Aging-related changes in cell death and cell survival pathways and implications for heart failure therapy
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
New York, N.Y. :Springer Science+Business Media, 2014
Aging and heart failure : mechanisms and management / Jugdutt, B.I. [edit.]
University of Antwerp
Underlying the aging process is a lifelong accumulation of molecular damage. When DNA damage is too extensive to be repaired or when the repairing cascades are impaired, e.g., during chronic oxidative stress associated with aging, apoptosis occurs. A very low, albeit elevated, rate of apoptosis can be an important factor in the pathogenesis of heart failure, making it a potential target for therapy. Necrosis is even more prominent in failing human hearts than apoptosis. Autophagy is an essential and protective pathway in the heart. However, during aging, the rate of protective autophagy declines. The progressive inhibition of autophagy in the aging heart is in part attributed to intralysosomal accumulation of lipofuscin. Cross-linked polymeric lipofuscin cannot be degraded by lysosomal hydrolases and leads to preferential allocation of lysosomal enzymes to lipofuscin-loaded lysosomes at the expense of active autolysosomes. Impaired autophagy further stimulates accumulation of damaged mitochondria, which are deficient in ATP production and which produce large amounts of reactive oxygen species (ROS). Moreover, oxidatively modified cytosolic proteins form large indigestible aggregates, enhancing lipofuscinogenesis and sensitizing cardiomyocytes to undergo apoptosis/necrosis, eventually leading to heart failure. Pharmacological inhibition of apoptosis and necrosis improves heart function and survival. Currently used drugs in heart failure therapy, such as ACE-inhibitors and β-adrenergic receptor blockers, prevent apoptosis. However, complete inhibition of apoptosis might have adverse effects. Furthermore, compounds that supplement the decreased levels of autophagy during aging, such as AMPK activators, mTOR inhibitors, and/or sirtuin activators, might be of great value in heart failure therapy by preventing apoptosis and necrosis and stimulating cardiomyocyte survival. However, the dosing should be carefully set in order to avoid excessive autophagic cell death.