Benefits and Pathways

Originally developed to treat Type 2 diabetes, SGLT-2 inhibitors like Canagliflozin and Bexagliflozin have emerged as promising longevity interventions. These medications target key metabolic and molecular pathways associated with aging, acting as calorie restriction mimetics while addressing core hallmarks of aging.

By inhibiting the SGLT2 protein in the kidneys, these therapies increase glucose excretion through urine, resulting in the loss of up to 70–90 grams of glucose per day (~280–360 calories).

Longevity Benefits

1. Improved Metabolic Health:
   • Enhances glucose regulation by promoting glucose excretion, reducing hyperglycemia, and improving insulin sensitivity.
   • Encourages fat oxidation and reduces lipid synthesis, supporting a leaner body composition.
2. Reduced Inflammation:
   • Lowers markers of chronic inflammation, such as TNF-α and IL-6, mitigating age-related tissue damage caused by persistent low-grade inflammation (inflammaging).
3. Cellular Senescence Reduction:
   • Short-term SGLT-2 inhibition has shown a 40–50% reduction in senescent cells in preclinical models of high-fat diet and cardiovascular disease, suggesting potential benefits for tissue health.
4. Neuroprotection:
   • Crosses the blood-brain barrier to reduce neuroinflammation, improve cerebral metabolism, and protect against age-related declines in memory and cognition.
   • Reduces activation of harmful glial cells (microgliosis and astrogliosis) in brain regions like the hippocampus.
5. Cardiovascular and Renal Protection:
   • Reduces glomerular pressure and proteinuria, protecting kidney function.
   • Lowers blood pressure and reduces vascular stress, decreasing the risk of cardiovascular events and supporting long-term heart and kidney health.

Longevity Pathways Targeted

1. AMPK Activation:
   • SGLT-2 inhibitors activate AMPK, a cellular energy sensor that promotes fat oxidation, enhances mitochondrial function, and stimulates autophagy—key processes for longevity.
2. mTORC1 Inhibition:
   • By reducing insulin signaling, SGLT-2 inhibitors lower mTORC1 activity, which slows cellular growth and favors repair processes like autophagy, aligning with mechanisms seen in calorie restriction and rapamycin treatment.
3. Calorie Restriction Mimetic Effects:
   • Mimics the benefits of calorie restriction by depleting glucose stores and shifting energy metabolism to lipids, promoting fat oxidation and metabolic flexibility without the need for severe caloric restriction.
4. Senescence and Inflammatory Pathways:
   • Reduces the accumulation of senescent cells, which release inflammatory signals that drive tissue damage.
   • Suppresses pro-inflammatory cytokines (TNF-α and IL-6) that are elevated during aging.
5. Mitochondrial Function:
   • Enhances mitochondrial efficiency by reducing oxidative stress and activating pathways that support energy production and cellular health.
6. Insulin Sensitivity and Glycemic Control:
   • Lowers insulin levels and improves insulin sensitivity, reducing fat storage and protecting against age-related metabolic dysfunction.

Body Composition Benefits

1. Reduction in Fat Mass:
   • Preclinical studies show significant reductions in fat mass, particularly in females (19% fat loss compared to 8% in males).
   • Shifts the body's energy balance toward fat oxidation, promoting the breakdown of stored fat for energy.
2. Improved Lean-to-Fat Ratio:
   • Reduces fat mass while preserving or enhancing lean mass, improving the lean-to-fat ratio—a key marker of metabolic and functional longevity.
3. Calorie Restriction Mimetic Effects:
   • Depletes glucose stores and reduces lipid synthesis, mimicking some effects of calorie restriction without dietary changes.
4. Reduction in Visceral Fat:
   • Although specific data on visceral fat is limited, SGLT-2 inhibitors’ fat metabolism benefits suggest reductions in visceral fat, which is strongly linked to metabolic disease and cardiovascular risk.
5. Glycemic Control with Secondary Body Composition Effects:
   • By reducing blood glucose and insulin levels, SGLT-2 inhibitors minimize insulin's anabolic effects on fat storage, supporting sustainable fat loss.
6. Weight Loss:
   • Promotes modest weight loss, attributed to:
     • Glucose excretion (~70–90 grams/day, equating to 280–360 kcal/day).
     • Reduced appetite and improved satiety through better glucose and fat metabolism.
7. Reduction in Inflammatory Adipose Tissue:
   • Reduces senescent cell accumulation in adipose tissue, which is linked to inflammation and impaired metabolic function. This may improve the health of fat stores and reduce inflammaging.

