SGLT2 Inhibitors: The Unexpected Longevity Molecules and Their Mechanistic Impact on Aging Science

Background

SGLT2 inhibitors were originally approved by the FDA in 2013 for the pharmaceutical company Janssen Pharmaceuticals under the brand name "Invokana" for the treatment of Type II Diabetes. SGLT2 inhibitors work via a completely different mechanism to other Diabetes drugs such as Metformin and Acarbose, which are biguanides and Alpha-glucosidase inhibitors, respectively. In short, these traditional drugs either (1) inhibit liver glucose production, (2) increase insulin sensitivity, or (3) slow down the digestion of carbohydrates, which all result in drastically improved blood sugar regulation. However, SGLT2 inhibitors are sodium-glucose cotransporter-2 inhibitors, which work by blocking the SGLT2 protein in the kidneys responsible for reabsorbing glucose from the urine back into the bloodstream [1]. By inhibiting SGLT2, these medications increase the excretion of glucose through the urine, effectively lowering blood glucose levels – Notably, it has been estimated that SGLT2 inhibitors can result in up to 70-90 grams of glucose being excreted in your urine per day [2], which is equivalent to the sugar content of 24 oz of Coca Cola.

The National Institute on Aging (NIA) Interventions Testing Program (ITP) has tested >50 molecules over the last 20 years, with only 12 showing a significant increase in lifespan: Acarbose, Aspirin, Astaxanthin, Captopril, Glycine, Meclizine, Nordihydroguaiaretic acid, Protandim, Rapamycin, 16-Hydroxyestriol, 17α-Estradiol, and SGLT2 inhibitors [3]. The first study on SGLT2 inhibitors showed that placing 6-month-old mice (equivalent to a 30-year-old human) on the drug Canagliflozin at a dose of 180 parts per million/day, which equates to ~30mg/kg/day [4]. This dose resulted in a 14% increase in lifespan in male mice but no effect in female mice, which was quite surprising as females had distinctly higher levels of the medication in plasma, brain, and kidney, which likely suggests sex-specific pharmacokinetic differences in drug metabolism. On the contrary, female mice on SGLT2 inhibitors display significantly more weight loss than male mice (19% vs. 8%), which is largely driven by a greater reduction in fat mass, resulting in a much leaner, healthier body composition compared to the control group [4]. As this study was done in "young" mice, it's often tested as to whether these molecules can have an effect when started late in life, as a potential tool for older adults to still gain improvements in metabolic health and lifespan extension.

A new 2024 publication just landed testing this exact hypothesis [5]. Using the same dose but in 16-month-old mice (equivalent to late 50s in humans), SGLT2 inhibitors still extended lifespan by 14% in males but an unusual decline of 6% in females [5]. Similar to the younger cohort, the blood levels of SGLT2 inhibitor, Canagliflozin, were 20-fold higher, suggesting a potential toxic accumulation in females, and a much lower dose (~50% lower) is likely needed compared to males.

Since there are such robust increases in lifespan with SGLT2 inhibitors, there has been a large interest in deciphering the mechanism by which they alter any of the Hallmarks of Aging.

Due to the ability of SGLT2 inhibitors to activate several key longevity metabolic pathways, they have recently been described as calorie restriction mimetics, as they, to a certain degree, mimic many of the benefits of calorie restriction without having to restrict your caloric intake by 20-30%. Several recent advances have begun to shed light on these molecular mechanisms, and we'll provide an overview of how SGLT2 inhibitors slow your rate of aging at a molecular level.

Nutrient Sensing

Elevated mTORC1 signaling is a key regulatory hallmark of accelerated aging and shortened lifespan [6], with several longevity interventions, such as Rapamycin or dietary restriction, having a direct effect in inhibiting mTORC1 and restoring cellular health [7, 8].

Although SGLT2 inhibitors are not as potent as Rapamycin, they do have robust effects on mTORC1 inhibition. In a recent 2023 study, Professor Richard Miller's group at the University of Michigan found that a lower dose of the SGLT2 inhibitor Canagliflozin (14.4 parts per million/day or 2.4mg/kg/day) showed large inhibition of mTORC1 in males but not females, which may explain why females do not experience the lifespan benefits seen with SGLT2 inhibitors [9].

Another aspect of nutrient sensing and longevity signaling is the role of AMPK. Many longevity-promoting interventions increase AMPK activity (i.e., calorie restriction [10], metformin [11], and exercise [12]), and this pathway is critical in the regulation of autophagy/mitophagy [13], mitochondrial function [14], inflammation [15], and epigenetic modifications [16].

