Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Abstract

SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. 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 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.

The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity

“…This has led to the suggestion of a mitochondrial “death spiral” that can accelerate aging. [93] Thus, efficient mitophagy is associated with increased or maintained ATP levels, which is compatible with the EMTA.…”

“…Therefore, insufficient ATP levels can inhibit mitophagy, which in turn further reduces ATP levels. This has led to the suggestion of a mitochondrial “death spiral” that can accelerate aging . Thus, efficient mitophagy is associated with increased or maintained ATP levels, which is compatible with the EMTA.…”

Targeting mitochondrial function and proteostasis to mitigate dynapenia

“…However, increasing mitochondrial protein turnover, even in the absence of an increase in content, can also improve mitochondrial function (Menshikova et al 2006; Siegel et al 2013; Romanello and Sandri 2015). It is even possible that with aging, improving the turnover of existing mitochondrial proteins is a better strategy to improve muscle function, since increasing mitochondrial content without improving function, may just lead to greater ROS production (Stern 2017). Therefore, when examining strategies to mitigate dynapenia, assessments of mitochondrial function are equally, if not more important than mitochondrial content.…”

Chemokine C–C motif ligand 2 overexpression drives tissue-specific metabolic responses in the liver and muscle of mice

“…High circulating levels of CCL2 correlate with biological age in mammals and are closely associated with a deleterious course of chronic diseases 24 – 27 . Our findings indicated that CCL2 may be locally involved in multiple metabolic pathways and, more importantly, shows paracrine effects with different outcomes in important metabolic organs 28 . Indeed, our study showed that overexpression of CCL2 in mice is associated with increased liver and decreased muscle weights, which largely mimics a phenotype frequently found in some human metabolic diseases, such as obesity, chronic liver disease or metabolic syndrome, and in aging.…”