Browse the evidence

The cortisol-to-DHEAS ratio is a more accurate predictor of frailty and mortality than cortisol or DHEAS levels alone, as DHEAS antagonizes cortisol's catabolic and immunosuppressive effects.

Focus on maintaining a healthy cortisol-to-DHEAS balance by managing stress and body composition. While DHEA supplementation exists, its benefits are inconsistent, and lifestyle interventions that naturally support hormonal balance are more reliable for preventing frailty.

Therapeutic doses of glucocorticoids (methylprednisolone) significantly increase 24-hour energy expenditure and spontaneous food intake in healthy young men, primarily by suppressing sympathetic nervous system activity and stimulating appetite.

If you are taking therapeutic doses of glucocorticoids like methylprednisolone, expect a significant increase in hunger and energy expenditure. The drug suppresses your sympathetic nervous system, which reduces energy burning and increases appetite. To manage weight, you must actively monitor and control food intake, as your body's natural regulation will shift towards consuming more calories.

Gastric accommodation (proximal stomach relaxation) is a primary physiological mechanism for controlling meal volume and satiation, and its impairment contributes to functional dyspepsia and gastroesophageal reflux disease (GORD).

If you suffer from early fullness or bloating (functional dyspepsia), standard 'motility' drugs might not help because the issue may be your stomach's inability to relax and accommodate food (gastric accommodation). Therapies that target this relaxation, such as specific receptor agonists (e.g., buspirone, tandospirone, or acotiamide where available), may offer symptomatic relief by improving how your stomach stretches.

In patients with nonalcoholic steatohepatitis (NASH), circulating bile acid profiles are significantly altered, characterized by increased primary bile acids (specifically conjugated cholate and taurocholate) and decreased secondary bile acids, which correlates with increased severity of hepatic steatosis, inflammation, and fibrosis.

This research highlights that NASH involves specific disruptions in bile acid metabolism, particularly an increase in primary bile acids like cholate and a decrease in secondary ones. While this paper does not prescribe a specific diet, it suggests that the composition of bile acids is a key driver of liver damage. Future interventions may focus on modulating bile acid profiles (e.g., via FXR agonists or dietary fiber to influence microbiome-derived secondary bile acids) to reduce inflammation and fibrosis risk.

Metformin produces a gene expression pattern closely aligned with long-term calorie restriction in mice, making it a promising calorie restriction mimetic candidate.

Metformin, a common diabetes drug, has been shown in mice to activate genes similar to those activated by calorie restriction. While this makes it a candidate for anti-aging benefits, the paper does not recommend it as a standalone longevity supplement for healthy humans without medical supervision, noting it is one of several candidates under investigation.

PPARgamma activation in immune cells (macrophages, dendritic cells, T cells) suppresses pro-inflammatory signaling pathways (NF-kB, AP-1) via transrepression, reducing the production of inflammatory cytokines like TNF-alpha, IL-1beta, and IL-6.

Chronic inflammation is linked to metabolic disease. PPARgamma activation (naturally or via drugs) helps calm this inflammation by blocking key inflammatory signals in immune cells.

Chronic elevation of glucocorticoids (stress) combined with insulin availability drives the redistribution of stored energy specifically into intraabdominal fat depots, leading to abdominal obesity.

If you are chronically stressed, your body is biologically primed to store fat in your abdomen, even if your total calorie intake isn't drastically higher than usual. This happens because stress hormones (glucocorticoids) and insulin work together to move fat from your limbs to your midsection. To combat this, managing chronic stress is as important as diet, because lowering stress hormones can help reverse this specific fat redistribution pattern.

Glucocorticoids increase the motivation (incentive salience) to eat, while insulin determines the preference for high-density (sweet/fat) foods.

Stress doesn't just make you eat more; it makes you crave high-fat, high-sugar foods more intensely. This is because stress hormones increase the 'drive' to eat, while insulin makes those specific foods taste better and feel more rewarding. To manage this, focus on stress reduction and avoiding highly palatable foods when stressed, as your brain will be biologically primed to seek them out.

Muscle-specific PPARγ is not required for the antidiabetic effects of thiazolidinediones (TZDs); TZDs improve glucose homeostasis and insulin sensitivity in the absence of muscle PPARγ.

If you are taking a TZD (like rosiglitazone or pioglitazone), you do not need to worry that your muscle PPARγ status determines whether the drug will work for your blood sugar. The drug's ability to improve insulin sensitivity does not depend on the PPARγ receptor being present in your skeletal muscle. The benefit is likely mediated through other tissues, such as adipose tissue or the liver.

Skeletal muscle PPARγ is required for the maintenance of normal adiposity and hepatic insulin sensitivity, but not for insulin-stimulated glucose uptake in muscle itself.

For general health, maintaining healthy muscle PPARγ activity (through exercise and diet) may help prevent excess fat storage and liver insulin resistance, even if it doesn't directly change how muscles burn glucose during exercise. This highlights the importance of muscle health for overall metabolic balance.

Chronic caloric overfeeding resulting in a 10% weight gain causes a more than 3-fold elevation in basal serum leptin levels in healthy humans, correlating linearly with increased body fat percentage.

Gaining 10% of your body weight through overfeeding causes your leptin levels to triple. This is a normal physiological response to increased fat mass, not a malfunction. The paper suggests this high leptin state is associated with the development of leptin resistance, where the body's ability to use leptin to regulate energy balance is impaired.

Acute massive overfeeding (120 Cal/kg over 12 hours) causes a moderate (~40%) rise in serum leptin that persists into the next morning, independent of insulin levels.