 

Longform Explanations of Benefits

AMPK/mTOR Pathways

Elevated mTORC1 signaling is a hallmark of accelerated aging and shortened lifespan, with several longevity interventions, such as Rapamycin and dietary restriction, demonstrating potent mTORC1 inhibition to restore cellular health and improve lifespan.

While SGLT-2 inhibitors like Canagliflozin and Bexagliflozin are not as potent as Rapamycin, they still exert robust effects on mTORC1 inhibition. A 2023 study by Professor Richard Miller's group at the University of Michigan demonstrated that lower doses of Canagliflozin (14.4 parts per million/day or ~2.4 mg/kg/day) resulted in significant mTORC1 inhibition in males but not females, potentially explaining the sex-specific effects on lifespan seen in some models.

Another critical pathway for longevity is AMPK activation, which serves as a key sensor of cellular energy status. AMPK is activated by several well-studied interventions, such as calorie restriction, Metformin, and exercise, and it regulates processes critical for cellular and metabolic health:

• Autophagy and Mitophagy: Supports cellular recycling and mitochondrial quality.
• Mitochondrial Function: Enhances energy production and reduces oxidative stress.
• Inflammation: Suppresses inflammatory pathways linked to aging.
• Epigenetic Modifications: Influences gene regulation associated with longevity.

A 2017 study led by Professor Graham Hardie at the University of Dundee found that Canagliflozin at a dose of 100 mg/kg robustly increased AMPK activation, with AMPK phosphorylation increasing by over 200%. The mechanism underlying this effect is similar to Metformin: Canagliflozin and Bexagliflozin inhibit Complex I of the mitochondrial respiratory chain, leading to an increase in cellular AMP levels and subsequent AMPK activation.

These effects have downstream benefits, including:

• Reduced Lipid Synthesis: Limits fat accumulation.
• Increased Fat Oxidation: Encourages the body to burn stored fat for energy, partially explaining the rapid fat loss associated with SGLT-2 inhibitors.

Overall, while SGLT-2 inhibitors may not match Rapamycin’s potency, they uniquely inhibit mTORC1 and activate AMPK—dual pathways critical for longevity and nutrient sensing. These combined effects, along with improved mitochondrial function, fat oxidation, and autophagy, position Canagliflozin and Bexagliflozin as promising candidates for healthspan-promoting therapies with sex-specific considerations for lifespan benefits.

Cellular Senescence

Most somatic cells have a finite lifespan and, after repeated rounds of replication, enter a state of irreversible growth arrest known as cellular senescence. This process is one of the "twelve hallmarks of aging", and the accumulation of senescent cells over time contributes to chronic inflammation, tissue dysfunction, and age-related diseases.

To date, efforts to reduce senescent cells have largely focused on senolytic compounds such as the nutritional supplements Quercetin and Fisetin, which have demonstrated potent senolytic effects both alone and in combination.

However, a recent 2024 publication in Nature Aging demonstrated that short-term treatment with SGLT-2 inhibitors like Canagliflozin for as little as 7–14 days resulted in significant reductions in senescent cell accumulation, albeit in models of high-fat diet and cardiovascular disease:

• In a model of a traditional high-fat "American-style" diet, senescent cell accumulation in adipose tissue increased by ~750% within 8 weeks. Remarkably, treatment with Canagliflozin for just 7 days at a dose of 10 mg/kg led to a 40% reduction in senescent cell accumulation.
• In a cardiovascular disease model, 14 days of treatment reduced senescence in the aorta by 40–50% and was accompanied by a ~37% reduction in atherosclerosis in the aorta wall.

The study further revealed that the senolytic effects of Canagliflozin are dependent on AMPK activation. Pharmacological inhibition of AMPK activity blunted these senolytic benefits, suggesting AMPK as a critical pathway for Canagliflozin’s anti-senescence effects.

