Six Functions of Respiration: Isn't It Time to Take Control over ROS Production in Mitochondria, and Aging Along with It?

Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function #6, which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation. Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging.

Perspectives of Homo sapiens lifespan extension: focus on external or internal resources?

Homo sapiens and naked mole rats (Heterocephalus glaber) are vivid examples of social mammals that differ from their relatives in particular by an increased lifespan and a large number of neotenic features. An important fact for biogerontology is that the mortality rate of H. glaber (a maximal lifespan of more than 32 years, which is very large for such a small rodent) negligibly grows with age. The same is true for modern people in developed countries below the age of 60. It is important that the juvenilization of traits that separate humans from chimpanzees evolved over thousands of generations and millions of years. Rapid advances in technology resulted in a sharp increase in the life expectancy of human beings during the past 100 years. Currently, the human life expectancy has exceeded 80 years in developed countries. It cannot be excluded that the potential for increasing life expectancy by an improvement in living conditions will be exhausted after a certain period of time. New types of geroprotectors should be developed that protect not only from chronic phenoptosis gradual poisoning of the body with reactive oxygen species (ROS) but also from acute phenoptosis, where strong increase in the level of ROS immediately kills an already aged individual. Geroprotectors might be another anti-aging strategy along with neoteny (a natural physiological phenomenon) and technical progress.