Browse the evidence

Genetic factors contribute to individual differences in NEAT, including the efficiency of movement and the tendency to increase NEAT in response to overfeeding.

Understand that your genetic makeup may influence your natural activity levels. However, this does not mean you are powerless. You can still increase NEAT by modifying your environment and making conscious choices to move more.

SIRT1 activation via resveratrol or genetic overexpression can extend healthspan and protect skeletal muscle from catabolic stress (e.g., TNF-alpha, disuse), but its effect on basal muscle mass and differentiation is complex and potentially inhibitory.

SIRT1 activators like resveratrol are popular for longevity, but their effect on muscle is nuanced. They may help protect muscle during illness, injury, or disuse by reducing inflammation and oxidative stress. However, they might also inhibit muscle growth and differentiation in healthy, well-fed individuals. Therefore, using SIRT1 activators for muscle building is not supported, but they might have a role in maintaining muscle during periods of stress or aging.

FGF21 analogs reduce hepatic steatosis and lipotoxicity in NASH by suppressing de novo lipogenesis and increasing mitochondrial fatty acid oxidation, independent of weight loss.

FGF21 analogs are emerging therapies that target the hormonal drivers of liver fat. They work by telling the liver to stop making new fat and burn existing fat, rather than just restricting calories. This addresses the root cause of NASH (steatosis) rather than just the scarring (fibrosis).

FGF21 analogs exert direct anti-inflammatory effects in NASH by suppressing pro-inflammatory cytokine expression (TNF-a, IL-6, IL-1b) and inhibiting immune cell infiltration into the liver.

FGF21 analogs help reduce liver inflammation by blocking the signals that recruit immune cells and produce damaging cytokines. This helps prevent the progression from fatty liver to scarring (fibrosis).

Endogenous FGF21 levels are elevated in NASH patients but are insufficient to ameliorate disease due to a 'FGF21-resistant state' caused by receptor downregulation and enzyme-mediated inactivation.

Your body naturally produces more FGF21 when you have fatty liver, but it doesn't work well enough to fix the problem. This is why specialized FGF21 analogs are being developed to bypass this resistance.

Lower levels of IGF-1 are associated with longer life span in mice, and this region overlaps with human longevity quantitative trait loci, suggesting a conserved mechanism where IGF-1 regulation influences longevity.

Research in mice suggests that lower IGF-1 levels may be associated with a longer life span. While human data is still correlational, this highlights the importance of metabolic health. Avoid excessive anabolic interventions that might spike IGF-1 unnecessarily, and focus on balanced nutrition and exercise.

In elderly individuals, lower circulating levels of Insulin-like Growth Factor-1 (IGF-1) and Mechanical Growth Factor (MGF) are independently associated with reduced appendicular skeletal muscle mass (ASMI) and sarcopenia.

If you are over 60, your natural production of IGF-1 and MGF declines, which contributes to muscle loss. While you cannot easily change your age, you can support your hormonal health through adequate protein intake (at least 0.6 g/kg/day) and resistance training, which may help mitigate the decline in these growth factors.

Gastric bypass surgery reduces circulating ghrelin levels significantly, which may contribute to weight loss by suppressing appetite, although the mechanism is not fully understood.

For those undergoing gastric bypass, the significant drop in ghrelin may help manage hunger long-term. This hormonal change is a key factor in the surgery's efficacy, alongside the physical restriction of stomach size.

Resveratrol inhibits adipogenesis (fat cell formation) by down-regulating key transcription factors C/EBPα and PPARγ in pre-adipocytes.

Resveratrol may help prevent the formation of new fat cells by interfering with the genetic signals (PPARγ, C/EBPα) that tell stem cells to become fat cells. This effect is observed in cell and animal studies, particularly at higher concentrations (20-100 µM in vitro). While human bioavailability is low, its metabolites may still contribute to this anti-adipogenic effect.

Resveratrol promotes apoptosis (programmed cell death) in mature adipocytes at high concentrations.

At high concentrations, resveratrol can trigger the death of existing mature fat cells (apoptosis). This effect is seen in cell cultures but requires doses much higher than typical dietary intake. It is a potential mechanism for reducing fat cell number, distinct from preventing new fat cell formation.

Certain pharmaceutical drugs (ACE inhibitors, statins, mTOR inhibitors) and lifestyle interventions (exercise) can increase circulating Klotho levels, potentially offering therapeutic benefits for age-related diseases.

Regular physical activity and adherence to prescribed medications for blood pressure, cholesterol, or metabolic health may naturally support higher Klotho levels. This suggests that standard health maintenance practices contribute to longevity mechanisms.

Insulin resistance and hypertension are evolutionary adaptations (thrifty genotype) designed to conserve energy and sodium during famine, infection, or stress, which become maladaptive in modern environments characterized by caloric and sodium abundance.

Recognize that insulin resistance and high blood pressure are not just random errors but evolved survival mechanisms. In a modern world of abundant food and salt, these mechanisms overcompensate. Management requires actively counteracting these ancient drives through lifestyle choices that mimic the 'scarcity' conditions (e.g., physical activity, controlled sodium intake) that originally selected for these traits.

Intra-arterial administration of unacylated ghrelin (200 µg/min) improves endothelium-dependent vasodilation in patients with metabolic syndrome by increasing nitric oxide bioavailability.