While further research is needed, this data indicates that a relatively short duration of SGLT-2 inhibitor treatment (7–14 days) can lead to dramatic reductions in senescent cell accumulation. Prolonged use may offer even greater protection against the buildup of senescent cells in various tissues, potentially mitigating key contributors to the aging process.

Inflammation

Aging is associated with persistent, low-grade inflammation, a phenomenon often termed “inflammaging”. As one of the twelve hallmarks of aging, inflammaging is believed to result from disruptions in other biological processes of aging and may serve as a common final pathway contributing to tissue dysfunction and chronic disease.

One challenge in addressing inflammation is the lack of consensus on definitive biomarkers for inflammaging. Traditional markers include C-reactive protein (CRP) and pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). However, distinguishing age-specific inflammation from disease-specific inflammation remains difficult, as these markers can be influenced by comorbid conditions.

Nevertheless, reducing inflammatory cytokines and tissue inflammation is strongly associated with improvements in healthspan and longevity. For example, a landmark study in Nature demonstrated that inhibiting IL-11, a pro-inflammatory cytokine, extended lifespan by ~25% while improving metabolic and muscle function into later life.

In the context of SGLT-2 inhibitors such as Canagliflozin and Bexagliflozin, emerging human data suggest these medications can contribute to reversing inflammatory processes:

• Longitudinal studies in patients with diabetic kidney disease showed that two years of treatment with Canagliflozin (300 mg/day) reduced circulating levels of:
  • TNF receptor 1 (TNFR1)
  • IL-6 (a marker of systemic inflammation)
  • Matrix metalloproteinase 7 (MMP-7) and Fibronectin 1 (FN1) (markers of extracellular matrix turnover and fibrosis).

These findings suggest that SGLT-2 inhibitors not only reduce systemic inflammation but also influence processes related to tissue remodeling and fibrosis, which are key contributors to age-related decline.

Reducing circulating inflammatory markers likely supports broader health benefits, including improvements in brain function and cognitive health, as chronic inflammation is strongly linked to neurodegeneration and impaired cognitive aging.

Blood Glucose Control

As SGLT-2 inhibitors, Canagliflozin and Bexagliflozin effectively lower blood glucose concentrations and maintain healthy glucose levels throughout the day. Originally developed as anti-diabetic medications, these drugs have shown significant metabolic benefits even in non-diabetic individuals. In a standardized mixed meal tolerance test—a meal consisting of 55% carbohydrates, 30% fat, and 15% protein (including 75g of glucose)—treatment with Canagliflozin at 300 mg reduced glucose absorption into the bloodstream by 35% and lowered insulin levels by 43% compared to placebo.

This improvement in glucose handling was due to the medication’s primary mechanism of action: blocking the SGLT-2 protein in the kidneys, which prevents glucose reabsorption and results in glucose being excreted through the urine. In the same test, participants treated with Canagliflozin excreted approximately 24% of the glucose consumed, reflecting a significant increase in glucose clearance. These findings highlight the ability of SGLT-2 inhibitors to reduce the body’s reliance on insulin while improving glucose regulation.

Compared to traditional glucose-lowering therapies such as Metformin or Acarbose, SGLT-2 inhibitors like Canagliflozin and Bexagliflozin offer a unique advantage by enhancing urinary glucose excretion, which contributes to improved metabolic flexibility. By maintaining stable blood glucose levels and reducing excessive insulin signaling, these medications help alleviate the metabolic burden associated with hyperglycemia—a key driver of aging and metabolic dysfunction.

Body Composition Benefits of Canagliflozin

Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has demonstrated notable benefits in body composition, particularly in reducing fat mass and improving the lean-to-fat ratio. Clinical studies have shown that approximately two-thirds of the weight loss observed with canagliflozin is due to a reduction in fat mass rather than lean mass, indicating a favorable impact on body composition.

Diabetes Journals

In a 52-week study comparing canagliflozin to glimepiride, canagliflozin treatment resulted in significant reductions in body weight, with a substantial portion attributed to fat mass loss. This suggests that canagliflozin promotes fat oxidation and shifts the body's energy balance towards utilizing fat as an energy source.

