The role of mitochondria in aging

Abstract

The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.

Figure 1. Immune activation by mtDNA release through both intracellular and extracellular pathways.

The innate immune system has at least three sensors for detecting mtDNA: TLR9 for sensing circulating (extracellular) mtDNA, and the NLRP3 inflammasome and the cGAS/STING pathway for sensing cytoplasmic (intracellular) mtDNA release. A host of downstream signaling pathways and cytokines are induced following activation of each of these distinct pathways. The precise mechanism through which mtDNA is released into the cytosol or the circulation remains uncertain.

Figure 2. Aging impairs mitophagic removal of stressed mitochondria.

The age-dependent decline in mitophagy might provide the mechanism to explain the known interrelationship between increased ROS, decreased bioenergetic capacity, and age-dependent functional decline. Agents such as spermidine and urolithin A appear to stimulate mitophagy and thereby prevent age-related pathologies, which are described in more detail in the main text.

Figure 3. A range of quality control mechanisms exist to deal with stress in the mitochondria.

The magnitude of these mechanisms ranges in accordance with the severity of the perceived stress. From lowest to highest magnitude of response, they include activation of the UPR^mt to initiate a transcriptional program to potentially relieve the stress; removal of part of the mitochondria into a mitochondrial-derived vesicle (MDV) in hopes of preserving the undamaged part; activation of mitophagy to remove the entire damaged mitochondria; and induction of cell death through apoptosis or necrosis to remove the entire damaged cell. As such, the magnitude of response can be titrated to the level of perceived stress.