Caloric restriction and mitochondrial function in the ageing myocardium.
Extension of life span by caloric restriction is assumed to result from retardation of a genetically determined program of ageing, but the new concept of hormesis regards caloric restriction as mild stress, which triggers active, protective reactions with reparative capacities. Here, we discuss two potential hormetic reactions with protective efficacy against dysfunctional mitochondria: restoration of neuregulin signalling by upregulation of erbB receptors and enhanced biogenesis of functionally active mitochondria by an eNOS-dependent mechanism. Mitochondrial ageing is considered to result from a vicious cycle of mitochondrial ROS-formation, ROS-mediated damage of mitochondrial DNA, disproportional respiratory chain composition and thereby additionally enhanced ROS production leading to apoptotic cell loss. Proof-of- principle for such a cycle was obtained from transgenic mice with impaired mitochondrial DNA repair capacity. Indirect arguments suggest this cycle operating also in ageing wild-type mammals, accelerated by downregulation of mitochondrial gene expression in insulin resistance, by inflammatory excess NO formation, and by downregulation of erbB receptors in cardiac ageing and failure. Attenuated neuregulin signalling induces a shift in the splice products of the Bcl-x gene from the antiapoptotic Bcl-xL protein towards the proapoptotic Bcl-xS protein, resulting in mitochondrial dysfunction and apoptosis in cardiomyocytes. Transient caloric restriction upregulates erbB receptors and restores mitochondrial Bcl-x-isoform patterns and mitochondrial dysfunction in the ageing heart.
Rohrbach
Susanne
S
Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Street, 40, 06112 Halle, Germany. susanne.rohrbach@medizin.uni-halle.de
Niemann
Bernd
B
Abushouk
Amir M A
AM
Holtz
Juergen
J
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D031204:Caloric Restriction; D004272:DNA, Mitochondrial / Q000502:physiology; D051379:Mice; D008929:Mitochondria, Heart / Q000235:genetics / Q000502:physiology*; D020880:Neuregulins / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology
D004272:DNA, Mitochondrial; D020880:Neuregulins; D051020:bcl-X Protein; D009569:Nitric Oxide