Glucose metabolism, and insulin sensitivity in particular, plays a key role in maintaining metabolic health throughout life. Insulin sensitivity is the ability of cells to respond to insulin, which enables efficient glucose absorption and its use as an energy source. Disturbances in this process lead to insulin resistance, which is associated with the development of diseases such as type 2 diabetes, atherosclerosis, and even neurodegenerative diseases. In this article, we present how supporting proper insulin sensitivity can delay the aging process and reduce the risk of age-related diseases.
Insulin resistance, defined as the reduced ability of cells to respond to insulin, is a major risk factor for developing type 2 diabetes and other metabolic disorders. Maintaining high insulin sensitivity as we age is crucial because it reduces the risk of cardiovascular and neurodegenerative diseases.
Glucose metabolism and aging processes
Insulin plays a fundamental role in regulating glucose metabolism. This hormone controls glucose storage in the liver and its transport to muscle and fat tissue, supporting the body's energy homeostasis. With age, there is a natural decline in insulin sensitivity, which is the result of:
- Chronic inflammation Inflammaging: The development of chronic, low-grade inflammation that characterizes aging leads to increased levels of pro-inflammatory cytokines such as IL-6 and TNF-α, which negatively impact insulin action.
- Oxidative stress: An increase in the level of reactive oxygen species (ROS) contributes to cell damage, including insulin receptors, reducing their effectiveness.
- Mitochondrial dysfunction: Mitochondria are responsible for energy production in cells. Their function weakens with age, which disrupts glucose metabolism and contributes to the development of insulin resistance.
Insulin sensitivity and age-related diseases
- Type 2 diabetes: Insulin resistance is the main cause of the development of type 2 diabetes. Chronic increase in glucose and insulin levels leads to fatigue of the beta cells of the pancreas, which results in their failure and full-blown diabetes. Type 2 diabetes increases the risk of kidney damage, vision and the risk of cardiovascular disease.
- Metabolic syndrome: This is a set of coexisting metabolic disorders including abdominal obesity, hypertension, hyperglycemia and dyslipidemia, which significantly increase the risk of heart disease and stroke. Insulin resistance is a central element of this syndrome and contributes to accelerated aging of the body.
- Neurodegenerative diseases: Insulin resistance in the brain, known as "type 3 diabetes," is linked to the development of Alzheimer's disease. Impaired glucose metabolism in the brain leads to the accumulation of beta-amyloid and tau, which affects neuronal function and contributes to cognitive decline.
- Cardiovascular diseases: Hyperinsulinemia, a condition resulting from insulin resistance, leads to endothelial dysfunction and increased triglyceride levels in the blood, which accelerates the development of atherosclerosis. Consequently, this increases the risk of heart attack, stroke and other cardiovascular complications..
Dietary interventions to support insulin sensitivity
- Low-carb diet: Studies show that low-carb diets (e.g., ketogenic) improve insulin sensitivity and reduce fasting insulin and glucose levels.These diets also promote the production of ketones, which provide an alternative energy source for the brain and may protect against oxidative stress.
- Mediterranean diet: This diet, rich in vegetables, fruits, fish, nuts and healthy fats such as olive oil, is effective in reducing inflammation and improving glucose metabolism. Studies have shown that regular use of the Mediterranean diet reduces the risk of developing type 2 diabetes and cardiovascular disease..
- Calorie restricted diet: Dietary calorie reduction leads to reduced activity of the mTOR pathway and increased expression of genes associated with longevity. Studies in animal models show that low-calorie diets can extend life and delay the onset of age-related diseases.
The Role of Intermittent Fasting in Improving Insulin Sensitivity
Intermittent fasting is one of the most promising approaches to improving metabolic health and extending lifespan. It involves restricting calorie intake during specific time periods, such as 16/8 (fasting for 16 hours, followed by an 8-hour eating window) or 5:2 (two low-calorie days per week, the rest of the days unrestricted).
Mechanism of action: During fasting, insulin levels decrease and glucagon levels increase, which promotes lipolysis (the breakdown of fats) and ketogenesis (the production of ketone bodies). This reduces insulin levels and reduces insulin resistance, which in the long term improves glucose metabolism. Intermittent fasting also supports autophagy processes, which involve recycling damaged cellular organelles such as mitochondria.
Health benefits: Animal and clinical studies indicate that regular intermittent fasting reduces the risk of developing type 2 diabetes, improves metabolic health, and may delay the development of neurodegenerative diseases by improving cognitive function. Additionally, intermittent fasting reduces inflammation and oxidative stress, which promotes cardiovascular health and may extend a healthy lifespan.
Examples of intermittent fasting patterns:
- 16/8: In this regimen, eating is restricted to 8 hours a day, e.g. from 12:00 to 20:00, followed by 16 hours of fasting.
