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Why Some Stressors Make Us More Resilient

Exercise induces "hormetic" adaptive responses that boost antioxidant defenses.

Key points

  • "Hormesis" describes the favorable adaptive response to something that would otherwise be a harmful stressor.
  • Exercise facilitates hormesis by increasing an enzyme called NOX4 in skeletal muscles; NOX4 boosts antioxidant defenses.
  • Exercise-induced reactive oxygen species (ROS) may drive hormetic adaptive responses that prevent oxidative damage.

"What does not kill me makes me stronger." (German Was mich nicht umbringt, macht mich stärker) —Friedrich Nietzsche from Twilight of the Idols (1888)

Source: KieferPix/Shutterstock

When Kelly Clarkson belts out her interpretation of Nietzsche's famous aphorism in her 2012 smash hit, "Stronger (What Doesn't Kill You)," she's probably not thinking about the hormetic effect a grueling workout has on kickstarting adaptive responses that increase resilience via the expression of an enzyme called NOX4.

What Is Hormesis?

Hormesis is a dose-response phenomenon in which a potentially harmful substance can benefit a living organism.

New research in mice (Xirouchaki et al., 2021) suggests that exercise triggers a favorable (hormetic) adaptive response to stressors that would otherwise be harmful. Because of hormesis, when it comes to exercise, in many ways, "what doesn't kill you" does, in fact, "make you stronger."

Accumulating evidence suggests that the induction of mitochondrial biogenesis, which enhances respiratory capacity and boosts endurance, is a vital hormetic response to exercise. The latest findings on how exercise-induced NOX4 is required for hormetic adaptive responses were published on December 15 in the peer-reviewed journal Science Advances.

"Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise," the authors explain in their paper's abstract. "Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance."

Hormesis in Action: NOX4 Transforms Potentially Harmful ROS Into Something Beneficial

Theoretically, without skeletal muscle NOX4, exercise could be toxic. In mice treated with a substance that blocked NOX4, the researchers found that aerobic exercise increased oxidative stress. According to the researchers, this demonstrates that NOX4 is "essential for promoting antioxidant defense and mitochondrial biogenesis, preventing mitochondrial oxidative stress, and maintaining insulin sensitivity."

Xirouchaki et al. also report that skeletal muscle NOX4 tends to decrease with age and obesity; these factors can lead to the development of insulin resistance. "Our findings demonstrate that skeletal muscle NOX4 is of fundamental importance in exercise-induced hormetic responses that promote muscle function and metabolic health," the authors explain.

When NOX4 is depleted, aging and obesity can increase "harmful" mitochondrial ROS production that causes oxidative stress. However, exercise-induced ROS is hormetic; it triggers a "helpful" adaptive response that prevents oxidative damage. NOX4 is essential for this antioxidant defense response.

Exercise-Induced Mitochondrial ROS Boosts Antioxidant Defenses. But How Much Exercise Is Too Much or Not Enough?

"Triggering the activation of the adaptive mechanisms orchestrated by NOX4 with drugs might ameliorate key aspects of aging, including the development of insulin resistance and type 2 diabetes," senior author Tony Tiganis of the Department of Biochemistry and Molecular Biology at Australia's Monash University said in a news release.

Human studies are needed to see if the adaptive mechanisms triggered by exercise have the same effect on NOX4 production in people as Tiganis and colleagues observed in mice. Future research should also identify the ideal "dose" (duration/intensity/frequency) of cardio and/or strength training workouts needed to activate an optimal hormetic response.

In terms of hormesis and optimizing the exercise-induced generation of ROS by skeletal muscle NOX4, there's probably a sweet spot between doing too much or too little physical activity throughout the week. But we need more research to clearly define this Goldilocks zone.

Until we know the optimal dose-response for hormesis, doing 150–300 minutes of moderate-intensity cardio per week or 75–150 minutes of vigorous-intensity aerobic exercise plus two strength-building workouts per week has been shown to have innumerable benefits. (See "New Physical Activity Guidelines Based on Decade of Research.")


Chrysovalantou E. Xirouchaki, Yaoyao Jia, Meagan J. McGrath, Spencer Greatorex, Melanie Tran, Troy L. Merry, Dawn Hong, Matthew J. Eramo, Sophie C. Broome, Jonathan S. T. Woodhead, Randall F. D’souza, Jenny Gallagher, Ekaterina Salimova, Cheng Huang, Ralf B. Schittenhelm, Junichi Sadoshima, Matthew J. Watt, Christina A. Mitchell, Tony Tiganis. "Skeletal Muscle NOX4 Is Required for Adaptive Responses That Prevent Insulin Resistance." Science Advances (First published: December 15, 2021) DOI: 10.1126/sciadv.abl4988

Katrina L. Piercy, Richard P. Troiano, Rachel M. Ballard, Susan A. Carlson, Janet E. Fulton, Deborah A. Galuska, Stephanie M. George, Richard D. Olson. "The Physical Activity Guidelines for Americans." JAMA (First published online: November 12, 2018) DOI: 10.1001/jama.2018.14854

Mark P. Mattson. "Hormesis Defined." Ageing Research Reviews (First published: December 05, 2007) DOI: 10.1016/j.arr.2007.08.007