Eating a large amount of food in one day (120 Cal/kg) causes your leptin levels to rise by about 40% and stay elevated overnight. This happens even if your insulin levels don't change in the same way, suggesting leptin responds directly to the energy intake.

Acarbose treatment improves metabolic parameters (BMI, insulin resistance, lipid profile) in type 2 diabetes patients by altering gut microbiota to increase the ratio of primary to secondary bile acids, but this benefit is contingent on the patient's baseline microbiota composition.

If you are starting treatment for Type 2 Diabetes, ask your doctor about the potential role of your gut health. This research suggests that a specific type of diabetes medication (Acarbose) works better for people who have a certain gut bacteria profile (high Bacteroides). It alters bile acids to improve metabolism, not just blood sugar. This is not a general recommendation for all patients, but a stratification strategy.

Activation of AMP-activated protein kinase (AMPK) in adipose tissue inhibits lipolysis and fatty acid efflux, thereby reducing plasma free fatty acid availability.

While exercise and fasting activate AMPK, this enzyme actually helps keep fat stored within fat cells for local use rather than releasing it into the blood. This reduces the amount of fat circulating in your bloodstream, which helps improve insulin sensitivity in muscles.

Maintenance of a reduced body weight induces leptin-reversible changes in regional neural activity in response to visual food stimuli, specifically increasing activity in brainstem, limbic, and executive control regions while decreasing activity in the hypothalamus and cingulate gyrus, thereby driving increased hunger and food intake.

If you have lost weight, your brain is biologically wired to make you hungrier and more responsive to food cues due to lower leptin levels. This is not a failure of willpower but a physiological defense mechanism. To maintain weight loss, you may need strategies that specifically address this increased neural drive, such as environmental control or potentially future pharmacological aids that mimic leptin's effect on the brain.

Hypertrophic white adipocytes in obesity secrete pro-inflammatory cytokines (TNFα, IL-6, IL-1β) and adipokines (leptin, resistin) that induce local and systemic insulin resistance and chronic inflammation, leading to metabolic disorders like type 2 diabetes and cardiovascular disease.

If you are obese, your fat tissue is actively sending signals that promote inflammation and insulin resistance, which worsens your metabolic health. This is not just 'extra weight'; it is a biologically active state. Addressing obesity through sustainable lifestyle changes can reduce the secretion of these harmful adipokines and improve metabolic markers.

Non-Hispanic Blacks have higher rates of insulin resistance and hyperinsulinemia compared to Non-Hispanic Whites, independent of adiposity, contributing to higher diabetes risk.

Biological factors like insulin resistance may be higher in Black individuals even at the same weight as White individuals. This is a risk factor for diabetes that should be monitored by a doctor.

Oligofructose (OFS) improves glucose tolerance and hepatic insulin sensitivity in high-fat-fed diabetic mice, but these benefits strictly require a functional Glucagon-Like Peptide 1 Receptor (GLP-1R).

If you are looking to use oligofructose to help manage blood sugar, understand that its effectiveness depends on your body's ability to respond to GLP-1. In animal models, if the GLP-1 receptor is blocked or missing, oligofructose provides no metabolic benefit. This suggests that individual variations in GLP-1 receptor function might influence how well this specific fiber works for glucose control.

Liraglutide (1.8 mg/day) induces histological resolution of NASH without worsening fibrosis in non-diabetic and diabetic patients, primarily by improving hepatic insulin sensitivity and reducing de novo lipogenesis, independent of weight loss magnitude.

If you have NASH, ask your doctor about liraglutide. The LEAN study showed that 1.8 mg daily significantly increased the chance of resolving liver inflammation and fat without making scarring worse, especially in those who did not have diabetes. While weight loss helps, the drug also works by directly improving how your liver handles insulin and fat production.

Pioglitazone (30 mg/day) improves NASH histology in non-diabetic patients, but its clinical use is limited by side effects including weight gain and potential cardiovascular risks.

Pioglitazone (30 mg daily for 96 weeks) can improve liver inflammation in non-diabetics, but it is rarely used first-line because it causes weight gain and has cardiovascular safety concerns. It is generally reserved for cases where other treatments are not suitable or available.

Obeticholic acid (25 mg/day) significantly improves NASH histology and fibrosis in non-cirrhotic patients, but is associated with pruritus and adverse lipid changes.

Obeticholic acid (25 mg daily for 72 weeks) significantly improves liver inflammation and scarring in non-cirrhotic NASH patients. However, it causes itching in nearly a quarter of users and can negatively impact cholesterol levels. It is a potent option but requires careful monitoring for side effects.

Estrogen levels are inversely associated with adiposity in premenopausal women, with higher estradiol levels found in healthy-weight women compared to obese women, suggesting a role for estrogens in restraining adipose tissue accumulation.

For premenopausal women, maintaining healthy weight may be biologically easier due to protective estrogen effects, but this protection diminishes after menopause. Focus on maintaining healthy weight before menopause to mitigate the inevitable fat gain associated with estrogen loss.

Gut microbiota dysbiosis is associated with the development and severity of specific diabetic complications, including nephropathy, retinopathy, neuropathy, and cardiovascular disease.

Your gut health is linked to your diabetes complications. While high blood sugar is a major factor, your gut bacteria also play a role in inflammation and disease progression. This doesn't mean you are to blame, but it does mean that supporting your gut health (through diet and potentially probiotics) might be part of a comprehensive strategy to protect your kidneys, eyes, and heart.

Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, and is not recommended for improving cognitive function, depressive symptoms, or exercise capacity in hypogonadal men.

Do not take testosterone to fix your memory, mood, or physical frailty. It is not effective for these issues. Also, do not take it if you have untreated prostate or breast cancer.