Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

Abstract

Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.

FIGURE 1.

Mitochondrial Hormesis (Mitohormesis). While the Free Radical Theory of Aging suggests a linear dose-response relationship between increasing amounts of ROS and oxidative stress on the one hand, and mortality events on the other (red curve), the concept of mitohormesis indicates a non-linear dose-response relationship where low doses of ROS exposure decrease mortality, while higher doses promote mortality.

FIGURE 2.

Lifespan-promoting ROS signaling can occur transiently and hence requires time-resolved quantification. A) Disruption of the insulin/IGF-1 receptor, named DAF-2, in C. elegans extends lifespan. The constitutive daf-2 mutant exhibits reduced ROS levels. This has led to the conclusion that impairing DAF-2 primarily causes reduced ROS levels. However, as recently published (Zarse et al. 2012), the opposite is the case: When studying the acute effects of an RNAi-mediated daf-2 knockdown, a transient increase in ROS production was observed (“acute response”). As shown in the publication (Zarse et al. 2012), this ROS signal induces various endogenous ROS defense mechanisms that ultimately reduce ROS levels. This leads to a persistent reduction of ROS levels in daf-2 RNAi-treated worms in the steady state. This also exemplifies that quantifying ROS at an inappropriate time point may lead to opposing results: ROS determined during the acute response against RNAi would indicate increased levels, while ROS determined three days later during the steady-state would indicate reduced levels. B) Exogenously added antioxidants prevent the acute induction of a ROS signal (Zarse et al. 2012). The lack of this ROS signal leads to a complete lack of the original adaptive response shown in panel A. This causes higher steady-state ROS levels than in the absence of exogenous antioxidants which only can be explained in the framework of mitohormesis, while the linear dose-response would consider this phenomenon as paradoxical.

FIGURE 3.

Transiently increased ROS levels cause a vaccination-like adaptive response that promotes endogenous ROS defense capacity. The figure exemplifies the organismal stress response to low-level and/or short-term ROS exposure in comparison to the long-standing vaccination process, where inactive or impaired microbes exert an organismal immune response leading to a long-lasting defense capacity against future infections.

FIGURE 4.

Overview on how ROS transcriptionally influence stress resistance and lifespan. High levels cause damage resulting in death of the cell and eventually the corresponding organism, whereas low levels are capable of activating transcription factors that mediate adaptive stress response culminating in increased lifespan.

FIGURE 5.

A non-exhaustive overview on lifespan-extending interventions linked to mitohormetic ROS signaling. As outlined in the text of the current review, a number of apparently diverse interventions lead to a mitohormetic response mechanism, insinuating that distinct molecular pathways culminate in a common mechanistic denominator by promoting a ROS-dependent stress response.