SGLT-2 inhibitors function by reducing glucose reabsorption in the kidneys, leading to the excretion of excess glucose through urine. This process helps lower blood sugar levels and shifts the body’s energy reliance to stored fat, promoting fat oxidation and enhancing metabolic flexibility.

The Healthspan SGLT-2 Metabolic Protocol incorporates two SGLT-2 inhibitors: Bexagliflozin and Canagliflozin. Both medications belong to the class of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which function by reducing glucose reabsorption in the kidneys, thereby increasing glucose excretion through urine. This mechanism not only lowers blood glucose levels but also triggers downstream metabolic benefits such as enhanced fat oxidation, improved metabolic flexibility, and activation of key longevity pathways, including AMPK activation and mTORC1 inhibition.

Although Bexagliflozin and Canagliflozin are distinct molecules, they share a similar mechanism of action and pharmacological profile, supporting their interchangeable use in targeting the biological pathways central to the protocol. By leveraging these therapies, the protocol promotes fat loss, preserves lean muscle mass, and addresses systemic inflammation and cellular aging.

Healthspan’s selection of these SGLT-2 inhibitors is based on their robust safety and efficacy profiles, as demonstrated in clinical and preclinical studies, making them ideal components of a scientifically grounded strategy to enhance healthspan and resilience against age-related metabolic and cellular dysfunctions.

SGLT-2 inhibitors are highly effective in managing glucose levels, even in healthy, non-diabetic individuals. In clinical studies, participants taking an SGLT-2 inhibitor demonstrated a 35% reduction in post-meal blood glucose levels during a mixed meal tolerance test. This test evaluates how well the body processes glucose from a standardized meal. Additionally, insulin levels were reduced by 43%, indicating enhanced metabolic efficiency.

These inhibitors work by promoting glucose excretion through urine, with approximately 24% of consumed glucose eliminated during the test. This mechanism not only reduces the glucose burden on the body but also improves overall glucose handling, making SGLT-2 inhibitors a promising option for maintaining stable blood glucose levels beyond traditional therapies like Metformin or Acarbose.

The dose you will receive as part of the SGLT-2 Metabolic Protocol is carefully personalized to your unique health profile, metabolic needs, and longevity goals. At Healthspan, we prioritize precision in dosing to maximize therapeutic benefits while maintaining safety. Factors such as your body composition, kidney function, and metabolic health are thoroughly evaluated through comprehensive baseline testing.

For most individuals, the protocol starts with a clinically validated dose of either 20 mg of bexagliflozin or 125 mg of canagliflozin. Your doctor will help determine the most appropriate medication and dose based on your specific needs. These starting doses are designed to enhance glucose excretion, promote fat oxidation, and preserve lean muscle mass—key factors in supporting healthspan and metabolic flexibility.

Ongoing monitoring and follow-up testing ensure that the dose can be optimized as needed, based on your progress and response to the therapy. This personalized approach provides the best opportunity to achieve meaningful improvements in your healthspan and resilience against age-related conditions. Should you have any questions or concerns, our clinical team is here to support you every step of the way.

SGLT-2 inhibitors have demonstrated significant cardiovascular and kidney health benefits in clinical studies, particularly in patients with diabetes or heart failure. The CANVAS trial, which included over 10,000 participants, reported a 14% reduction in cardiovascular event risk, a 27% reduction in albuminuria risk (a marker of kidney damage), and a 40% improvement in kidney filtration rate. These findings highlight their ability to reduce cardiac mortality and improve renal function.

Mechanistically, SGLT-2 inhibitors improve heart health by minimizing cardiac hypertrophy, reducing cardiovascular inflammation, and preventing fibrosis accumulation, which collectively enhance cardiac structure and function.

While these benefits have been extensively studied in diseased populations, their potential as a preventative therapy in healthy individuals remains an area of ongoing research. With rising risks of cardiovascular disease linked to Western diets, SGLT-2 inhibitors may offer a future strategy to maintain heart and kidney health across the lifespan.

We have carefully selected each biomarker below to provide you with the broadest and deepest understanding of your ever-changing health. The following biomarkers are included with your panel. The SGLT2 Metabolic Protocol offers a comprehensive health assessment, integrating a complete metabolic profile, complete blood count (CBC), lipid panel, Hemoglobin A1C (HbA1C), and High-sensitivity C-reactive protein (Hs-CRP) tests.This panel is designed to deliver a holistic view of your health, focusing on key aspects such as metabolic efficiency, blood health, cardiovascular risk, and systemic inflammation. By utilizing advanced algorithms, the panel goes beyond traditional assessments to calculate your biological age, providing a deeper insight into your body's aging process in comparison to your chronological age. This analysis is crucial in identifying potential health risks and areas for improvement, guiding you towards a personalized pathway for optimizing your longevity and maintaining a robust metabolic engine.

