Mitochondrial Dysfunction & Chronic Fatigue: Key Takeaways From ‘The Human Upgrade’

Mitochondrial function is central to energy production and overall health.

Biohacker Dave Asprey discusses preventing mitochondrial dysfunction and managing or avoiding chronic fatigue in his podcast, ‘The Human Upgrade’ Unsplash+ License

The May 9 episode (How to Double Your Energy!) of Dave Asprey’s podcast, The Human Upgrade, focused on understanding and overcoming chronic fatigue by enhancing mitochondrial function. Guest Ari Whitten, an author with extensive experience in natural health science, discussed mitochondria’s critical role in energy production and overall well-being. The episode explored how various factors contribute to mitochondrial dysfunction, which Whitten identifies as the primary cause of fatigue. These factors include circadian rhythm disruptions, poor sleep, excessive body fat, inadequate muscle mass, suboptimal gut and microbiome health, blood sugar imbalances, nutritional deficiencies and neurotransmitter and hormone imbalances.

Sign Up For Our Daily Newsletter

By clicking submit, you agree to our <a href="">terms of service</a> and acknowledge we may use your information to send you emails, product samples, and promotions on this website and other properties. You can opt out anytime.

See all of our newsletters

Whitten also emphasized the importance of understanding resilience, cell defense, nutrition and supplementation to improve energy levels. In addition to sharing insights into the role of specific supplements that could enhance mitochondrial function, the conversation covered practical strategies to improve one’s health. 

The episode’s key takeaways on preventing mitochondrial dysfunction and managing or avoiding chronic fatigue are:

  • Regulate Circadian Rhythms and Improve Sleep Quality: Maintain a regular sleep schedule and ensure quality sleep to support mitochondrial health. Disruptions in circadian rhythms can significantly impact energy levels and overall well-being.
  • Optimize Body Composition: Reducing excess body fat and increasing muscle mass can improve mitochondrial function and energy levels. Physical activity and strength training are essential components of this strategy.
  • Maintain Gut Health: A healthy gut microbiome is linked to better overall health, including optimal mitochondrial function. Eating a balanced diet rich in fiber and fermented foods can support gut health. 
  • Manage Blood Sugar Levels: A low-glycemic diet and monitoring carbohydrate intake can help avoid large fluctuations in blood sugar, helping maintain energy levels and prevent stress on the mitochondria. 
  • Address Nutritional Deficiencies: Ensuring a diet rich in essential nutrients, vitamins and minerals supports mitochondrial health. Supplements may be necessary to address specific deficiencies.
  • Balance Neurotransmitters and Hormones: Imbalances can impact energy levels and mitochondrial function. Consulting with healthcare providers to test and address these imbalances can be crucial.
  • Incorporate Red Light Therapy: Discussed as a beneficial tool for increasing mitochondrial efficiency and promoting overall cellular health.

What is mitochondrial dysfunction?

Mitochondria are organelles that produce adenosine triphosphate (ATP), the cell’s main energy currency. Beyond energy production, mitochondria are also involved in a range of other processes, including signaling, cellular differentiation, and the control of the cell cycle and cell growth. Mitochondrial dysfunction is when the mitochondria—the cell’s powerhouses—fail to function properly. This dysfunction can impact how efficiently cells generate energy, leading to cellular and systemic issues. 

Mitochondrial dysfunction can result from a variety of causes:

  • Genetic mutations: Both inherited and spontaneous mutations in mitochondrial DNA or nuclear DNA can affect mitochondrial function.
  • Environmental factors: Exposure to toxins, certain medications and other environmental stressors can impair mitochondrial function.
  • Aging: Mitochondrial function tends to decrease with age, contributing to the aging process and the development of age-related diseases.

Mitochondrial dysfunction and oxidative stress

Beyond chronic fatigue, mitochondrial dysfunction can have widespread implications. Because mitochondria produce most of the cell’s energy, their dysfunction can result in insufficient energy for normal cell function. Dysfunctional mitochondria may also produce excessive amounts of reactive oxygen species (ROS), leading to oxidative stress, a condition that occurs when there’s an imbalance between free radicals and antioxidants in your body. Free radicals are oxygen-containing molecules with an uneven number of electrons, allowing them to easily react with other molecules. Antioxidants are substances that can donate an electron to a free radical without becoming destabilized themselves, thus neutralizing the free radical and preventing harmful reactions. This phenomenon can significantly impact your health, primarily due to the damaging effects of free radicals. 

On a surface level, oxidative stress can have negative impacts on the skin:

  • Accelerated Aging: Oxidative stress accelerates the skin’s aging process. Free radicals damage important cellular components such as DNA, proteins, and lipids, which can lead to early signs of aging. These include wrinkles, fine lines, and a loss of elasticity and firmness in the skin.
  • Decreased Collagen Production: Collagen is a vital protein that helps keep the skin firm and youthful. Oxidative stress can break down collagen fibers, reducing their abundance and strength. This degradation contributes to the loss of skin elasticity and firmness, further promoting the aging process. 
  • Increased Inflammation: Oxidative stress can trigger inflammatory pathways in the skin. Chronic inflammation can lead to various skin conditions, including eczema, psoriasis and other inflammatory dermatoses. This inflammation can also exacerbate the breakdown of collagen and elastin, compounding the effects of aging.
  • Hyperpigmentation: Exposure to oxidative stress, particularly from UV radiation, can increase melanin production, leading to uneven skin tone and hyperpigmentation. Areas of the skin may appear darker than others, commonly referred to as age spots or sun spots.
  • Weakened Skin Barrier: The skin barrier protects the body from external agents and prevents excessive water loss. Oxidative stress can weaken this barrier, making the skin more susceptible to infections, irritants and dehydration.
  • Dull and Uneven Skin Texture: Oxidative damage can make the skin look dull and feel rough. The skin loses its radiance and smooth texture, largely due to the diminished turnover of skin cells and the accumulation of damaged proteins and lipids on the skin’s surface.

