If there were an "anti-aging superdrug family," the group of anti-glycemic drugs including metformin, canagliflozin, and acarbose would undoubtedly be one of the most prominent. In recent years, they have been successively found to have anti-aging and lifespan-extending effects[1-3]—a "family of three superdrugs" that once dominated the field.
Recently, a discovery by the research team led by Professor Liu Dongfang from the Second Affiliated Hospital of Chongqing Medical University[4] has welcomed a fourth member to this distinguished family: empagliflozin, a common anti-glycemic drug, which has also been proven to effectively extend lifespan!
1. A New Member of the "Lifespan-Extending Family"
Nir Barzilai, a leading advocate of metformin and initiator of the renowned anti-aging clinical trial TAME project, once conducted a comprehensive evaluation of several anti-aging drugs. He found that one class of drugs showed higher anti-aging success rates in large-scale clinical trials than others[5]—sodium-glucose cotransporter 2 (SGLT2) inhibitors, which include empagliflozin (the focus of this study) and its predecessor canagliflozin.
SGLT2 inhibitors are a new class of oral anti-diabetic drugs. They mainly reduce glucose reabsorption by inhibiting the SGLT2 receptor in the proximal renal tubule, thereby promoting glucose excretion from the body.
Figure Note: Without inhibition, the sodium-glucose complex dissociates into sodium ions and glucose when passing through the SGLT2 channel. Glucose then returns to the bloodstream with the help of GLUT2 transporters, leading to increased blood glucose levels (Source: Public online resources).Studies have also shown that SGLT2 inhibitors can activate the AMPK pathway and inhibit the mTOR pathway—effects even similar to calorie restriction[6]. This led scientists to hypothesize: as a member of the SGLT2 inhibitor family, could empagliflozin also have the same anti-aging and lifespan-extending effects? Driven by this expectation, Professor Liu Dongfang’s team launched their experiment.
2. 5.9% Lifespan Extension! Plus Anti-Inflammation, Improved Motor/Cognitive Function, and Gut Microbiota
The experiment divided 100 naturally aged 13-month-old mice into two groups: one fed empagliflozin, and the other as a control group.
Results showed that in addition to a significant reduction in body weight, the empagliflozin-fed group also had a marked lifespan extension. Mice in the control group began to die as early as week 53.9, while the first death in the empagliflozin group occurred four weeks later.
In terms of median lifespan:
- Control group: 98.57 weeks
- Empagliflozin group: 104.4 weeks
Empagliflozin increased their median lifespan by 5.9%—a less dramatic effect than canagliflozin’s 14%, but still a promising result.
Figure Note: The survival rate of the empagliflozin group (purple line) was significantly higher than that of the control group (green line).
Interestingly, the research team also found that mice taking empagliflozin had fewer white hairs and significantly reduced hair loss—a welcome finding for those facing hair loss concerns.
Figure Note: Mice in the empagliflozin group (right) had darker, shinier fur compared to the control group (left).
Beyond lifespan and appearance, empagliflozin exerted comprehensive benefits on the mice:
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Motor and cognitive function: The "elderly" mice showed significant improvements in balance, motor ability, and learning/memory. While control mice wandered aimlessly in the water maze, empagliflozin-treated mice quickly found the safety platform.
Figure Note: Control mice (left) wandered randomly in the water, while empagliflozin-treated mice (right) had clearer, more goal-directed movement trajectories, reaching the target quickly.
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Gut microbiota: Empagliflozin significantly increased the richness and diversity of the mice’s gut microbiota. Further analysis revealed an increase in the number of beneficial bacteria that improve the intestinal environment—another boon for gut health and overall metabolic health.
Figure Note: The gut microbiota richness of mice in the empagliflozin group was significantly higher than that in the control group (left).
Concerns like "What if it harms the liver like other anti-aging drugs?" were addressed by the data: multiple indicators showed that after taking empagliflozin, the elderly mice’s livers not only had no damage but also showed significant improvements in inflammation and fibrosis—proving empagliflozin has strong liver anti-aging effects.
