Giving Fatigue A Kick Start
Mar 31, 2025
Fatigue is characterised by feelings of tiredness/malaise and a lessened capacity or motivation for work.[1]
What Are The Drivers Of Fatigue?
- There are numerous potential drivers of fatigue and subsequent pathophysiology’s to consider. However, overall, these drivers negatively affect mitochondrial function and the generation of energy in the form of adenosine triphosphate (ATP), which fuel biochemical reactions. Mitochondria are susceptible to the impacts of:
- Nutrient deficiencies: Several vitamins and minerals are required for mitochondrial ATP production (Figure 1), with deficiencies negatively affecting cellular bioenergetics and antioxidant systems.[2]
- Hypothalamic-pituitary-adrenal (HPA) axis dysfunction: Chronic or severe stress causes maladaptive brain plasticity, which is associated with decreased aerobic oxidation and reductions in aerobic metabolism within mitochondria, leading to cognitive/mental fatigue.[3] Excessive glucocorticoid production, associated with a maladaptive stress response, has also been shown to supress immune function and increase susceptibility to infection and chronic immune dysregulation, further contributing to fatigue.[4]
- Cell danger response (CDR) dysfunction: Disruptions to the CDR cycle, which regulates cellular healing, triggers inflammation and oxidative stress that compromises cellular energy production.[5]
- Infection: Proinflammatory cytokines produced during infectious occurrences subsequently activate microglia and cytokine expression in the brain, generating neuroinflammation and mitochondrial impairments in brain tissue. Neuropsychological symptoms, including fatigue, low mood/depression and cognitive impairment, have been associated with infectious events.[6]
- Immune exhaustion: Chronic or recurrent infection causes alterations in T cell phenotype and numbers, thereby reducing the efficacy of the immune system in response to pathogenic threats and increasing predisposition to fatigue.[7]
- Glycaemic dysregulation: Fluctuating glucose levels, including hypoglycaemia and hyperglycaemia, contribute to fatigue pathogenesis via disruption of glucose metabolism, resulting in reduced glucose uptake and utilisation by cells, decreased cellular generation of ATP and subsequent fatigue.[8]
- Thyroid dysfunction: Thyroid hormone output plays a critical role in energy production, with dysfunction associated with decreased utilisation of fats and carbohydrates required for ATP production, as well as mitochondrial biogenesis deficits.[9]
- Poor sleep quality: Sleep dysregulation is associated with increased production of inflammatory mediators and reactive oxygen species (ROS), which damage mitochondrial structure and impede cellular energy production.[10],[11]
- The mitochondria are a vulnerable target to the aforementioned drivers of fatigue. Such insults trigger inflammation and oxidative stress, damaging the lipid membranes and constituents in the mitochondria, altering their structure and function, and inhibiting ATP production.[12]
- Fatigued individuals are to found possess mitochondria that are pathologically enlarged, contain damaged respiratory chain constituents, deoxyribonucleic acid (DNA) mutations, and frank deficits in energy production, compared to healthy controls.[13],[14],[15],[16],[17] These alterations affect the mitochondria’s ability to generate energy and sustain normal cellular function.
- Supporting the mitochondria, brain function, HPA axis, immune system and metabolic health in fatigued patients can address the core physiological defects underlying fatigue.
Figure 1: Overview of nutrients involved in mitochondrial bioenergetics.[18]
Key: alpha-KGDH: alpha-ketoglutarate dehydrogenase; LDH: lactate dehydrogenase; ADP: adenosine diphosphate; ATP: adenosine triphosphate; Pi: Inorganic phosphate; CoA: coenzyme A; CO2: carbon dioxide; Cofactor Q10: Coenzyme Q10; NADH: nicotinamide adenine dinucleotide; PDH: pyruvate dehydrogenase; H+: hydrogen.
Mitochondria are tiny powerhouses that create fuel for all the energy-consuming elements of human cells. Cells would die without the vital roles that mitochondria play. Insufficient or dysfunctional mitochondria are associated with difficult-to-diagnose symptoms that can negatively affect one's quality of life, including extreme muscle weakness, chronic fatigue, gastrointestinal disorders, and even neurological dysfunction (1).
