What is Mitochondrial Hormesis?

So, firstly… What is Hormesis? 

Hormesis (or “Non-Linear Response”) is a biological phenomenon in which a beneficial effect (such as improved health, stress tolerance, or longevity) results from exposure to low doses of an agent that is otherwise toxic or harmful at higher doses. This concept applies across various fields, including medicine, toxicology, and environmental science.

Mitochondrial hormesis, often called mitohormesis, is a specific type involving the mitochondria, the energy-producing organelles in cells. 

Mitohormesis underscores the idea that moderate mitochondrial stress associated with interventions such as caloric restriction, intermittent fasting, exercise, and dietary phytonutrients is essential for optimal cellular function and long-term health, improving stress resistance, energy metabolism & longevity (Tapia, 2006). Think of it like exercising: lifting weights puts stress on your muscles, but that stress helps them grow stronger.

WHY IS MITOCHONDRIAL HEALTH IMPORTANT?

Mitochondria are vital cellular organelles responsible for generating most metabolic energy while also playing a significant role in the aging process and the onset of age-related diseases. During oxidative phosphorylation**, mitochondria produce more than 90% of intracellular reactive oxygen species (ROS), group of highly reactive molecules as a by-product (Ristow & Schmeisser, 2014).

** Oxidative phosphorylation is the process by which the body uses O2 and nutrients from food to produce an energy molecule called ATP (adenosine triphosphate), which acts like a ‘battery to power many cellular activities.‘

**The mitochondrial life cycle encompasses several key processes that regulate mitochondrial function and health:

1. Mitochondrial Fusion and Fission: These processes involve the merging (fusion) or splitting (fission) of mitochondria. Fusion helps mitochondria share content and repair damage, while fission allows for the distribution of mitochondria and the removal of dysfunctional ones​.
2. Mitochondrial Biogenesis refers to creating new mitochondria, typically triggered by increased cellular energy demands or stress. 
3. Mitophagy: Mitophagy is the selective degradation of damaged or ineffective mitochondria via autophagy, maintaining mitochondrial quality and preventing cellular damage​

These steps are essential for maintaining mitochondrial integrity and supporting cellular energy metabolism.

The key aspects of Mitohormesis::

1. Stress-Induced Adaptation:

Repeated exposure to mild mitochondrial stress may trigger a variety of adaptive responses, enhancing resilience to more severe mitochondrial stress.

At moderate levels (e.g., exercise-induced ROS production), ROS function as signaling molecules that stimulate protective pathways, while at high levels, they may cause oxidative stress, which has been suggested to be linked with various diseases, including diabetes, cancer, and neurodegenerative disorders such as Alzheimer’s, and Parkinson’s disease and accelerating aging (Ristow & Schmeisser, 2014).

2. Mechanisms of Mitohormesis:

• Mitochondrial Biogenesis: Mitochondrial stress may activate pathways like PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), a ‘chief’ regulator of the mitochondrial life cycle: fusion/fission,, and mitophagy promoting the formation of new, more efficient mitochondria (Abu Shelbayeh et al., 2023).

• ‘Antioxidant Response: Low levels of ROS stimulate transcription factor NrF2, another ‘chief regulator controlling the activation of genes responsible for antioxidant defense, and metabolic adjustments, leading to the production of antioxidant enzymes and endogenous antioxidants like glutathione** (Kasai et al., 2020).

**Glutathione is a powerful antioxidant naturally produced by the body and is critical for maintaining cellular health. It helps combat oxidative stress by neutralizing reactive oxygen species (ROS) that can damage cells and DNA. It supports the liver in detoxifying toxins and heavy metals and strengthens the immune system by maintaining the function of lymphocytes, which are essential for fighting infections. It helps recycle other antioxidants like vitamins C and E, can contribute to protein synthesis and DNA repair & has anti-aging properties. Foods rich in sulfur, such as garlic, onions, broccoli, and asparagus, may support its production.

• Autophagy: Mitohormesis stimulates mitochondrial quality control processes, such as mitophagy, which removes damaged or dysfunctional mitochondria, ensuring the maintenance of healthy mitochondrial populations within cells. This mechanism is essential for preserving mitochondrial function to support extended lifespan and protection against age-related illnesses (Sun et al., 2024). 

3. Examples of Mitohormesis in Action:

• Regular Exercise: Regular physical activity induces controlled oxidative stress in muscle cells, triggering adaptations that can improve mitochondrial function and slow markers of aging by promoting mitochondrial dynamics like fusion, fission and supporting biogenesis (Craige et al., 2024, Musci, Hamilton and Linden, 2019).

Aerobic exercise can activate mitochondrial and antioxidant pathways, including those mediated by PGC-1α and NrF2. These pathways may promote metabolic health, and reduce oxidative damage of mitochondria and skeletal muscle dysfunction (Musci, Hamilton and Linden, 2019).

In skeletal muscles, mitohormesis can also enhance endurance and metabolic efficiency (Musci, Hamilton and Linden, 2019).

• Intermittent Fasting (IF): This dietary intervention can improve energy efficiency and mitochondrial biogenesis by activating longevity pathways such as AMP-activated protein kinase (AMPK), the energy sensor & regulator of energy homeostasis and sirtuin 1 (SIRT1)** (Zhang et al., 2024). It has also been proposed that IF can decrease free radical production (ROS), stimulate mitochondrial autophagy and fusion, and protect neurons from oxidative stress by boosting the expression of mitochondrial antioxidant enzymes with potential therapeutic benefits for neurodegenerative and autoimmune disorders (Zhang et al., 2024).

** SIRT1 is a member of the sirtuin family of proteins that play critical roles in cellular regulation, including aging, metabolism, stress response, and gene expression.