Notably, a 2017 study by Professor Graham Hardie and his team at the University of Dundee in the UK showed that a 100mg/kg dose of Canagliflozin (~2.5mg per mouse) robustly increased the phosphorylation of AMPK by over 200% [17].

The mechanism of action is similar to Metformin in that SGLT2 inhibitors inhibit complex I of the mitochondrial respiratory chain, resulting in increases in cellular AMP and activation of AMPK [17].

SGLT2 inhibitors also result in lowered levels of lipid synthesis and higher fat oxidation, partially explaining the rapid fat loss associated with these drugs [17].

Overall, while SGLT2 inhibitors are less potent than Rapamycin, they still inhibit mTORC1 and activate AMPK, pathways linked to longevity and nutrient sensing, with sex-specific effects on lifespan, potentially due to their impact on mitochondrial function, fat oxidation, and autophagy-related processes. Overall, SGLT2 inhibitors show promise in their ability to promote dual longevity pathways simultaneously.

Cellular Senescence

Most somatic cells have a finite lifespan and, following exhaustive rounds of replication, undergo a state of essentially irreversible growth arrest, termed cellular senescence [18]. This pathophysiological state is one of the "twelve hallmarks of aging," and there has been a strong drive to develop senolytic compounds to reduce the accumulation of senescent cells over the last several years [18].

To date, these efforts have largely focused on the nutritional supplements Quercetin [19] and Fisetin [20], which, both alone and in combination, have potent senolytic properties.

However, a recent 2024 publication in Nature Aging showed that short-term treatment with SGLT2 inhibitors for as little as 7-14 days reduced senescence by as much as ~50%, albeit in a model of either high-fat diet or cardiovascular disease (i.e., ApoE-KO mice), so not a model of "healthy aging" per se [21].

In particular, they showed a traditional high-fat "American style" diet induced a rapid ~750% increase in the accumulation of senescent cells in adipose tissue in as little as 8 weeks - So imagine how many senescent cells we have in our body after years of poor diets. However, adding Canagliflozin to the diet for as little as 7 days at a dose of 10mg/kg resulted in an impressive 40% reduction in senescent cell accumulation.

In a model of heart disease, the authors showed a 40-50% reduction in senescence in the aorta following 14 days of SGLT2 inhibitor treatment, which was concurrent with a ~37% reduction in atherosclerosis in the aorta wall. Interestingly, they found that the senolytic properties of SGLT2 inhibitors were dependent on AMPK, and the pharmacological inhibition of AMPK activity blunts the senolytic benefits of these drugs.

Overall, a relatively short period of SGLT2 inhibitor treatment of 7-14 days results in dramatic reductions in senescence. Therefore, prolonged dosing may result in total amelioration of and/or protection against the accumulation of senescent cells in every tissue.

Inflammation

Aging is associated with chronic low-grade inflammation, often termed "inflammaging" [22]. As one of the twelve hallmarks of aging, inflammaging is likely triggered by derangements stemming from other aging hallmarks and may be a common final pathway of biological aging for many individuals.

An issue with inflammation is the acceptability of criteria to define inflammaging, as there is no current consensus as to what constitutes this process. Traditional biomarkers for inflammaging include acute phase reactants such as C-reactive protein (CRP) and plasma concentrations of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF). However, these are likely influenced by disease-specific inflammation, and separating them from age-specific inflammation is likely impossible.

Nevertheless, a reduction in inflammatory cytokines and tissue inflammation is highly beneficial to human health and longevity. This has recently been shown in a landmark study in Nature, which demonstrated that the inhibition of IL-11, a pro-inflammatory cytokine, increased lifespan by ~25% while simultaneously improving metabolic and muscle function into later life [23].

In the context of SGLT2 inhibitors, longitudinal data in humans with diabetic kidney disease suggests that two years of treatment of Canagliflozin at 300mg/day reduced plasma levels of TNF receptor 1 (TNFR1), IL-6, matrix metalloproteinase 7, and fibronectin 1 (FN1), suggesting that SGLT2 inhibitors contribute to reversing the molecular processes related to inflammation, extracellular matrix turnover, and fibrosis [24, 25].

Reducing circulating markers of inflammation likely contributes to the reduction in other age-related comorbidities, in particular brain and cognitive function.

Neuroprotection

The aging brain is characterized by a slow but progressive increase in neuroinflammation and cerebral insulin resistance, which contribute to the development of cognitive impairment and increased risk of neurodegenerative diseases (i.e., Alzheimer's disease and Parkinson's disease) [26].