- 5:2: Two days a week (not necessarily in a row) a calorie restriction of around 500-600 kcal is applied, while the remaining days of the week are without calorie restrictions.
- Eat-Stop-Eat: Once or twice a week, a complete fast is practiced for 24 hours.
Synergy with a low-carb diet
Combining intermittent fasting with a low-carb diet increases the efficiency of ketogenesis and leads to better insulin regulation and improved metabolic health. Ketones produced during fasting and low-carb diets can serve as an alternative energy source for the brain, protecting against damage caused by oxidative stress.
Physical activity as a strategy to improve insulin sensitivity
Regular physical activity is one of the most important factors in improving insulin sensitivity. Training directly affects glucose uptake by muscles, independently of insulin action, which makes it an effective preventive measure against the development of insulin resistance.
The role of aerobic exercise: Aerobic exercise, such as running, swimming, or cycling, increases blood flow to the muscles, which improves glucose transport into cells. Long-term aerobic activity also helps improve insulin sensitivity by increasing the number of insulin receptors on the surface of muscle cells and improving mitochondrial function.
Strength training: Weightlifting and resistance training increase muscle mass, which in turn leads to greater glucose uptake and improved metabolism. Muscle is the largest store of glucose in the body, so their activity significantly affects blood sugar regulation. Regular resistance training also reduces visceral fat, which is key to improving insulin sensitivity.
HIIT (High-Intensity Interval Training): High-intensity interval training, which consists of short, intense intervals of exercise interspersed with short periods of rest, has been shown to have particularly powerful effects on improving insulin sensitivity. Studies show that HIIT stimulates increased expression of glucose transport proteins (GLUT4) and improves mitochondrial function even more than traditional aerobic training.
Examples of exercise combinations:
- Aerobic training: 30 minutes of running three times a week.
- Strength training: Exercises for all muscle groups twice a week.
- HIIT: 15-minute intense workout twice a week.
Pharmacological interventions to improve insulin sensitivity
Pharmacological support in improving insulin sensitivity plays a key role, especially in patients with advanced insulin resistance or type 2 diabetes. Although lifestyle changes (diet, physical activity) are the basis of treatment, pharmacotherapy can enhance these effects and in some cases is necessary to maintain metabolic health. Below are the most well-known and effective drugs that support the improvement of insulin sensitivity.
Metformin
Metformin is one of the most commonly used drugs in the treatment of type 2 diabetes, known since the 1950s. Its mechanism of action is based on the activation of the AMPK (AMP-activated kinase) pathway, which results in a decrease in glucose production in the liver and an improvement in glucose uptake by peripheral tissues. AMPK is a key energy regulator that activates catabolic processes (the breakdown of molecules to obtain energy) and inhibits anabolic processes (the synthesis of new molecules), which leads to an improvement in glucose and lipid metabolism.
Benefits of using metformin:
- Improved insulin sensitivity: Metformin increases glucose uptake by muscle and fat cells.
- Reduction of glucose production in the liver: Inhibits the process of gluconeogenesis, which reduces fasting blood glucose levels.
- Life extension: Animal studies suggest that metformin may have lifespan-prolonging effects by affecting aging-related pathways such as mTOR and AMPK. In addition, metformin is being tested for aging prevention in humans as part of the TAME (Targeting Aging with Metformin) project
SGLT-2 inhibitors
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, such as empagliflozin or canagliflozin, work by reducing glucose reabsorption in the kidneys, resulting in increased urinary glucose excretion.Reducing blood glucose levels improves insulin sensitivity and reduces insulin concentration in the body.
Benefits:
- Improved glycemia: Reduction of blood glucose levels without the risk of hypoglycemia.
- Cardiovascular benefits: Clinical trials such as EMPA-REG OUTCOME have shown that the use of SGLT-2 inhibitors reduces cardiovascular risk, which is crucial in patients with type 2 diabetes and insulin resistance.
- Weight loss: Urinary glucose excretion leads to a reduction in body weight, which additionally supports the improvement of insulin sensitivity.
Thiazolidinediones (TZD)
Thiazolidinediones such as pioglitazone work by activating the PPAR-γ (peroxisome proliferator-activated receptor gamma) receptor, which increases the expression of genes related to glucose uptake in fat and muscle cells.
Action:
- Increasing insulin sensitivity by improving adipocyte (fat cell) function.
- Reducing inflammation and improving lipid profile.
- Supporting the development of healthy, young adipocytes, which reduces the accumulation of visceral fat and the risk of developing insulin resistance.
Supplements to support metabolic health
Supplementation can provide additional support for improving insulin sensitivity, especially when combined with diet and exercise. Here are some key supplements that have shown potential to improve metabolic health:
Berberine
Berberine is a natural alkaloid found in the roots of plants such as Berberis vulgaris. It works by activating AMPK, similar to metformin, which improves insulin sensitivity, reduces glucose production in the liver, and supports lipid metabolism.
