Tag Archives: metabolism

Metabolic Flexibility: Retraining the Metabolism for Optimal Health

In an attempt to ease digestion, improve energy levels, and promote weight loss, many popular health recommendations focus on increasing metabolic rates. However, while manipulating metabolic speeds may help burn a few extra calories, the efficiency with which the body expends energy largely relies on age and genetic factors. A critical factor is often overlooked in the pursuit of improving metabolism: metabolic flexibility.

A key to optimal wellbeing, longevity, and chronic disease prevention, metabolic flexibility directly measures the body’s ability to respond and adapt to conditional changes in metabolic demands. Access to high-calorie processed foods as part of the standard American diet combined with increasingly sedentary lifestyles have directly impacted the ability of the metabolism to be flexible, and thus, support sustained energy production. Studies have shown that metabolic flexibility can prevent and treat metabolic diseases like diabetes and insulin resistance and help the body run at its optimal levels.

The real key to long-term health is not a fast metabolism – it is a flexible one.

What is Metabolic Flexibility?

Metabolic flexibility refers to the capacity of the organism to adapt fuel oxidation to fuel availability as energetic demands and nutrient availability fluctuate. The mechanisms governing fuel selection between glucose and fatty acids impact the risk for insulin resistance. If they are not functioning correctly, long-term health consequences ranging from hypertension to type 2 diabetes and obesity can arise.

The body of literature regarding metabolic flexibility expands as more clinical data points to its vast implications on overall health. Authors of a recent manuscript published in Cell Metabolism highlight that advances in omics technologies have spurred research that aims to interrogate mechanisms for improved metabolic flexibility in skeletal muscle and adipose tissue with the goal of preventing and treating metabolic disease.

Risks Associated with Metabolic Inflexibility

Due to poor dietary habits and sedentary lifestyles, metabolic inflexibility has become the patient standard. In the short term, this may manifest as decreased energy after meals, midday energy crashes, weight management difficulties, and mental illness symptoms, such as anxiety.

Over time, the physiological impact of weakened metabolic flexibility, including elevated glucose levels and insulin resistance, can lead to type 2 diabetes, hypertension, and other long-term health conditions. Impaired fat utilization associated with metabolic inflexibility can lead to weight gain and obesity, furthering the risk of chronic disease. Additionally, a weakened metabolism can alter the mass, structure, and function of the mitochondria in cells, thus causing elevated free radical levels in the body.

Health Benefits of a Flexible Metabolism 

Sustained energy, fewer glucose-related energy crashes, decreased cravings, and optimized fat usage, are only a few of the many benefits of having a flexible metabolism. When the body can seamlessly shift between fuel sources, it can adequately utilize energy instead of inefficiently storing it, resulting in improved weight maintenance, increased energy levels, and decreased risk of metabolic disease. Furthermore, metabolic flexibility is associated with consistent glucose levels, optimized workout performance, better sleep, and improved overall health.

Retraining the Modern Metabolism

Current data suggests that only 15% of the population has a flexible metabolism. While the concept continues to be a subject of scientific research and beneficial interventions are likely to emerge, there are already several methods that can help retrain a disrupted metabolism.

Dietary Interventions

The standard American diet emphasizes carb consumption and frequent eating, which accustoms the body to seeking out carbs for energy and promotes fat storage. On the other hand, low-carb, high-fat diets promote ketosis – or the state in which the body burns fat instead of blood sugar – forcing the body to adapt to changing metabolic demands.

Intermittent fasting has proven to achieve metabolic flexibility and address insulin resistance as well. By restricting the food intake for 12-18 hours per day, intermittent fasting allows the body enough time to burn stored fat for energy and release a healthy level of toxins. Combined with intermittent fasting, the benefits of low-carb diets rich in whole, real food are numerous: glowing skin, fat loss, improved brain function, and elevated healthspan.

Regular Physical Activity

Physical inactivity is one of the leading causes of metabolic inflexibility, while regular exercise is one of the most effective techniques for boosting metabolic flexibility. Incorporating as much movement throughout the day can train the metabolism to respond to shifts in energetic demands. Consistent physical activity is the key to increasing mitochondrial content, improving glycemic control, and improving insulin sensitivity.

All forms of physical activity are beneficial to overall health; however, experts believe that a combination of aerobic cardio and strength training exercises can yield optimal results for metabolic flexibility.

