Glucose metabolism, particularly insulin sensitivity, plays a key role in maintaining metabolic health over a lifetime. Insulin sensitivity is the ability of cells to respond to insulin, allowing glucose to be efficiently absorbed and used as an energy source. Disruption of this process leads 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 outline how promoting normal 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 the storage of glucose in the liver and its transport to muscle and adipose tissue, promoting the body's energy homeostasis. With age, there is a natural decline in insulin sensitivity as a result of:
- Chronic inflammation (inflammaging): The buildup of chronic low-grade inflammation, characteristic of aging, leads to increased levels of pro-inflammatory cytokines such as IL-6 and TNF-α, which negatively affects insulin action.
- Oxidative stress: Increased levels of reactive oxygen species (ROS) contribute to cellular damage, including insulin receptors, reducing their effectiveness.
- Mitochondrial dysfunction: Mitochondria are responsible for energy production in cells. With age, their function weakens, impairing glucose metabolism and contributing to the development of insulin resistance.
Insulin sensitivity and age-related diseases
- Type 2 diabetes: Insulin resistance is a major cause of the development of type 2 diabetes. Chronic increases in glucose and insulin levels lead to fatigue of pancreatic beta cells, resulting in their failure and full-blown diabetes. Type 2 diabetes increases the risk of kidney damage, vision damage and the risk of cardiovascular disease.
- Metabolic syndrome: This is a cluster of comorbid metabolic disorders including abdominal obesity, hypertension, hyperglycemia and dyslipidemia that significantly increase the risk of heart disease and stroke. Insulin resistance is central to this syndrome and contributes to accelerated aging.
- Neurodegenerative diseases: Insulin resistance in the brain, referred to as “type 3 diabetes,” has been linked to the development of Alzheimer's disease. Abnormal 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 an increase in blood triglycerides, 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-carbohydrate (low-carb) diets: Studies show that low-carbohydrate diets (e.g., ketogenic diets) improve insulin sensitivity and reduce insulin and fasting glucose levels. These diets also promote the production of ketones, which provide an alternative energy source for the brain and can 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: Reducing dietary calories leads to a decrease in mTOR pathway activity and increases the expression of genes associated with longevity. Studies in animal models show that low-calorie diets can prolong 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 life expectancy. It involves restricting caloric intake over specific time intervals, such as 16/8 (fasting for 16 hours followed by an 8-hour eating window) or 5:2 (two low-calorie days per week, other days unrestricted).
Mechanism of action: During the fasting period, insulin levels decrease and glucagon levels increase, which promotes lipolysis (breakdown of fats) and ketogenesis (production of ketone bodies). This has the effect of lowering insulin levels and reducing insulin resistance, which in the long run improves glucose metabolism. Intermittent fasting also promotes autophagy processes, which involve the recycling of damaged cellular organelles such as mitochondria.
Health benefits: Studies in animal models and clinical trials indicate that regular use of 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. In addition, intermittent fasting reduces inflammation and oxidative stress, which promotes cardiovascular health and may extend healthy life expectancy.
Examples of intermittent fasting regimens:
- 16/8: In this regimen, food intake is limited to 8 hours a day, such as from 12pm to 8pm, followed by 16 hours of fasting.
- 5:2: Two days a week (not necessarily in a row) a calorie restriction of about 500-600 kcal is applied, while the other days of the week are without caloric restriction.
- Eat-Stop-Eat: Once or twice a week, total fasting is applied for 24 hours.
Synergy with a low-carbohydrate diet
Combining intermittent fasting with a low-carbohydrate (low-carb) diet increases the efficiency of ketogenesis and leads to better insulin regulation and improved metabolic health. Ketones produced in the fasting state and with a low-carbohydrate supply can serve as an alternative energy source for the brain, protecting against oxidative stress-induced damage.
Physical activity as a strategy to improve insulin sensitivity
Regular physical activity is one of the most important factors in improving insulin sensitivity. Workouts directly affect muscle glucose uptake independently of insulin action, making them an effective preventive measure against the development of insulin resistance.
Role of aerobic exercise: Aerobic exercise, such as running, swimming and cycling, increases blood flow to muscles, which improves glucose transport into cells. Long-term aerobic activity also promotes improved 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 contribute to increased muscle mass, which in turn leads to greater glucose uptake and improved metabolism. Muscles are the body's largest storehouse of glucose, 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, consisting of short, intense intervals of effort interspersed with short periods of rest, has been shown to have particularly powerful effects in 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 for 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 cornerstone of treatment, pharmacotherapy can enhance these effects, and in some cases is essential for maintaining metabolic health. The most well-known and effective medications for promoting improved insulin sensitivity are described below.