One of the novel properties of SGLT2 inhibitors is their ability to cross the blood-brain barrier and have a direct effect on brain function [27]. Notably, two recent publications from 2022 and 2024 have shown the neuroprotective effects of SGLT2 inhibitors and how they may be used as potential therapeutics to offset brain aging and maintain youthful cognitive function into later life [27, 28].

The first study showed that SGLT2 inhibitors can reduce microgliosis and astrogliosis in the hippocampus, the part of the brain that is important for memory, learning, and emotion [27]. This is significant because increased and excessive activation of microglia and astrocytes results in neuroinflammation and neuronal damage, leading to the accelerated development of Alzheimer's disease or Parkinson's disease [27].

The second study focused on a different brain region, the hypothalamus, a critical brain region that regulates body temperature, appetite, and hormone production, among other functions [28]. Interestingly, the authors found long-term SGLT2 inhibitor treatment increased metabolic rates in both males and females and markedly increased the formation of both orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) neural projections to the hypothalamus, mostly in females [28].

From a molecular perspective, they undertook comprehensive RNA sequencing analysis, which allows scientists to unbiasedly examine tens of thousands of genes in biological samples.

From this analysis, they discovered a significant increase in a cluster of genes related to "neuropeptide signaling," overall showing SGLT2 inhibitors to have strong neuroprotective properties on the aging brain. SGLT2 inhibitors may, therefore, have the potential to prevent age-related decline in brain function and maintain cognitive health in later life.

What Does the Human Data Say?

SGLT2 inhibitors are clearly multi-talented players in longevity science. Since their FDA approval, they have gained significant attention due to the drastic metabolic and health improvements observed in patients with diabetes, heart failure, and kidney disease. Here, we will examine the human clinical data demonstrating how SGLT2 inhibitors improve blood glucose control, enhance cardiovascular and kidney function, and reduce all-cause mortality—key markers of an extended healthspan.

Blood Glucose Control

As an anti-diabetic medication, SGLT2 inhibitors' primary mechanism is to reduce blood glucose concentrations and maintain healthy levels throughout the day, and they are incredibly effective at this. In healthy non-diabetic individuals, SGLT2 inhibitors have been shown to reduce the blood glucose response to a mixed meal tolerance test [29] – This is a standardized meal consisting of 55% carbohydrate, 30% fat, and 15% protein, of which 75g is glucose.

This sort of test allows researchers to measure the ability of the body to regulate the amount of glucose that appears in the blood after the meal and how effectively the body clears this glucose.

In healthy people who took 300mg of the SGLT2 inhibitor Canagliflozin, 35% less glucose was absorbed into the blood, which was concurrent with a 43% reduction in insulin compared to those who were given the placebo [29].

As previously mentioned, SGLT2 inhibitors result in glucose excretion in the urine; the treatment group urinated ~24% of the 75g glucose they consumed in the mixed meal test, showing drastic improvements in glucose handling [29]. SGLT2 inhibitors may, therefore, offer a new therapeutic option for maintaining stable blood glucose levels compared to traditionally prescribed Metformin or Acarbose-based therapies.

Cardiovascular and Kidney Function

Prior to its FDA approval, there was a clinical trial called "The Canagliflozin Cardiovascular Assessment Study (CANVAS)," whose sole purpose was to determine the cardiovascular safety of the SGLT2 inhibitor Canagliflozin. In 2017, data from over 10,000 participants was published in the New England Journal of Medicine [30]. 

These data showed a ~14% reduced risk of a cardiovascular event, ~27% reduction in albuminuria risk, and a ~40% reduction in estimated glomerular filtration rate, overall showing marked improvements in cardiovascular and kidney health with Canagliflozin [30]. 

A more recent meta-analysis combining data from six studies totaling nearly 47,000 patients showed similar data, overall suggesting a robust effect of Canagliflozin on reducing cardiac mortality rate and improving kidney health [31]. 

Similarly, the impact of empagliflozin, an SGLT2 inhibitor, on cardiovascular outcomes and overall mortality in patients with type 2 diabetes at high cardiovascular risk was assessed in the EMPA-REG OUTCOME trial. This study aimed to determine whether empagliflozin, when added to standard care, could reduce cardiovascular morbidity and mortality in this vulnerable population.

A total of 7020 patients were randomly assigned to receive empagliflozin (10 mg or 25 mg) or placebo, administered once daily. The primary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, evaluated for the pooled empagliflozin groups versus the placebo group. The key secondary composite outcome incorporated the primary outcomes plus hospitalization for unstable angina [37].