In this series, we covered what mitochondria are and why mitochondrial health is essential to the health of the whole human. We reviewed ways that mitochondria can become dysfunctional and why it matters. reviewed nutritional strategies to counter mitochondrial dysfunction, including a brief review of various mitochondria-boosting nutritional supplements.

This third part of our mitochondrial health series examines biohacking strategies to boost mitochondrial function.
What is Biohacking?
Biohacking, also known as "human enhancement," is the conscious manipulation of the body's biology to achieve some improvement in "health, performance, or well-being” (2). It's an attempt to achieve change quickly, a shortcut to getting good results by knowing how the body works. As the understanding of the human body advances, the opportunity for manipulating outcomes has multiplied. Since mitochondrial health translates to a healthier human, are there specific biohacking strategies that can increase mitochondrial health, diminish mitochondria damage, or increase the number of mitochondria?
Biohacking Strategy #1: Temperature manipulation
Any energy expenditure from within the body creates heat, and because muscles are so big, they create a lot of heat when exercised. Metabolic heat helps the body maintain its core temperature in cold weather but can also be evaporated off the body's surface to cool it in hot temperatures. Notably, this mechanism which maintains temperature homeostasis can be manipulated to increase health benefits.
1. Heat Therapy
Therapeutic heat has been enjoyed in spas, saunas, and hot springs for thousands of years. The warmth of hot water or steam noticeably relaxes muscles. Modern electric heating pads are often used to help reduce the pain of stiff or sore muscles. However, heat doesn't just feel good.
Researchers have revealed heat to be a superb biohacking strategy for increasing the number and function of mitochondria.
Increased numbers of mitochondria result in the ability to create more energy for the needs of the cell, while the increased function of mitochondria provides an increase in performance.
A 2018 study published in the Journal of Applied Physiology showed that lightly heating cultured muscle cells (muscle cells in a petri dish) created more mitochondria and increased the function of mitochondria's respiratory capacity (ability to generate ATP) (3). What's interesting about this study is that in the human participants, no exercise was performed, yet the applied heat still caused the increase in mitochondria numbers and function. This aspect makes it especially useful to those who are intolerant to exercise; that is, they have severe physical repercussions from attempting vigorous exercise. The implications are significant because heat therapy could increase mitochondria numbers and function even in those experiencing sarcopenia (wasting of muscles) or other conditions associated with mitochondrial deficits without the need for exercise (3).
Benefits of heat therapy:
-
Heat stimulation of muscles increases the number and function of mitochondria without exercise (3).
-
Sauna bathing reduces the risk of a particular type of blood clot (venous thromboembolism), in middle-aged male Caucasians (4).
-
Hot Finnish sauna bathing reduces the risk of cardiovascular disease, high blood pressure, lung diseases, skin diseases, headaches, arthritis, mental health disorders, and all-cause mortality (5).
-
Heat can help the body excrete toxic heavy metals such as lead and mercury through the sweat, resulting in detoxification (6).
How you can apply it:
1) A sauna is an easy way to increase your temperature and court mitochondria growth and strength.
2) Hot baths (such as soaking in a hot tub for 20-30 minutes) can stimulate mitochondria. However, saunas are likely more efficient than hot baths. Saunas are whole-body, whereas, in hot baths, the head stays above the water. Also, saunas can employ different heat sources, such as infrared, which has shown multiple health benefits in human studies. If using a hot tub, be sure your hot tub is free of harsh chemicals.
3) Heating pads can serve as spot treatments for the body's larger muscles, such as the thighs. However, most heating pads do not penetrate very deeply and will not have the health benefits of whole-body heat or hot water immersion.
Caveats: There are many ways to induce heat and many different devices to deliver that heat. Always ensure that any device you use is certified, reputable, and maintained properly by credentialed entities. Short exposures to heat are best to reduce the risk of serious issues such as heat stroke. If you have multiple health conditions or are taking medications, please consult your doctor to ask about complications from overheating. Lastly, commercially operated hot tubs can have chemicals such as chlorine to help reduce bacterial levels, which dry out the skin and can reduce vital, healthy populations of bacteria on the skin.