Diabetes Journals

Additionally, canagliflozin has been associated with reductions in visceral fat mass, which is closely linked to metabolic health and the risk of age-related diseases. By targeting visceral fat, canagliflozin may contribute to improved metabolic profiles and reduced cardiovascular risk.

SpringerLink

These findings highlight canagliflozin's potential as a therapeutic agent for improving body composition and metabolic health, which are critical factors in promoting healthspan and longevity.

Cardioprotective Benefits of SGLT-2 Inhibitors

SGLT-2 inhibitors, including Canagliflozin, Bexagliflozin, and others in this drug class, offer notable cardioprotective effects that extend beyond their glucose-lowering mechanisms. Recent studies have demonstrated significant improvements in heart failure outcomes and overall cardiovascular health, making SGLT-2 inhibitors a promising intervention for cardiometabolic aging and heart disease prevention [32,33].

The cardioprotective effects of SGLT-2 inhibitors are linked to multiple mechanisms:

1. Reduction in Sympathetic Nervous System Activity:

   SGLT-2 inhibitors suppress sympathetic nervous system (SNS) activity, which is a major contributor to heart failure progression. Normally, activation of free fatty acid receptor 3 (FFAR3) on sympathetic neurons triggers norepinephrine release, leading to myocardial stimulation and increased cardiac workload [34,35]. By increasing circulating levels of β-hydroxybutyrate (a ketone body), SGLT-2 inhibitors block FFAR3 activation, reducing sympathetic tone and alleviating myocardial stress [34,35].

2. Ketone Body Utilization and Metabolic Efficiency:

   SGLT-2 inhibitors, such as Canagliflozin and Bexagliflozin, increase β-hydroxybutyrate levels, a metabolic substrate produced during fasting or energy deprivation [34,35,36]. This ketone body serves as a more efficient energy source for the heart, particularly in individuals with heart failure, where glucose and fatty acid metabolism are less effective. By shifting the heart’s energy preference toward ketone bodies, SGLT-2 inhibitors improve cardiac energy production and overall myocardial efficiency [35].

3. Hemodynamic Benefits:

   SGLT-2 inhibitors lower both preload and afterload, two key determinants of cardiac workload:

   • Preload is reduced via osmotic diuresis, which occurs as glucose is excreted in the urine, leading to a decrease in blood volume and cardiac filling pressure [32,33].
   • Afterload decreases as a result of improved arterial stiffness and lowered blood pressure, which reduces vascular resistance and cardiac strain [32,33,34].

4. Class-Wide Cardioprotection:

   While early studies focused on Dapagliflozin, growing evidence indicates that the cardioprotective benefits of SGLT-2 inhibitors are a class-wide phenomenon. Both Canagliflozin and Bexagliflozin have shown similar effects in suppressing sympathetic activity, increasing ketone body levels, and reducing cardiac strain [32,34,35].

5. Basak D, Gamez D, Deb S. SGLT2 Inhibitors as Potential Anticancer Agents. Biomedicines. 2023;11:1867 https://doi.org/10.3390/biomedicines11071867. Article PubMed PubMed Central CAS Google Scholar

6. Saisho Y. SGLT2 Inhibitors: the Star in the Treatment of Type 2 Diabetes? Diseases. 2020;8 https://doi.org/10.3390/diseases8020014. Lymperopoulos A, Borges JI, Cora N, Sizova A. Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland. Int J Mol Sci. 2021;22:7684 https://doi.org/10.3390/ijms22147684. Article PubMed PubMed Central CAS Google Scholar

7. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA. 2011;108:8030–5. https://doi.org/10.1073/pnas.1016088108.Return to ref 35 in article Article PubMed PubMed Central Google Scholar

8. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial Substrate Metabolism in the Normal and Failing Heart. Physiological Rev. 2005;85:1093–129. https://doi.org/10.1152/physrev.00006.2004. Article CAS Google Scholar

9. Halvorsen Y-DC, Lock JP, Freeman MW. 1117-P: Cardiovascular and Glycemic Benefits of Bexagliflozin as an Adjunct to Metformin for the Treatment of Type 2 Diabetes in Adults: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Diabetes. 2020;69:1117-P https://doi.org/10.2337/db20-1117-P.