Benefits:
- Reduction of glucose levels: Berberine has been shown to lower fasting and postprandial glucose levels.
- Improving lipid profile: Reduces triglyceride and LDL-C levels, which promotes cardiovascular health.
- Reduction of inflammation: Berberine has anti-inflammatory effects, which additionally supports metabolic health and improves insulin sensitivity.
Alpha lipoic acid (ALA)
Alpha lipoic acid is a powerful antioxidant that plays a key role in protecting mitochondria from oxidative stress. It acts as a cofactor in many metabolic reactions, supporting energy production and cellular health.
Action:
- Improving insulin sensitivity: ALA increases glucose uptake by muscle cells.
- Reduction of oxidative stress: As a powerful antioxidant, ALA protects cells from ROS-induced damage, which supports mitochondrial health.
Magnesium
Magnesium plays a key role in many metabolic processes, including regulating glucose and insulin levels. Studies have shown that low magnesium levels are associated with the development of insulin resistance and type 2 diabetes.
Benefits:
- Improved glucose metabolism: Magnesium acts as a cofactor for enzymes involved in glucose metabolism.
- Reducing the risk of insulin resistance: Magnesium supplementation improves insulin sensitivity, especially in people with low levels of this element.
Future Research Directions on Glucose Metabolism and Longevity
Further research into the role of glucose metabolism in longevity is focused on innovative strategies that can support healthy metabolism in old age. Current research is looking not only at drugs but also at genetic modulation methods, the influence of the gut microbiome, and advanced dietary therapies. Here are the most important directions of research:
New Genetic Therapies
With the development of gene therapies, scientists are looking for ways to modulate the expression of genes related to insulin sensitivity and glucose metabolism. For example, manipulation of genes encoding insulin receptors (INSR) or elements of the AMPK and mTOR pathways can lead to improved insulin sensitivity and regulation of metabolism in peripheral tissues.
- Modification of genes encoding insulin receptors: Studies in animal models suggest that changing the expression of genes responsible for the function of insulin receptors can improve their ability to respond to insulin, reducing the risk of developing insulin resistance.
- Manipulation of the mTOR pathway: Activation of the mTOR pathway is associated with anabolism and protein synthesis. Excessive mTOR activity leads to reduced autophagy and accelerated aging. Reducing mTOR activity (e.g., via rapamycin) may support metabolic health and extend lifespan.
Gut microbiome modulation
The health of the gut microbiome has a fundamental impact on glucose metabolism and insulin sensitivity. A growing body of research links the composition of the gut microbiota with the development of insulin resistance and metabolic diseases. For example, dysbiosis (imbalance of gut microbiota) leads to increased intestinal permeability (so-called “leaky gut”), which promotes the development of chronic inflammation and worsening insulin sensitivity.
- Probiotics and prebiotics: Use of probiotics (e.g. Lactobacillus and Bifidobacterium) may improve insulin sensitivity by reducing inflammation and supporting the healthy production of short-chain fatty acids (SCFAs) such as butyrate, which play a key role in regulating glucose metabolism.
- Gut Microbiota Transplant Therapies (FMT): Novel therapies such as gut microbiota transplantation may be a promising research direction for modulating the microbiome composition to improve metabolic health.
Targeted therapies for senescent cells
Senescent cells play a key role in the development of insulin resistance and other age-related diseases. Modern senescent therapies that eliminate these cells or modify their secretory phenotype (SASP) can improve metabolic health and delay the aging process.
- Senolytics: These substances selectively eliminate senescent cells, which may improve tissue health. Preliminary studies of dasatinib and quercetin suggest that such interventions may improve metabolic health, extending healthy lifespan.
- Senomimetics: Drugs that modify the secretion of SASP (Senescence-Associated Secretory Phenotype), reduce inflammation and improve cell function in response to insulin.
Insulin sensitivity is a key factor in healthy aging, influencing longevity and reducing the risk of metabolic diseases.Improving insulin sensitivity can be achieved through lifestyle changes such as regular physical activity, low-carb and Mediterranean diets, and intermittent fasting. In some cases, pharmacological interventions (e.g., metformin) and supplementation (berberine, alpha lipoic acid) can additionally support metabolic health. Effective strategies should be personalized to integrate different approaches to maximize effects and improve metabolic health in the long term.
Sources:
- Triglyceride Glucose-Body Mass Index Is a Simple and Clinically Useful Surrogate Marker for Insulin Resistance in Nondiabetic Individuals
- Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan
- Amyloid β-induced elevation of O-GlcNAcylated c-Fos promotes neuronal cell death
- Mechanisms of Insulin Action and Insulin Resistance