Many approaches shown to slow aging in animal studies involve an increased efficiency of cell maintenance processes such as the ubiquitin-proteasome system and various types of autophagy. Here researchers discuss the improvement of autophagy in order to slow the age-related decline of mitochondrial function. Mitochondria are the power plants of the cell, with the vital role of producing chemical energy store molecules to power cellular operations. Autophagy involves targeting damaged cell structures and molecules for recycling, conveying them to be engulfed by a lysosome for disassembly into raw materials that can be reused. The subset of autophagic processes targeting damaged mitochondria for removal is termed mitophagy. Loss of mitochondrial function with age appears connected to a loss of efficiency in mitophagy, allowing for worn and dysfunctional mitochondria to persist in a cell, with various lines of supporting evidence arriving at this conclusion from different directions.
Aging manifests in a continuous decline of organismal homeostasis. Accumulating defects on the cellular level can result in cellular dysfunction that impairs normal physiology. This damage can be of extrinsic origin e.g., mutagenic radiation and toxins, or intracellular origin, like harmful reactive oxygen species (ROS) generated by defective mitochondrial respiration, advanced glycation end products or the accumulation of toxic protein aggregates. The consequences of such harm are particularly devastating to post-mitotic, fully differentiated cells with low cellular turnover rates, such as neuronal cells and cardiomyocytes.
To mitigate the detrimental effects of extrinsic and intrinsic harms, eukaryotic cells have developed various protective mechanisms. One such mechanism is proteostasis, a collective term for a network of protein quality control and degradation pathways that ensure the normal expression, folding, and turnover of proteins. During aging, proteostasis, like other cellular functions, suffer from a progressive decline, which renders the body more vulnerable to damage and age-related diseases.
In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.