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.

Molecular Targets of Cannabidiol in Neurological Disorders

“…In neurodegenerative disease, the ETC is often impaired [211]. This might therefore suggest that CBD, like many other compounds that can inhibit mitochondrial function, can induce an adaptive upregulation of mitochondrial function and resistance to oxidative stress, a well-described process involving reactive oxygen species [212,213].…”

“…In fact, TRPV1-mediated modulation of presynaptic neurotransmitter release is partly dependent on mitochondrial calcium signaling, and TRPV1 activation can enhance mitochondrial function [231,232]. That TRPV1 can both enhance and inhibit mitochondrial function can be reconciled by the fact that calcium tightly controls mitochondrial function and biogenesis such that a small amount can stimulate function but too much can induce apoptosis [212,233]. Finally, vanillin-induced TRPV1 activation reduced markers of oxidative stress in model of HD and improved motor function, suggesting further validity for this target in relation to CBD [234].…”

Current versus future reproduction and longevity: a re-evaluation of predictions and mechanisms

“…We know from studies of moderate exercise, moderate calorie restriction and hypothermia in a diver that elevated energy expenditure can also have protective effects on the body due to both a reduction in ROS production (Powers and Jackson, 2008;Ristow and Schmeisser, 2014; mechanisms described above) and the beneficial signalling properties of ROS that occur when they are produced in a regulated manner ( Fig. 3; D 'Autreaux and Toledano, 2007;Ristow and Schmeisser, 2011;Schieber and Chandel, 2014;Rey et al, 2016).…”

Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial

“…42,43 In mitohormesis, mitochondria generate ROS as part of a cellular adaptation involving downregulation of the cellular respiration. 44 This preserves Bcl-2 and inhibits the mPTP. 45 B-cell lymphoma 2 prevents the decline in pH and cardiac adenosine triphosphate (ATP) stores during ischemia.…”

“…46 Metabolic regulation shifts from glucose to fatty acid oxidation to restore cellular homeostasis. 44 Concern has been raised over the potential negative impact of propofol-mediated insulin resistance and fatty acid oxidation on the heart. 47 Nevertheless, fatty acid oxidation reverses an energy deficit and improves function of the post-ischemic insulin-resistant heart.…”