The Aging Mitochondria

Abstract

Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a crucial role in aging pathways at the cellular and organismal level, the original hypothesis in which mitochondrial dysfunction and production of free radicals represent the main driving force of cell degeneration has been strongly challenged. In this review, we will first describe mitochondrial dysfunctions observed in aged tissue, and how these features have been linked to mitochondrial reactive oxygen species (ROS)-mediated cell damage and mitochondrial DNA (mtDNA) mutations. We will also discuss the clues that led to consider mitochondria as the starting point in the aging process, and how recent research has showed that the mitochondria aging axis represents instead a more complex and multifactorial signaling pathway. New working hypothesis will be also presented in which mitochondria are considered at the center of a complex web of cell dysfunctions that eventually leads to cell senescence and death.

Keywords: MFRTA; ROS; aging; lifespan; mitochondria; mitochondrial function; mtDNA mutations; mutator mouse.

Figure 1

Mitochondrial Health at the center of a Cause–Consequence cell crossroad. The original, simplistic view of the Mitochondrial Free Radical Theory of Aging (MFRTA), postulating a mitochondrial activity/ROS/mtDNA isolated interaction, was progressively replaced by a more integrative view in which healthy mitochondria are the result of multiple cellular pathways and activities, impacting different aspects of aging, in diverse tissues and in different manners. See text for details.