2. Cold Therapy
Just as increasing core body temperature can benefit mitochondrial health, decreasing body temperature can also positively influence the body. Studies show that cold therapy can directly and indirectly affect mitochondria. Directly, cold can cause an increase in mitochondrial numbers. Indirectly, the mitochondria benefit from reduced mitochondria-damaging ROS (Reactive Oxygen Species) in tissues due to cold application (7).
Cold therapy became a cultural phenomenon, primarily due to the promotion by cold therapy practitioner, advocate, and educator, Wim Hof. After training himself through cold therapy, meditation, and breathing techniques for many years, Wim Hof exhibited such incredible control over his autonomic nervous system (breath, circulation, heart rate) that he was the subject of an experiment in 2012 to quantify his abilities (8).
However research has been done suggesting that such therapies may impair muscle growth aka hypertrophy.
-
How Cold Therapy Might Affect Muscle Growth:
- Interferes with Anabolic Processes: Cold water immersion can reduce the activation of key signaling pathways and proteins involved in muscle protein synthesis (MPS) and muscle growth, such as mTOR and satellite cells.
- Attenuates Post-Exercise Responses: CWI might blunt the body's natural responses to resistance training, including the increase in heat shock proteins (HSP) and other factors that promote muscle repair and growth.
- Reduced Muscle Protein Synthesis: Studies have shown that cold water immersion after strength training can reduce muscle protein synthesis, which is essential for muscle growth.
- May Activate Catabolic Factors: Regular cold water immersion may also activate factors responsible for catabolism (muscle breakdown).
- Interferes with Anabolic Processes: Cold water immersion can reduce the activation of key signaling pathways and proteins involved in muscle protein synthesis (MPS) and muscle growth, such as mTOR and satellite cells.
-
What the Research Shows:
- A meta-analysis in the European Journal of Sport Science concluded that cold water immersion may result in a small reduction of hypertrophy.
- A study in the Journal of Physiology found that cold water immersion attenuated long-term gains in muscle mass and strength.
- Another study in the Journal of Strength & Conditioning Research showed decreases in strength using cold immersion.
- A study in the Journal of Physiology found that cold water immersion after strength training reduced the activation of satellite cells and the muscle-building enzyme mTOR, both of which are vital for muscle growth.
- A meta-analysis in the European Journal of Sport Science concluded that cold water immersion may result in a small reduction of hypertrophy.
-
Considerations for Athletes and Fitness Enthusiasts:
- If your primary goal is to maximize muscle growth, consider avoiding cold water immersion immediately after resistance training.
- If you choose to use cold water immersion, timing and frequency may be important. Experiment to see what works best for your recovery and training goals.
- Some research suggests that cold showers may also reduce muscle soreness, accelerate recovery, reduce inflammation, and boost metabolism.
- If your primary goal is to maximize muscle growth, consider avoiding cold water immersion immediately after resistance training.
What Are Some Of The Reported Benefits of Cold Therapy:
-
Combined with exercise, cold therapy increases the process of mitochondrial creation (9).
-
Cold water reduces muscle soreness and damage from exercise (10).
-
A hot-to-cold shower (cold exposure for 30-90 seconds) reduces the frequency of reported illness (11).
-
Exposure to cold increases brown adipose tissue (which increases metabolic rate, mitochondria, and ability to process blood sugar and fats in the blood) (12).
How you can apply it:
1) Finish a hot shower with cold water for one minute.
2) Take a cold plunge. A tub of cold water or a brief cold shower in your own home is safe.
3) Take a quick ice bath- Athletes use ice baths to help muscles recover from excessive use. Add a 5-lb bag of ice to a bathtub of cold water and sit in it (up to your neck) for 5 - 10 minutes for recovery after an endurance event.
Caveats: Exposure to extremely cold water (50-60 degrees Fahrenheit) can cause cold shock (which can end in death) (13). Pioneers such as Wim Hof adapted their bodies to cold over long periods of time. Extreme cold is a severe threat to the body and can cause reflexive bodily responses which cannot be controlled consciously, including heart failure and stroke (13). It's better to err on the side of caution. Don't jump into bodies of water with unknown temperatures.