Key Takeaways

The majority of the population has an inflexible metabolism that cannot respond effectively to changing energy demands and nutrient availability. As a result, many struggle with weight management, chronic disease, and poor health and wellbeing. Retraining the metabolism with dietary and other lifestyle interventions can help develop metabolic flexibility – a key component of overall health.

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PHD3 Loss, Fat Metabolism, and Exercise Endurance

Tolerance of exercise and endurance can both decrease with age and declining metabolic health yet physical activity remains a cornerstone of physical and mental health regardless of age. Enzyme systems have received increasing attention for their potential to reduce exercise fatigue and improve endurance by providing the body with access to energy reserves and optimizing their use. Sugars are the primary fuel of cellular processes however, when nutrients are scarce – such as in cases of starvation or extreme exertion – cells switch to breaking down fats for energy. At this time, the mechanisms behind the rewiring of cellular metabolic pathways in response to fluctuations in resource availability are poorly understood.

New research published earlier this month in Cell Metabolism suggests a surprising consequence when one such mechanism is turned off – an increased capacity for endurance exercise. Recently conducted by researchers from the Harvard Medical School, the study revealed that blocking the activity of a fat-regulating enzyme in the muscles of mice could lead to an increased capacity for endurance exercise

Boosting Exercise Endurance in Mice

Led by Marcia Haigis, professor of cell biology at Harvard Medical School, a team of researchers investigated the function of the enzyme prolyl hydroxylase 3 (PHD3) – which they believed played a role in regulating fat metabolism in certain cancers. The study’s authors investigated the impact of PHD3 inhibition in genetically modified mice by carrying out a series of endurance exercise experiments.

Under normal conditions, PHD3 chemically modifies the enzyme ACC2 which prevents fatty acids from entering mitochondria to be broken down into energy. The team of researchers found that blocking PHD3 production in mice resulted in dramatic improvements in fitness measures: mice lacking the PHD3 enzyme ran 40% longer and 50% farther on treadmills and had a higher VO2 max – indicating increased aerobic endurance – than control subjects.

After endurance experiments, the muscles of PHD3-deficient mice revealed heightened rates of fat metabolism and an altered fatty acid composition and metabolic profile. According to the authors, their findings held true in genetically modified mice demonstrating that PHD3 loss in muscle tissues may be sufficient to boost exercise capacity.

PHD3 Enzyme Regulates Metabolic Pathways

After performing a series of molecular analyses to detail precise molecular interactions allowing PHD3 to modify ACC2 and how its activity repressed by AMPK, Haigis and her team reported that PHD3 and AMPK, another enzyme, simultaneously control the activity of ACC2 to regulate fat metabolism depending on energy resource availability.

Their research identified the critical role of the enzyme prolyl hydroxylase 3 (PHD3) in sensing nutrient availability and regulating the ability of muscle cells to metabolize fats, revealing that when nutrients are abundant, PHD3 acts as a brake inhibiting unnecessary fat metabolism that is released during exercise. Whole body or skeletal muscle PHD3 loss enhances acute exercise capacity during endurance exercise experiments.

“The findings shed light on a key mechanism for how cells metabolize fuels and offer clues toward a better understanding of muscle function and fitness,” the authors wrote.

“Understanding this pathway and how our cells metabolize energy and fuels potentially has broad applications in biology, ranging from cancer control to exercise physiology,” senior author Haigis explained. Although, further research is needed to identify whether this pathway can be manipulated in humans to improve muscle function, in the treatment of various diseases, and to better understand how PHD3 inhibition improves exercise capacity.

The latest findings carry implications for a potential novel approach to enhancing exercise performance, treating muscle disorders, as well as developing therapeutic methods for certain cancers in which mutated cells express decreased levels of PHD3. At this time, whether there are any negative effects – including weight loss, blood sugar changes and other metabolic markers – associated with PHD3 loss remains unknown although, this will hopefully be elucidated by future research.

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The Role of Sirtuins in Longevity

Despite strenuous controversies, the field of sirtuin research is growing with an increasing number of recent studies revealing their promising connection to longevity. After many years of investigation, understanding of the activity of the silent information regulator 2 (Sir2) family (‘sirtuins’) has greatly expanded, proving its significant involvement in the regulation of many fundamental biological processes. Dr. Leonard Guarente, co-founder of Elysium Health and director of MIT’s Glenn Center for Biology of Aging, stands at the forefront of sirtuin research efforts.

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