Opposing Effects of Age and Calorie Restriction on Molecular Determinants of Myocardial Ischemic Tolerance

Abstract

We test the hypothesis that moderate calorie restriction (CR) reverses negative influences of age on molecular determinants of myocardial stress resistance. Postischemic contractile dysfunction, cellular damage, and expression of regulators of autophagy/apoptosis and of prosurvival and prodeath kinases were assessed in myocardium from young adult (YA; 2-to 4-month-old) and middle-aged (MA; 12-month-old) mice, and MA mice subjected to 14 weeks of 40% CR (MA-CR). Ventricular dysfunction after 25% -2%), as was cell death indicated by troponin I (TnI) efflux (1,701 -214 ng vs. 785 -102 ng in YA). MA hearts exhibited 30% and 65% reductions in postischemic Beclin1 and Parkin, respectively, yet 50% lower proapoptotic Bax and 85% higher antiapoptotic Bcl2, increasing the Bcl2/Bax ratio. Age did not influence Akt or p38-mitogen-activated protein kinase (MAPK) expression; reduced expression of increasingly phosphorylated ribosomal protein S6 kinase (p70S6K), increased expression of dephosphorylated glycogen synthase kinase 3b (GSK3b) and enhanced postischemic p38-MAPK phosphorylation. CR countered the age-related decline in ischemic tolerance, improving contractile recovery (60% -4%) and reducing cell death (123 -22 ng of TnI). Protection was not associated with changes in Parkin or Bax, whereas CR partially limited the age-related decline in Beclin1 and further increased Bcl2. CR counteracted age-related changes in p70S6K, increased Akt levels, and reduced p38-MAPK (albeit increasing preischemic phosphorylation), and paradoxically reduced postischemic GSK3b phosphorylation. In summary, moderate age worsens cardiac ischemic tolerance; this is associated with reduced expression of autophagy regulators, dysregulation of p70S6K and GSK3b, and postischemic p38-MAPK activation. CR counters age effects on postischemic dysfunction/cell death; this is associated with reversal of age effects on p70S6K, augmentation of Akt and Bcl2 levels, and preischemic p38-MAPK activation. Age and CR thus impact on distinct determinants of ischemic tolerance, although p70S6K signaling presents a point of convergence.

Differential effects of soluble epoxide hydrolase inhibition and CYP2J2 overexpression on postischemic cardiac function in aged mice

“…Similarly, improved postischemic left ventricular function was observed in aged sEH null mice (31.1% vs. 12.9%, respectively, p<0.05) (Fig 1a, 1b). Consistent with previous reports of decreased tolerance of aged hearts against ischemic injury [26, 27], we observed significant reduction in postischemic functional recovery of aged WT as compared to young WT (Fig 1b). Both, young and aged, sEH null mouse hearts demonstrated significantly higher contraction and relaxation rate compared to age matched WT (Fig 1c, 1d).…”

Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium

“…Since p70s6K phospho-inhibits GSK3β (Sutherland et al ., 1993), declining expression will amplify detrimental effects of elevated GSK3β in aged tissue. These changes are consistent with data for middle-aged hearts (Peart et al ., 2012), and demonstrate that age induces an expression profile favoring signal dysfunction, mitochondrial injury and cell death. The basis of the differential changes in pro-survival (caveolin-3, p70s6K) vs .…”

Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast

“…CR stimulation of autophagy promotes cardiomyocyte function associated with attenuated cardiac senescence (Han et al 2012; Shinmura et al 2011). CR has been shown to sustain autophagy in liver (Donati et al 2012), and has a role in counteracting reduced ischemic tolerance in the heart (Peart et al 2012). Inhibition of autophagy inhibits the life span extending effects of CR (Rubinsztein et al 2011).…”