** Interestingly, caloric restriction (CR) has demonstrated significant potential to promote health and longevity in humans. In a pivotal two-year study involving 218 non-obese individuals, CR led to notable benefits such as weight loss, improved lipid profiles, reduced inflammatory markers (TNF-α), and better metabolic rates. Additionally, compared to individuals consuming an unrestricted diet, CR slowed the pace of biological aging, as measured by advanced biomarkers. Specifically, participants practicing CR showed an annual biological age increase of only 0.11 years compared to 0.71 years in those on an ad libitum diet (Ravussin et al., 2015).

Although supportive evidence has been gathered from animal models and preliminary clinical studies in decelerating biological aging, the long-term impacts on lifespan, and overall health in humans, additional large-scale, long-term randomized controlled trials are essential to confirm CR safety and assess its clinical efficacy.

• A diet rich in dietary Phytochemicals: Compounds like polyphenols- the natural components of plants, fruits, vegetables & cereals (e.g., resveratrol from red grapes, quercetine from apples or onions, epigallocatechin-3-gallate from green tea, isoflavones from soybeans, curcumin from turmeric ) can promote mitochondrial biogenesis and enhance mitochondrial function (Chodari et al., 2021).

**Experimental studies have shown that resveratrol can effectively regulate mitochondrial dynamics, fusion and fission processes, and other quality control mechanisms in cardiomyocytes (cardiac cells). This regulation supports mitochondrial integrity and functionality, which are crucial for maintaining the health of cardiomyocytes and their resilience against oxidative stress (Gal et al., 2023).

4. Benefits of Mitohormesis:

1. Improved mitochondrial efficiency and reduced oxidative damage.
2. Enhanced stress resistance at the cellular and systemic levels.
3. Delayed aging and reduced risk of age-related diseases like neurodegeneration and metabolic disorders.

5. To summarize all of these aspects, what is essential? 

• Engage in Regular Exercise:

-> Incorporate aerobic and resistance training to stimulate mitochondrial function and antioxidant defenses.

-> Even moderate-intensity exercise can improve energy metabolism and delay cellular aging.

• Practice Intermittent Fasting:

-> Try time-restricted eating or fasting protocols (e.g., 16:8) to enhance mitochondrial quality control and longevity pathways.

-> Avoid overeating, as excess caloric intake may lead to mitochondrial dysfunction.

• Adopt a Diet Rich in Phytonutrients:

-> Include foods high in antioxidants and polyphenols like berries, dark leafy greens, garlic, broccoli, turmeric, and green tea

-> Focus on whole, unprocessed foods to reduce oxidative stress.

• Embrace Stress in Moderation:

-> Minor, manageable stressors (like exercise or fasting) are beneficial, but excessive or chronic stress (e.g., overtraining or prolonged starvation) can cause mitochondrial dysfunction. Balance is the key!

References: 

Abu Shelbayeh, O., Arroum, T., Morris, S. & Busch, K., B., 2023. PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response. Antioxidants, [online]. Available at: https://doi.org/10.3390/antiox12051075 [Accessed 10 May 2023].

Craige, S., M., Mammel, R., K., Amiri, N., Willoughby, O., S. & Drake, J., C., 2024. Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling. Redox Biology, [online]. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11474192/ [Accessed 24 September 2024]. 

Gál, R., Halmosi, R., Gallyas, F., Jr., Tschida, M., Mutirangura, P., Tóth, K., Alexy, T. & Czopf, L., 2023. Resveratrol and beyond: The Effect of Natural Polyphenols on the Cardiovascular System: A Narrative Review. Biomedicines, [online]. Available at: https://doi.org/10.3390/biomedicines11112888 [Accessed 12 December 2024].

Kasai, S., Shimizu, S., Tatara, Y., Mimura, J. & Itoh, K., 2020. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Biomolecules, [online]. Available at: https://doi.org/10.3390/biom10020320 [Accessed 12 December 2024].

Musci, R., V., Hamilton, K., L., Linden, M., A. 2019. Exercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension. Sports, [online]. Available at: https://www.mdpi.com/2075-4663/7/7/170 [Accessed 31 May 2019]. 

Ravussin, E., Redman, L., M., Rochon, J., Das, S., K., Fontana, L., Kraus, W., E., Romashkan, S., Williamson, D., A., Meydani, S., N., Villareal, D., T., Smith, S., R., Stein, R., I., Scott, T., M., Stewart, T., M., Saltzman, E., Klein, S., Bhapkar, M., Martin, C., K., Gilhooly, C., H., Holloszy, J., O., Hadley, E., C. and Roberts, S., B., CALERIE Study Group, 2015.  A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. Journal of Gerontology: Biological Sciences and Medical Sciences, [online]. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC4841173/ [Accessed 17 July 2015]. 

Ristow, M. & Schmeisser, K., 2014. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose-Response, [online]. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC4036400/ [Accessed 31 January 2014]. 

Sun, Y., Jin, L., Qin, Y., Ouyang, Z., Zhong, J., and Zeng, Y., 2024. Harnessing Mitochondrial Stress for Health and Disease: Opportunities and Challenges. Biology, [online]. Available at: https://doi.org/10.3390/biology13060394 [Accessed 24 May 2024].

Tapia, P., C., 2006. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise, and dietary phytonutrients: “Mitohormesis” for health and vitality. Medical Hypotheses, [online]. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0306987705004676?via%3Dihub. [Accessed 2006]. 

Zhang, A., Wang, J., Zhao, Y., He, Y. and Sun, N., 2024. Intermittent fasting, fatty acid metabolism reprogramming, and neuroimmuno microenvironment: mechanisms and application prospects. Frontiers in Nutrition, [online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11541237/

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