Caloric restriction delays cardiac ageing in rats: role of mitochondria.
OBJECTIVE
We tested whether long-term caloric restriction (CR) corrects pre-existing manifestations of cardiac ageing in rats.


RESULTS
The age-specific effects of CR (-40%, 6 months) on mortality, left ventricular (LV) function, mitochondrial function, oxidative damage, and apoptosis were analysed in young (6 + 6 months) and senescent rats (24 + 6 months). CR in senescent rats significantly reduced mortality. LV and cardiomyocyte hypertrophy were reduced together with the mRNA expression and plasma concentrations of overload indicators BNP/ANP. Mitochondrial function was improved, resulting in lower oxidative damage and apoptotic activation. In particular, the pro-apoptotic Bcl-xS/Bcl-xL isoform pattern, mitochondrial translocation of Bax, release of cytochrome C into cytosol, and caspase-9 activation were reduced in comparison to age-matched rats on the control diet. However, CR resulted only in minor changes in young rats. Serum obtained from old control or CR rats was used for in vitro experiments. H9C2 cardiomyoblasts and adult rat ventricular cardiomyocytes preconditioned with CR serum demonstrated a low Bcl-xS/Bcl-xL ratio. H9C2 cells were resistant against H(2)O(2)-mediated loss of mitochondrial membrane potential, apoptosis activation, and reduced cell viability. Thus, beneficial effects of CR are mediated through circulating factors and can be mimicked with CR serum. However, this protection critically depended on a high Bcl-xL protein expression as seen after siRNA-mediated Bcl-xL knockdown.


CONCLUSIONS
CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation and by preventing deterioration in LV function. Therefore, interventions that mimic these effects of CR may represent an additional therapeutic option for the aged or failing heart.
Niemann
Bernd
B
Department of Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, Germany.
Chen
Ying
Y
Issa
Hassan
H
Silber
Rolf-Edgar
RE
Rohrbach
Susanne
S
D000367:Age Factors; D000375:Aging; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D031204:Caloric Restriction; D002460:Cell Line; D016922:Cellular Senescence; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left
D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species