Biohacking Strategy #2: High-Intensity Interval Training (HIIT)
High-intensity interval training (HIIT) is a way of pulsing exercise that maximizes the health benefits of regular exercise (14). The "high intensity" aspect is some exercise performed at or near the maximum of one's capability. The "interval" part means that this near-maximum effort is not made continuously; it is pulsed on and off with milder or no exercise in between. Almost any exercise can be turned into HIIT by performing the activity at near-maximum effort in short bursts, such as squats, jumping jacks, or lunges (15).
For example, HIIT walking can be walking at near-maximum speed for 30 seconds, followed by walking slowly or standing still for 90 seconds. Repeated sets of these pulsed cycles condition the heart in terms of time intervals between heartbeats (heart rate variability, also known as "HRV") (16). There are no hard and fast rules for bursts versus mild exercise. However, the American Council on Exercise (ACE) says that the near-maximum effort should be 30 seconds or less (or to breathlessness). The recovery period should be longer than 30 seconds or until one gains control of the breath. At least five repetitions of these cycles are suggested. Also, ACE cautions restricting HIIT to 3 sessions a week to allow time for muscles to repair themselves (17).
Benefits of HIIT exercise:
-
HIIT increases mitochondria numbers above moderate-intensity interval training (18).
-
Strong decreases in abdominal fat were seen with HIIT training over 12 weeks as well as improved lung, heart, and metabolic health (19).
-
HIIT reduces cardiovascular disease risk factors, increases growth hormone (which encourages fat breakdown), and reduces blood sugar measurements such as fasting glucose and hemoglobin A1C (15).

How you can apply it:
1) HIIT walking - By far, HIIT walking is the least stressful on the body (and the easiest to do). Warm up by walking slowly for 5 minutes. Then walk as fast as you can (without jogging) for 30 seconds, followed by walking slowly or stopping for 90 seconds. Repeat. Work up to 8 sets of fast walking followed by rest in one 16-minute exercise session. Warm down by walking slowly for 5 minutes. Aim to do this three times a week. It doesn't seem like much, but in less than 30 minutes, you can experience all the benefits of HIIT exercise.
2) HIIT jogging/running - For those in better condition, sprinting followed by walking can burn even more calories and blood sugar. Warm up for 5 minutes with a slow jog. On even ground, sprint for 10-15 seconds at 80%-90% of maximum effort, followed by walking slowly for 1 minute. Repeat. Work up to 8 sets. Warm down by walking slowly for 5 minutes. Aim to do this three times a week.
3) HIIT swimming or "aqua jogging" - Swimming can also be done in a HIIT manner and is gentle on the joints. Because swimming involves more muscles to keep you afloat in the water, the near-maximum intensities should be reduced. To warm up, swim slowly for 2 minutes. Burst at 80-90% maximum effort for 10-15 seconds, followed by swimming slowly or floating on your back in the water for 30-60 seconds. Repeat. Work up to 8 sets. Warm down by swimming slowly or floating for 2-5 minutes. Aim to do this three times a week.
Modification: Aqua jogging is achieved by wearing a flotation belt around the waist which keeps your head above the water. The arms and legs can be pumped as if running underwater, with the water providing resistance. Warm up by moving your arms and legs underwater, as if walking. Burst at 80-90% maximum effort for 10-15 seconds, followed by floating in the water for 30-60 seconds. Repeat. Work up to 8 sets. Warm down by floating for 2-5 minutes, moving arms and legs slowly underwater. Aim to do this three times a week.
Can high-intensity exercise really be dangerous?
The short answer is yes. However, the biggest danger to health is an inactive lifestyle, which is much more widespread than overdoing exercise. The goal should be to slowly overload the body for higher levels of performance, rather than to suddenly increase activity levels. While high-intensity exercise can lead to overuse injuries or muscle and joint injuries, these are less likely to occur with the right preparation.
What Does Some Other Research Say?
