Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

Abstract

Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS). Moreover, mitochondrial function is strongly linked to mitochondrial Ca2+ homeostasis and mitochondrial shape, which undergo various alterations during aging. Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions. Accordingly, interventions delaying the onset of age-associated disorders involve the manipulation of mitochondrial function, including caloric restriction (CR) or exercise, as well as drugs, such as metformin, aspirin, and polyphenols. In this review, we discuss mitochondria’s role in and impact on cellular aging and their potential to serve as a target for therapeutic interventions against age-related cellular dysfunction.

Pathology and mechanisms of cochlear aging

“…Energy, provided through cellular respiration in the mitochondria, is required for cell survival, and the decreased ability to provide sufficient energy, through oxidative phosphorylation, is certainly a potential mechanism of cell loss in all tissues, especially the energy‐demanding cochlea (Madreiter‐Sokolowski, Sokolowski, Waldeck‐Weiermair, Malli, & Graier, ; Pickles, ). It seems likely that during the production of adenosine triphosphate, reactive oxygen species (ROS) are generated and these have the capability of damaging DNA leading to loss of proteins and apoptosis (Ames, ; Lee & Wei, ).…”

Mitochondrial Dysfunction as a Key Event during Aging: From Synaptic Failure to Memory Loss

“…Since mitochondrial dysfunction is a key event promoting aging, interventions that focus on maintaining or restoring the correct functioning of the mitochondria seem fundamental. For this purpose, two different experimental strategies could be used [127], physiological approaches or pharmacological approximations, which will be briefly summarized in this section.…”

“…From the physiological point of view, maintaining a lifestyle that includes recurrent physical exercise preserves mitochondrial function [127]. During aging a loss of age-associated muscle mass is directly related with decreased mitochondria-dependent metabolic capacity, as well as with reduced mitochondrial biogenesis [128].…”

“…Mitochondrial function can also be regulated pharmacologically, for example, through the administration of polyphenols such as resveratrol, green tea, and red wine [127,136]. Specifically, they act by promoting mitochondrial OXPHOS and activating cellular antioxidant mechanisms [137].…”

Enhanced inter-compartmental Ca2+ flux modulates mitochondrial metabolism and apoptotic threshold during aging

“…The hallmark of aging is a progressive decline in the ability of an organism to counteract stress, damage and disease, resulting in impaired physiological function, pathologies and, ultimately, death [1] . On the cellular level the process of aging is accompanied by a decreased proliferation rate, increased endoplasmic reticulum (ER) stress and production of potentially harmful reactive oxygen species (ROS) [2] . As central hubs for energy production, Ca 2+ homeostasis, cell signaling as well as for apoptosis, mitochondria are crucially involved in these aging processes [3] .…”