Figure Note: Levels of various pro-inflammatory factors in the control group (green) were significantly higher than those in the empagliflozin group (purple).
3. Activating Three Key Anti-Aging Pathways
How does empagliflozin exert its powerful anti-aging and lifespan-extending effects? Does it follow the same mechanism as its predecessor canagliflozin? The team continued their experiments to find out.
Since empagliflozin’s anti-aging effects were most evident in the liver, subsequent experiments focused on this organ.
1. Inhibiting Inflammatory Pathways
Data showed that levels of classic pro-inflammatory factors (e.g., TNF-α, IL-6) in the livers of empagliflozin-treated mice were significantly reduced—confirming effective inflammation suppression. The expression of key proteins in multiple inflammation-related signaling pathways (including NF-κB, HIF1α, AP-1, and P38MAPK) was also significantly inhibited.
2. Activating the PI3K-AKT Pathway
The PI3K-AKT pathway is a classic intracellular signaling pathway primarily involved in cell proliferation, survival, metabolism, and growth. Analysis revealed that empagliflozin significantly upregulated the expression of proteins related to this pathway in the liver, activating the pathway and giving cells a "rejuvenated" state.
Figure Note: The expression of PI3K-AKT pathway-related proteins (e.g., p-PI3K) was significantly higher in the empagliflozin group (purple) than in the control group.
3. Activating "Longevity Pathways" (AMPK and SIRT1)
Empagliflozin also significantly activated two well-known "longevity pathways": AMPK and SIRT1. Data showed that the expression of related proteins in the empagliflozin group was significantly upregulated.
Figure Note: Schematic of the study’s mechanism—empagliflozin improves inflammation, activates longevity pathways (AMPK, SIRT1), and regulates gut microbiota to promote anti-aging and lifespan extension.
Key Considerations
While empagliflozin’s 5.9% lifespan extension may seem modest compared to canagliflozin’s 14%, its discovery carries greater revelatory significance than practical impact: as the second SGLT2 inhibitor found to have anti-aging effects, does this mean the SGLT2 family is a "chosen group"? Could other members also have similar effects, and if so, what "genetic advantages" do they possess? These questions warrant further exploration.
A limitation of the study is that only male elderly mice were used. Whether empagliflozin, like metformin and canagliflozin, exhibits significant gender differences remains unknown. Additionally, like canagliflozin, empagliflozin carries a risk of amputation—an important safety consideration.
Further research is needed to address these uncertainties.
References
[1] Luo, S., et al., Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank. The Lancet Healthy Longevity, 2023. 4(7): p. e337-e344.[2] Bitto, A., et al., Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome. Nature Metabolism, 2023. 5(6): p. 955-967.[3] Katsuumi, G., et al., SGLT2 inhibition eliminates senescent cells and alleviates pathological aging. Nature Aging, 2024: p. 1-13.[4] Long, J., et al., Empagliflozin rescues lifespan and liver senescence in naturally aged mice. GeroScience, 2024: p. 1-18.[5] Kulkarni, A.S., et al., Geroscience‐guided repurposing of FDA‐approved drugs to target aging: A proposed process and prioritization. Aging Cell, 2022. 21(4): p. e13596.[6] La Grotta, R., et al., Repurposing SGLT-2 inhibitors to target aging: available evidence and molecular mechanisms. International Journal of Molecular Sciences, 2022. 23(20): p. 12325.[7] Claggett, B., et al., Long-Term Benefit of Empagliflozin on Life Expectancy in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease: Survival Estimates From the EMPA-REG OUTCOME Trial. Circulation, 2018. 138(15): p. 1599-1601.[8] Zinman, B., et al., Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine, 2015. 373(22): p. 2117-2128.[9] Giugliano, D., et al., SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs. Cardiovascular Diabetology, 2021. 20: p. 1-11.