myocardial fibrosis in aged WT mice was significantly greater than that in young WT mice, and this increase was attenuated in aged dnPI3K mice (area in %; 0.06 ±0.01 vs. 1.57 ±0.23 vs. 0.56 ±0.13, mean ±SEM). The amount of p16, the representative marker of aging, was increased in aged WT mice compared to that in young WT mice, and this increase was attenuated in aged dnPI3K mice. The age associated increases in proinflammatory cytokines and oxidative stress markers were attenuated in dnPI3K mice. Gene expression profiling using microarray analyses identified 157 genes whose expression was decreased in aged WT mice compared to young WT mice. The expression of these down-regulated genes was significantly preserved in aged dnPI3K mice. In conclusion, the insulin signaling is likely to be a conserved mechanism that regulates the aging process in mammals, and the suppression of insulin signaling attenuated an age-associated decline in cardiac function.