Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

Abstract

Aging is often associated with a loss of function. We believe aging to be more an adaptation to the various, and often continuous, stressors encountered during life in order to maintain overall functionality of the systems. The maladaptation of a system during aging may increase the susceptibility to diseases. There are basic cellular functions that may influence and/or are influenced by aging. Mitochondrial function is amongst these. Their presence in almost all cell types makes of these valuable targets for interventions to slow down or even reserve signs of aging. In this review, the role of mitochondria and essential physiological regulators of mitochondria and cellular functions, ion channels, will be discussed in the context of human aging. The origins of inflamm-aging, associated with poor clinical outcomes, will be linked to mitochondria and ion channel biology.

Keywords: aging; cellular senescence; inflammation; ion channels; mitochondria.

FIGURE 1

Age-related changes in ion channel function. Calcium (Ca²⁺) release-activated Ca²⁺ channels increase intracellular Ca²⁺ levels, activating K⁺ channel opening and sustained Ca²⁺ signaling, whilst efflux of chloride (Cl^-) ions inhibits Ca²⁺ influx. Downregulation of Ca²⁺ channels has been demonstrated in Alzheimer’s disease. Decreased expression of Ca²⁺-activated K⁺ channels have been noted with aging, particularly within the smooth muscle cells of the vascular system reducing arterial tone. Within the mitochondria, reduced Ca²⁺ ion channel activity results in reduced Ca²⁺ cycling. Potassium channel expression on the mitochondria are also reduced with age in the heart sarcolemma.

FIGURE 2

Mitochondrial dysfunction during aging. Healthy mitochondria produce ROS through regular oxidative (OXPHOS) activity which aid in normal cell processes, this ROS production is kept in check by various anti-oxidant systems to prevent oxidative damage. During aging, dysfunctional mitochondria accumulate due to reduced biogenesis and ROS control. This increased ROS production induces both further mitochondrial damage and cellular damage, resulting in reduced cell function and eventual apoptosis.

FIGURE 3

(A) Ion channels and inflammation. Increased extracellular reactive oxygen species (ROS) stimulates TRPA1 and calcium (Ca²⁺) influx. This increases intracellular ROS production, MAPK activation and pro-inflammatory IL-8 release. Mitochondria produce ROS and ATP through their normal activities which affect ion flux, for example by increasing calcium influx into the cell by increasing calcium ion channel activity and stimulating further ROS production. In turn the secretion of inflammatory molecules such as IL-8 is stimulated. (B) Mitochondria, ions and inflammation. Mitochondria form the major platform for NLRP3 inflammasome assembly through the mitochondrial antiviral signalling protein (MAVS). Mitochondria activate this inflammasome complex by releasing damage associated molecular patterns (DAMPs) such as ROS and ATP leading to the maturation of IL-1β and IL-18 inflammatory molecules. Similarly, increased influx of ions such as calcium, chloride and potassium can also influence inflammasome activation.