This study shows that ghrelin improves blood vessel function in people with metabolic syndrome by boosting nitric oxide. While the study used an invasive injection method, it suggests that maintaining healthy ghrelin levels through weight loss and exercise (which naturally raise ghrelin) may help protect your blood vessels. If you have metabolic syndrome, focusing on lifestyle changes that increase your body's natural ghrelin could support your cardiovascular health.

Gender-affirming hormone therapy (GHT) with estrogen in transgender females (TGF) is associated with an increased risk of myocardial infarction and ischemic stroke compared to cisgender females, whereas testosterone therapy in transgender males (TGM) does not show consistent evidence of increased cardiovascular or cerebrovascular disease risk.

If you are a transgender woman taking estrogen, be aware that your risk of heart attack and stroke may be higher than that of cisgender women, so regular cardiovascular check-ups are important. If you are a transgender man taking testosterone, current evidence does not show a significantly increased risk of heart or brain vessel disease, though blood pressure and lipids should still be monitored.

Gender-affirming hormone therapy (GHT) is associated with alterations in blood pressure, with some studies showing increases in both transgender females and males, while others show decreases or no change depending on the formulation and duration of therapy.

Your blood pressure may change after starting hormones. It can go up or down depending on the type of hormone and how long you've been taking it. Regular monitoring is key to catching any changes early.

Gender-affirming hormone therapy (GHT) with estrogen in transgender females (TGF) is associated with an increased risk of venous thromboembolism (VTE), whereas no increased risk of VTE has been demonstrated in transgender males (TGM).

If you are a transgender woman taking estrogen, be aware that your risk of blood clots may be higher than that of cisgender women, especially with oral formulations. Transdermal estrogen may carry a lower risk. Discuss formulation options with your provider.

SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes by regulating key enzymatic pathways including PPARα and SREBF1c.

SIRT1 activity is crucial for healthy fat cell function, promoting mitochondrial health and lipid metabolism. While boosting NAD+ precursors like NMN can support this pathway in cell models, human application requires understanding that SIRT1 is just one part of a complex metabolic system.

Phytoecdysteroids (plant-derived ecdysteroids) do not produce anabolic effects in humans comparable to Anabolic-Androgenic Steroids (AAS), despite structural similarities, likely due to poor bioavailability and lack of specific receptor affinity in human muscle tissue.

Do not expect phytoecdysteroid supplements to build muscle like anabolic steroids. While they share structural similarities, current evidence suggests they do not exert the same anabolic effects in humans, likely due to how the body metabolizes them.

Pharmacological inhibition or genetic knockdown of hypothalamic Sirt1 reduces food intake and body weight gain in rodents by activating the central melanocortin system.

This research identifies hypothalamic Sirt1 as a key regulator of hunger. Inhibiting this specific enzyme in the brain reduces food intake and body weight in rats by activating the melanocortin system. While not a direct human therapy yet, it highlights Sirt1 as a potential target for treating obesity.

Fasting increases hypothalamic Sirt1 expression and activity, which deacetylates FoxO1 to regulate the central melanocortin system.

Fasting increases the activity of Sirt1 in the brain, which helps regulate hunger signals through the FoxO1 pathway. This suggests that the body's response to fasting involves specific molecular changes in the hypothalamus.

In Type 2 Diabetes patients, increased plasma Interleukin-6 (IL-6) levels are significantly correlated with the abundance of Gram-negative gut bacteria, specifically Prevotella copri and Bacteroides vulgatus, suggesting these microbes drive systemic inflammation and insulin resistance.

This research highlights that in Type 2 Diabetes, high levels of specific gut bacteria (Prevotella and Bacteroides) are linked to higher inflammation (IL-6) and insulin resistance. While this paper does not prescribe a treatment, it suggests that managing gut health through diet may be a relevant factor in addressing the inflammatory component of diabetes, alongside standard medical care.

Resistin acts as a pro-inflammatory mediator that impairs insulin sensitivity through multiple mechanisms, including inhibition of glucose transporter activity, suppression of GLUT4 translocation, and activation of inflammatory pathways like NF-kappaB.

Resistin is a hormone linked to inflammation and insulin resistance. While high levels are associated with metabolic issues, human data is inconsistent. Focus on reducing systemic inflammation through diet and exercise, which may positively influence resistin levels and insulin sensitivity.

Visfatin (also known as NAMPT or PBEF) exhibits insulin-mimicking effects in vitro by stimulating glucose uptake and insulin signaling pathways, but its physiological role in humans regarding insulin sensitivity remains controversial and unclear.

Visfatin has insulin-like properties in lab settings, but its role in human health is complex and not fully understood. Current evidence does not support using visfatin levels to guide treatment. Focus on proven lifestyle interventions for metabolic health.

Prolonged endoplasmic reticulum stress (ERS) activates the unfolded protein response (UPR), which mediates chronic low-grade inflammation, insulin resistance, and cardiac dysfunction in obesity.

This research highlights that obesity triggers cellular stress (ERS) in the heart, leading to inflammation and insulin resistance. While this paper does not prescribe a specific diet, it underscores the importance of reducing metabolic stressors (like excess calories and free fatty acids) to prevent this cellular damage. Focus on sustainable weight management and metabolic health to reduce the burden on your cardiovascular system.