-
Increased Glycolytic Capacity:HIIT can increase the activity of enzymes involved in glycolysis (the breakdown of glucose for energy) and glycogenesis (the synthesis of glycogen), such as phosphofructokinase (PFK), lactate dehydrogenase (LDH), and glycogen synthase (Gys).
-
Enhanced Oxidative Capacity:HIIT training can increase the activity of enzymes involved in oxidative phosphorylation (the process that uses oxygen to produce energy), such as citrate synthase and β-hydroxyacyl-CoA dehydrogenase, improving the muscle's ability to utilize oxygen for energy production.
-
Antioxidant Enzyme Activity:Studies have shown that HIIT can increase the activity of antioxidant enzymes like glutathione peroxidase (GPX) in skeletal muscles, which helps protect against oxidative stress and muscle damage.
-
Muscle Protein Synthesis:HIIT can also stimulate muscle protein synthesis, which is important for muscle growth and repair.
-
Mitochondrial Biogenesis:HIIT can increase the number and function of mitochondria (the powerhouses of the cell), which are important for energy production and muscle function.
-
Muscle Damage Markers:While HIIT can lead to some muscle damage, the body also repairs and adapts to this stress, leading to increased muscle strength and size.
-
Other Benefits:HIIT can also improve insulin sensitivity, reduce blood pressure, and improve overall cardiovascular health.
Caveats: People experiencing frailty, multiple chronic illnesses, or heart conditions may need to consult their doctor before beginning HIIT exercises, due to the near-maximum effort that is required. However, HIIT programs are very flexible and can be adapted (with the help of a healthcare practitioner) to accommodate most conditions. If HIIT causes difficulty with breathing, move slowly until composure returns and plan to modify the program to adapt to your abilities.
Overtraining and HIIT
While a dedicated workout routine yields numerous benefits, overtraining can take a negative toll, and in some cases lead to potentially life-threatening outcomes.
One such condition is rhabdomyolysis, also termed rhabdo. Rhabdomyolysis occurs when, due to overexertion, muscle tissue breaks down and releases proteins such as creatine kinase (CK) and myoglobin that can damage the kidneys. Symptoms of rhabdomyolysis can include muscle aches; significant weakness; dark, murky urine; and, in severe cases, decreased to no urine output.
“Exertional rhabdomyolysis can occur after strenuous exercise and from high-intensity workouts during which the muscles are overused,” said Niloofar Nobakht, MD, associate clinical professor of nephrology. “You can also get rhabdo from direct trauma, such as a crushing injury from a motor vehicle accident or a fall.”
Overtraining occurs when the body is subjected to excessive physical stress without adequate time for recovery. Initially, exercise-induced stress can stimulate the body's adaptive response, leading to improved strength, endurance and physical performance. However, prolonged and intense training with inadequate periods of rest disrupts this delicate balance.
Overtraining can result in imbalances in hormones such as cortisol, testosterone and growth hormone. These imbalances can adversely affect metabolism and muscle growth. In addition, the strain on the body due to overtraining can suppress the immune system, making individuals more susceptible to infections, illnesses and prolonged recovery periods.
Other symptoms of overtraining can include decreased performance. Rather than achieving the desired outcome, excessive training without adequate recovery can lead to fatigue, decreased strength and endurance. Overtraining can also negatively affect mental health, causing symptoms like irritability, anxiety, depression and poor sleep quality.
Symptoms To Watch Out For With Overtraining
Overtraining can bring about a slew of symptoms, and the key to preventing overtraining is to listen to your body, pay attention to signs of fatigue, persistent soreness or decreased performance,” Au said “Rest and recovery are essential components of any training program.
Preventing Overtraining For Longevity
Some strategies include:
- Plan adequate rest days: Incorporate regular rest days into your workout routine to allow your body to recover, repair and adapt.
- Employ periodization: Periodization involves varying the intensity and volume of your workouts over time. This approach helps prevent overtraining by providing structured periods of active recovery.
- Prioritize sleep: Quality sleep is crucial for the body's recovery and repair processes. Aim for seven to nine hours of uninterrupted sleep each night.
- Nutrition and hydration: Properly fueling your body with a balanced diet and staying adequately hydrated are essential for optimal performance and recovery.