Metformin
Metformin is one of the most widely used drugs for the treatment of type 2 diabetes, known since the 1950s. Its mechanism of action is based on activation of the AMPK (AMP-activated kinase) pathway, resulting in decreased hepatic glucose production and improved glucose uptake by peripheral tissues. AMPK is a key energy regulator that activates catabolic processes (breakdown of molecules for energy) and inhibits anabolic processes (synthesis of new molecules), leading to improved glucose and lipid metabolism.
Benefits of metformin:
- Improved insulin sensitivity: Metformin increases glucose uptake by muscle and fat cells.
- Reduction in hepatic glucose production: Inhibits gluconeogenesis, which reduces fasting blood glucose levels.
- Life extension: Studies in animal models suggest that metformin may have life-extending effects by affecting aging-related pathways such as mTOR and AMPK. In addition, metformin is being tested in the context of preventing aging in humans as part of the TAME (Targeting Aging with Metformin) project
SGLT-2 inhibitors
Sodium-glucose cotransporter type 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 concentrations in the body.
Benefits:
- Improving glycemia: Reduce 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 weight loss, which further promotes improved insulin sensitivity.
Thiazolidinediones (TZDs)
Thiazolidinediones, such as pioglitazone, act by activating the PPAR-γ receptor (peroxisome proliferator-activated receptor gamma type), which increases the expression of genes related to glucose uptake in fat and muscle cells.
Action:
- Increase insulin sensitivity by improving adipocyte (fat cell) function.
- Reduce inflammation and improve lipid profile.
- Promote 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 to improve insulin sensitivity, especially when combined with diet and physical activity. Below are some key supplements that show potential in improving 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 hepatic glucose production and promotes lipid metabolism.
Benefits:
- Reduction of glucose levels: Berberine has been shown to reduce fasting and post-meal glucose levels.
- Lipid profile improvement: Reduces triglycerides and LDL-C, which promotes cardiovascular health.
- Reduction of inflammation: Berberine has an anti-inflammatory effect, which further 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:
- Improves insulin sensitivity: ALA increases glucose uptake by muscle cells.
- Reduce 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 glucose and insulin regulation. Studies have shown that low magnesium levels are linked to the development of insulin resistance and type 2 diabetes.
Benefits:
- Improved glucose metabolism: Magnesium acts as a cofactor for enzymes involved in glucose metabolism.
- Reduce risk of insulin resistance: Magnesium supplementation improves insulin sensitivity, especially in people with low magnesium levels.
Future directions for research on glucose metabolism and longevity
Further research into the role of glucose metabolism in the context of longevity is focusing on innovative strategies that can support healthy metabolism in advanced age. Current research is looking not only at drugs, but also at methods of genetic modulation, the impact of the gut microbiome and advanced dietary therapies. Here are the most important research directions:
New gene therapies
With the development of gene therapies, researchers are looking for ways that can 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 altering 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., through rapamycin) can promote metabolic health and prolong life.
Modulation of the gut microbiome
The health of the gut microbiome has a fundamental impact on glucose metabolism and insulin sensitivity. A growing number of studies have linked the composition of the gut microbiota to the development of insulin resistance and metabolic diseases. For example, dysbiosis (an imbalance of the gut microbiota) leads to increased intestinal permeability (known as “leaky gut”), which promotes the development of chronic inflammation and impaired insulin sensitivity.
- Probiotics and prebiotics: The use of probiotics (e.g., Lactobacillus and Bifidobacterium) can improve insulin sensitivity by reducing inflammation and promoting healthy production of short-chain fatty acids (SCFAs), such as butyrate, which play a key role in regulating glucose metabolism.
- Gut microbiota transplant (FMT) therapies: Novel therapies such as gut microbiota transplants may be a promising direction for research into modulating the composition of the microbiome to improve metabolic health.
Therapies targeting aging cells
Aging 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 aging cells, which may improve tissue health. Preliminary studies on dasatinib and quercetin indicate that such interventions may improve metabolic health, extending healthy lifespan.
- Senomimetics: Drugs that modify SASP (Senescence-Associated Secretory Phenotype) secretion, reduce inflammation and improve cellular function in response to insulin.
Insulin sensitivity is a key factor in healthy aging, affecting longevity and reducing the risk of metabolic diseases. Increasing insulin sensitivity can be achieved through lifestyle changes such as regular physical activity, low-carbohydrate and Mediterranean diets, and intermittent fasting. In some cases, pharmacological interventions (e.g., metformin) and supplementation (berberine, alpha-lipoic acid) can further promote metabolic health. Effective strategies should be personalized to integrate different approaches to maximize outcomes and improve metabolic health in the long run.
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