Fight Aging!

Mitochondria are the power plants of the cell, their activities essential for all energetic processes and actions in the body. They are descendants of symbiotic bacteria, a swarm in every cell, and carry their own DNA. Unfortunately that DNA can become damaged in ways that subvert the normal cellular quality control mechanisms to cause significant dysfunction; that a growing number of cells fall into this state over time is one of the contributing causes of aging and age-related disease. The author of this paper theorizes that mitochondrial DNA damage in aging is an example of antagonistic pleiotropy, meaning that it exists because evolution has guided mitochondrial structure and quality control processes to enhance early life success via mechanisms that also cause later failure and dysfunction.

From an evolutionary perspective, aging has been difficult to understand. Natural selection increases organismal fitness, and yet aging, which clearly decreases fitness, is not only observed, but also appears to be nearly universal within multicellular (and even some single-celled) organisms. To address this dilemma, it was proposed that aging occurs and is fixed in populations because alleles that have deleterious effects in old age benefit growth, survival, and reproduction in youth. This theory is called antagonistic pleiotropy (AP) theory. In this view, aging occurs because alleles that in the short term are beneficial in solving problems in growth and reproduction serve to exacerbate the problem in the long run. Therefore, aging can be viewed as a form of death spiral. A death spiral, also known as a vicious circle, is a specific form of positive feedback in which steps taken to handle a particular problem, while successful in the short term, exacerbate the problem in the long term.

If this premise is accepted, the next step is to identify the alleles that mediate AP, understand the nature of these alleles, how they might exert AP, and finally identify and define the critical cellular processes affected by AP. Although genes of the insulin signaling pathway likely participate in AP, the insulin-regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term.

I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial reactive oxygen species (ROS) generation, which signals inhibition of mitophagy via ROS-dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12579/full