Metabolic Markers: Apolipoprotein B (Apo B), Glucose, Hemoglobin A1C, Total Cholesterol, LDL Cholesterol, VLDL Cholesterol, HDL CholesterolTriglycerides, and Triglyceride:HDL C Ratio

Immune Markers: C-Reactive Protein, WBC, Neutrophil-Lymphocyte Ratio, Lymphs (Absolute), Lymphs, Monocytes (Absolute), Monocytes, Neutrophils (Absolute), Neutrophils, Eosinophils,Basophils, andImmature Granulocytes

Organ: Protein, BUN/Creatinine Ratio, Albumin, eGFR, Globulin, Sodium, A/G Ratio, Potassium, AST (SGOT), Carbon Dioxide, ALT, Anion Gap, Bilirubin, Calcium, Alkaline Phosphatase, BUN, Creatinine, RBC (Red cell count), Hemoglobin, Hematocrit, MCV (Mean corpuscular volume), MCH (Mean corpuscular hemoglobin), RDW (Red cell distribution width) and Platelets

SGLT-2 inhibitors impact key nutrient-sensing pathways that regulate cellular health and longevity. Elevated mTORC1 signaling is a hallmark of accelerated aging, and its inhibition has been linked to lifespan extension. Studies show that SGLT-2 inhibitors effectively reduce mTORC1 activity, though not as potently as Rapamycin, with notable sex-specific effects on lifespan observed in preclinical research.

Additionally, SGLT-2 inhibitors activate AMPK, a master regulator of energy balance and longevity. By inhibiting complex I of the mitochondrial respiratory chain, these therapies increase cellular AMP levels, driving AMPK activation. This leads to enhanced autophagy, improved mitochondrial function, reduced lipid synthesis, and increased fat oxidation—all of which contribute to better metabolic health and reduced biological aging markers.

While more potent alternatives like Rapamycin exist, SGLT-2 inhibitors uniquely target both mTORC1 and AMPK, offering dual-pathway benefits for nutrient sensing and longevity. This dual action underscores their promise as interventions for supporting metabolic health and promoting healthspan.

Cellular senescence, a state of irreversible growth arrest in somatic cells, is a hallmark of aging linked to tissue dysfunction and chronic inflammation. Research into reducing senescent cell accumulation has predominantly focused on senolytic compounds like Quercetin and Fisetin. However, SGLT-2 inhibitors have emerged as a promising intervention with senolytic properties.

A recent 2024 Nature Aging study demonstrated that short-term SGLT-2 inhibitor treatment (7-14 days) reduced senescent cell accumulation by 40-50% in models of high-fat diet and cardiovascular disease. In a high-fat diet model, senescence in adipose tissue increased by ~750% within 8 weeks, but SGLT-2 inhibitors significantly reversed this accumulation, reducing senescence by 40% in just 7 days. Similarly, in a cardiovascular disease model, aorta senescence was reduced by 40-50%, concurrent with a 37% reduction in atherosclerosis.

The mechanism behind this effect involves AMPK activation, a key longevity pathway. The senolytic benefits of SGLT-2 inhibitors are blunted when AMPK activity is inhibited, highlighting its central role in reducing cellular senescence.

These findings suggest that SGLT-2 inhibitors could offer a powerful therapeutic approach for addressing senescence-related aging processes. While short-term benefits are remarkable, prolonged treatment may provide even greater protection against the accumulation of senescent cells across tissues, further supporting their potential as healthspan-promoting interventions.

Chronic low-grade inflammation, termed "inflammaging," is a hallmark of aging linked to systemic tissue damage and age-related diseases. While specific biomarkers for inflammaging—such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)—often overlap with disease-specific inflammation, addressing these inflammatory pathways is critical for promoting longevity.

SGLT-2 inhibitors have demonstrated significant anti-inflammatory properties. Longitudinal studies in humans with diabetic kidney disease show that two years of treatment reduces plasma levels of TNF receptor 1 (TNFR1), IL-6, and other markers such as matrix metalloproteinase 7 and fibronectin 1 (FN1). These findings suggest that SGLT-2 inhibitors help reverse the molecular processes contributing to inflammation, extracellular matrix turnover, and fibrosis.

The ability of SGLT-2 inhibitors to lower inflammatory cytokines and tissue inflammation likely extends beyond metabolic health, influencing other age-related comorbidities. For instance, by reducing systemic inflammation, these therapies may help preserve cognitive and brain function, combatting processes linked to neurodegeneration.

By targeting inflammation at a molecular level, SGLT-2 inhibitors contribute to reducing inflammaging and promoting healthier aging, making them a promising tool for enhancing longevity and healthspan.

The aging brain is often characterized by increasing neuroinflammation and cerebral insulin resistance, both of which contribute to cognitive impairment and raise the risk of neurodegenerative diseases like Alzheimer’s and Parkinson’s. SGLT-2 inhibitors, including those with the ability to cross the blood-brain barrier, show promising neuroprotective effects that may offset brain aging and support cognitive function into later life.

Recent studies highlight how SGLT-2 inhibitors reduce microgliosis and astrogliosis in the hippocampus, a brain region crucial for memory, learning, and emotion. These reductions in glial activation help mitigate neuroinflammation and protect neurons from damage—key steps in delaying or preventing neurodegenerative diseases.

Additionally, long-term treatment with SGLT-2 inhibitors has been shown to influence the hypothalamus, a critical region for regulating appetite, metabolism, and hormone production. Research has demonstrated increased metabolic rates and enhanced neural projections in this region, particularly in females, suggesting a role in maintaining energy balance and neural health.

From a molecular perspective, RNA sequencing has revealed that SGLT-2 inhibitors upregulate clusters of genes involved in neuropeptide signaling, which are essential for communication within the brain. These findings underscore the potential of SGLT-2 inhibitors to prevent age-related declines in brain function, reduce neuroinflammation, and promote cognitive health as part of a broader healthspan-promoting strategy.