After a median follow-up of 3.1 years, the primary composite outcome occurred in 10.5% of patients in the pooled empagliflozin group, compared to 12.1% in the placebo group. Empagliflozin was associated with:

• A 38% reduction in cardiovascular mortality (3.7% vs. 5.9%; HR, 0.62).

• A 35% reduction in hospitalization for heart failure (2.7% vs. 4.1%; HR, 0.65).

• A 32% reduction in all-cause mortality (5.7% vs. 8.3%; HR, 0.68).

One of the primary mechanisms by which SGLT2 inhibitors improve cardiac health is their ability to minimize hypertrophy, decrease cardiovascular inflammation, and prevent the accumulation of fibrosis, thereby leading to improved cardiac structure [32].

It must be noted that all of the benefits of SGLT2 inhibitors on heart health are observed in patients with diabetes or heart failure. Therefore, how these benefits translate to healthy, non-diseased humans remains to be established. However, in a world where we're often exposed to a Western "American-style diet," the risk of developing cardiovascular disease is on the rise [33]. SGLT2 inhibitors could one day be utilized as a preventative therapeutic to maintain healthy heart function across the lifespan.

All-Cause Mortality

Unlike mouse-based research, where we can directly measure improvements in longevity due to their relatively short lifespans (~3 years), this is not possible in humans. Therefore, an indirect measure is to determine a population's "all-cause mortality" risk. 

All-cause mortality refers to the total number of deaths from any cause within a specified population, time period, or study group [34]. In medical research, all-cause mortality is often used as an endpoint in clinical trials and epidemiological studies to assess the overall impact of an intervention or treatment (such as a drug, diet, or exercise) on survival. This measure helps us, as scientists, to capture the broad, net effects of an intervention, as it accounts for both direct and indirect impacts on health, providing a more holistic perspective on mortality risk. 

In the context of SGLT2 inhibitors, an analysis of over 25,000 patients data from the EASEL study for cardiovascular outcomes with Sodium-Glucose Cotransporter 2 Inhibitors in the real world shows an impressive 43% reduction in all-cause mortality compared to non-SGLT2 inhibitor users [35]. 

A more recent 2023 publication in the British Journal of Cancer showed that the use of an SGLT2 inhibitor can dramatically improve survival in patients undergoing treatment for non-small cell lung cancer and reduce their mortality risk by 32%, suggesting SGLT2 inhibitors can have direct or indirect effects on slowing cancer progression [36]. 

This makes sense, as SGLT2 inhibitors have been shown in mice to suppress cancer growth and improve the response to radiotherapy in a model of prostate cancer. They show that SGLT2 inhibitors have a direct effect on slowing and inhibiting cancer growth via two distinct mechanisms:

• mTOR inhibition and blunts cellular proliferation of often overactive cancer cells. By inhibiting mTOR, SGLT2 inhibition reduces the unchecked growth that characterizes many tumors.

• HIF-1α Modulation: Hypoxia-inducible factor-1 alpha (HIF-1α) is another target of SGLT2 inhibitors. This molecule promotes cancer cell survival in low-oxygen environments, a hallmark of aggressive tumors. By blunting HIF-1α activity, SGLT2 inhibition further slows tumor growth and enhances the efficacy of conventional treatments.

Take home points

SGLT2 inhibition has a potent effect on cellular, molecular, and whole-body physiology in rodents. In humans, it displays positive effects on improving several health parameters, making it a potential candidate for longevity interventions in healthy, non-diseased individuals. In an era of repurposing drugs for anti-aging and longevity, SGLT2 inhibitors certainly tick the boxes on many of the requirements. 

Notably, certain individuals such as Dr. Peter Attia has already discussed on the Huberman Lab Podcast in 2023 that they take an SGLT-2 inhibitor due to the profound positive evidence already published on them. 

However, as we've mentioned, SGLT2 inhibitors do seem to have some gender-specificity in lifespan extension, with no effect in females. This is likely due to the sex-specific metabolism of the drug, as females displayed significantly elevated concentrations of the SGLT2 inhibitor in the blood following the same dose, so there may be a slight risk in females where optimized dosing of the drug is required. 

SGLT2 inhibitors, similar to Metformin and Acarbose, likely requires the ability to check your blood glucose throughout the day to ensure, due to the drug, that hypoglycaemic events are not repeatedly happening, as these can lead to adverse cognitive impairments. 

Overall, due to the safety profile of SGLT2 inhibitors, we can likely see this class of drugs being tested in Geroscience clinical trials, such as recent and currently ongoing Rapamycin trials, to determine the efficacy of these therapeutics to improve metabolic health and healthspan in healthy individuals.