Scientists have found that canagliflozin, an anti-diabetic drug known to extend the life of mice, Relieves a host of age-related diseasesEven if it is in males only .
Anti-diabetic and anti-aging
Canagliflozin, a widely used diabetes drug, belongs to the class of sodium glucose transporter 2 (SGLT2) inhibitors, which regulate glucose reabsorption by the kidneys. Recently, it joined two other anti-diabetic drugs, metformin and acarbose, in the list of anti-aging agents. While metformin unexpectedly failed to increase the lifespan of mice in ITP (Intervention Test Program)et al., both acarbose and canagliflozin showed a marked, albeit sex-specific, effect, extending life only in male rats. Specifically, canagliflozin extended the average lifespan of animals by 14% and maximum lifespan by 9%. .
Is it just cancer reduction?
While ITP is very powerful and is considered the current gold standard in anti-aging drug testing, it also has limitations. About 80% of genetically heterozygous mice used by ITP die from tumors – abnormal tissue growth, which usually means cancer. Thus, in order to significantly extend the life of these mice, it would be enough for any drug to reduce the risk of cancer.
On the other hand, human lifespan is limited by many other diseases, such as cardiovascular problems. Any “real” anti-aging drug for humans must mitigate many risks at once by affecting some of the fundamental pathways of aging. This, for example, is the case for rapamycin, which has been found to alleviate many age-related diseases. .
In this new study, researchers investigated whether canagliflozin had health benefits in mice beyond reducing cancer risks. 228 male mice were treated with canagliflozin from 7 to 22 months of age, which corresponds to approximately 20 to 70 human years. The tissues of the mice were then examined for a wide range of age-related lesions. The mice were of the same type as ITP (UM-HET3) and were treated at the three ITP centers according to the program’s strict criteria, while tissues were examined by researchers at the University of Washington.
Wide range of effects, but mostly in males
The scientists found that in male mice, the prevalence and/or severity of six types of lesions were significantly reduced by the treatment. This includes tumors localized to the adrenal glands (adrenal cortical adenomas). Atherosclerosis (hardening of the arteries). Heart weakness known as cardiomyopathy. Glomerulonephropathy, kidney disease. Hepatic steatosis, a fatty liver disease. and pancreatic atrophy. It should be noted that adrenal adenomas are not among the cancers with a significant contribution to mortality in mice – which would be blood, liver and lung cancers.
The only statistically significant effect of canagliflozin in female rats was a reduction in pancreatic atrophy. However, this effect was even stronger in males, which is in line with the sex-specific effect that canagliflozin has on life span. Also, female UM-HET3 mice generally live longer than males .
The reasons for the prolongation of life by most sex-based anti-aging drugs remain a mystery, although you can find some evidence In our interview with Richard MillerCo-founder of ITP and co-author of this new study.
The link between glucose spikes and aging
Canagliflozin and acarbose mostly work by moderating post-meal glucose spikes, though via entirely different pathways. Canagliflozin’s mode of action may explain its strong effect on kidney function. Pancreatic atrophy and cardiovascular dysfunction are often seen in diabetic patients as well. This highlights the importance of keeping glucose levels under control for healthy longevity and necessitates further research on the relationship between glucose spikes and age-related diseases.
Interestingly, although its mode of action differs, rapamycin has been shown to alleviate the same diseases in mice, including hepatic lipidosis and adrenal adenomas. However, rapamycin extends lifespan in both males and females.
This histopathological analysis was performed to test the idea that Qana-treated mice may have age-related pathology delays in multiple lesions, including those that are rarely fatal, and to see to what extent these effects may be sex-specific. The results are clear: Cana actually delays age-related changes in the heart, kidneys, liver, external pancreas, and adrenal glands, and this protective effect is seen only in males, except that protection against pancreatic atrophy is seen in both sexes. Since most UM-HET3 mice die from some form of oncological disease, the extended lifespan produced by Cana likely reflects the postponement of multiple types of cancer, whether by altering host defenses, neoplastic processes, or both. But current data demonstrate that Cana, such as rapamycin, calorie-restricted diets, and pituitary mutagenesis, can be considered an anti-aging intervention, as it delays many forms of fatal and non-fatal age-dependent decline.
Using histopathological analysis of tissues, this robust study provides a strong indication that canagliflozin, an antidiabetic drug already in clinical use, extends the life of male mice by relieving a wide range of age-related diseases rather than simply reducing the risk of cancer. This is likely to enhance the already strong interest of the longevity community in SGLT2 inhibitors. The study also confirms the gender-specific nature of canagliflozin’s effects, unfortunately without providing new insights into why this is so.
 Snyder, J. M., Casey, K. M., Galecki, A., Harrison, D. E., Jayarathne, H., Kumar, N., … & Ladiges, W. (2022). Canagliflozin delays age-related lesions of the heart, kidneys, liver, and adrenal glands in genetically heterozygous male mice. GeroScience, 1-13.
 Miller, R. A., Harrison, D. E., Allison, D. B., Bogue, M., Debarba, L., Diaz, V.,… & Strong, R. (2020). Canagliflozin extends life span in genetically heterozygous male but not female mice. JCI Vision, 5 (21).
 Wilkinson, J. E., Burmester, L, Brooks, SV, Chan, C. C., Friedlin, S, Harrison, D, … & Miller, R. A. (2012). Rapamycin slows aging in mice. Aging Cell, 11(4), 675-682.
 Ostad, S.N., & Fisher, K.E. (2016). Gender differences in age. Cellular Metabolism, 23(6), 1022-1033.