More importantly, oxidative stress is also believed to play a role in the development of various diseases

  • Cardiovascular diseases: Oxidation of LDL cholesterol (a type of bad cholesterol) is a significant factor in the development of atherosclerosis, which can lead to heart attacks and strokes.
  • Cancer: Damage to DNA caused by oxidative stress can lead to mutations that contribute to cancer development.
  • Neurodegenerative diseases: Alzheimer’s Disease and Parkinson’s are associated with oxidative stress due to the damage of neurons.
  • Type 2 Diabetes: Oxidative stress influences glucose metabolism and insulin sensitivity, which can contribute to the onset of type 2 diabetes.

Oxidative stress can also trigger and exacerbate inflammation, a natural response by the body to remove harmful stimuli and start the healing process. Persistent oxidative stress can impair immune function, reducing the body’s ability to fight infections and diseases. It can also affect the life cycle of cells, influencing their growth, activity and death. Over time, excessive oxidative stress can deplete the body’s natural antioxidants, further unbalancing the oxidative state and making the body more susceptible to damage. Severe mitochondrial dysfunction can trigger cell death through apoptosis (programmed cell death) or necrosis (uncontrolled cell death). It has also been linked to muscle and skeletal disorders, such as muscular dystrophy and age-related muscle loss.

Leading experts in mitochondrial dysfunction

Mitochondrial dysfunction is a complex field of study that spans multiple disciplines, including genetics, biochemistry and cellular biology. Here are some of the leading experts who have contributed significantly to the understanding of mitochondrial dysfunction:

  • Douglas C. Wallace – He is considered one of the pioneers in mitochondrial genetics and has made substantial contributions to understanding mitochondrial DNA (mtDNA) variations and their role in human disease and evolution. He is the Director of the Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia.
  • Marni J. Falk – Dr. Falk is an Executive Director and attending physician in the Mitochondrial Medicine Frontier Program at the Children’s Hospital of Philadelphia. Her work focuses on the diagnosis, management and treatment strategies for mitochondrial diseases, along with functional analyses of new mitochondrial disease genes.
  • Anu Suomalainen Wartiovaara – A professor at the University of Helsinki, she is known for her research on mitochondrial disease pathogenesis and therapies. Her work includes understanding the molecular mechanisms and therapeutic interventions in mitochondrial disorders.
  • Vamsi K. Mootha – An investigator at Howard Hughes Medical Institute and a professor at Harvard Medical School, his research includes using genomic and computational techniques to understand mitochondrial function and disease.
  • David Thorburn – Based at the Murdoch Children’s Research Institute in Melbourne, Australia, Thorburn’s research centers on mitochondrial disorders in children, diagnosis methods, and therapeutic approaches.

These researchers and their teams have been instrumental in advancing the understanding of mitochondrial dysfunction through their studies, clinical trials and contributions to various scientific journals and conferences. Their work often crosses the lines between fundamental research and clinical applications, significantly impacting both the scientific community and the healthcare approaches for patients with mitochondrial disorders.

Popular books about mitochondrial dysfunction

Several accessible, easy-to-read books tackle preventing mitochondrial dysfunction, often within broader discussions of health, aging and nutrition. The following books are chosen for their straightforward style, practical advice and appeal to general readers without a deep background in science. These books provide clear explanations and actionable steps readers can take to improve their mitochondrial health. Each author provides a unique perspective on how diet and lifestyle impact our cellular engines, making complex scientific concepts understandable and applicable to everyday life.


Dave Asprey Madison McGaw/

Who is Dave Asprey?

Dave Asprey is an entrepreneur, author, and public speaker best known for founding the “Bulletproof” brand, which encompasses a range of dietary supplements, products, and the popular Bulletproof Coffee—a drink consisting of coffee, grass-fed butter, and medium-chain triglyceride (MCT) oil. He is often associated with the biohacking community and promotes various techniques and lifestyle changes to enhance physical and cognitive performance. Asprey’s philosophy centers around optimizing human biology and performance, often drawing on his personal experiences with weight loss and health improvements. He has authored several books on these topics, including “The Bulletproof Diet,” where he advocates for a high-fat, low-carbohydrate diet that aims to help individuals improve their body composition, energy levels, and overall well-being. His work and ideas have been influential yet also controversial, as some of his claims lack robust scientific support. Despite this, he has built a large following and remains a prominent figure in discussions about health, wellness, and personal optimization.

Mitochondrial Dysfunction & Chronic Fatigue: Key Takeaways From ‘The Human Upgrade’