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Estrogen Metabolite Robustly Increases Lifespan in Male Mice

Some compounds only benefit one sex.

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In the newest study by the Interventions Testing Program, 16α-hydroxyestriol and canagliflozin significantly increased lifespan in male mice but were deleterious for females [1].

The golden standard

The Interventions Testing Program, now entering its 20th year, is a monumental undertaking by the National Institute on Aging aimed at rigorously testing compounds for their possible effects on lifespan in mice. The ITP is considered the golden standard of mouse longevity studies for a reason. It is run in three academic facilities simultaneously, on large cohorts of genetically heterogeneous, naturally aging mice that are kept in identical conditions.

ITP’s stamp of approval on a molecule is a big deal. Currently, the absolute champion is a combination of rapamycin and the anti-diabetes drug acarbose, which produced a 28% increase in median lifespan in females and a 34% increase in males [2].

From 2004 to 2023, the ITP tested dozens of compounds and published 77 research papers. The previous one highlighted the first supplement in the program’s history to produce significant life extension: astaxanthin.

Good for males, bad for females

Now, the newest ITP paper is out, so brace yourself for the results. In this latest cohort, the researchers tested several molecules: alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine, nebivolol, 16α-hydroxyestriol, and sodium thiosulfate. Additionally, it evaluated the effects of canagliflozin, which already produced significant life extension in one of the previous cohorts when administered late in life.

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16α-hydroxyestriol was the star of this study, producing a 15% increase in median lifespan in male mice. However, it lowered median lifespan in females by 7%. While many drugs affect lifespan sex-specifically, opposing effects are rare; in fact, this is the first case in ITP’s history. Interestingly, we have another example from the same study: canagliflozin, when started at 16 months of age, led to a 14% increase in median lifespan in males and a 6% decline in females. In a previous ITP study, when started at 6 months, canagliflozin increased male lifespan without affecting female lifespan. All other tested drugs did not have a statistically significant effect on lifespan in either sex.

ITP Interventions

The winners…

16α-hydroxyestriol is a metabolite of estrogen. Its inclusion in the study was due to the previous success of 17-α-estradiol, also called “the non-feminizing estrogen”, which increased median survival by 20% in males only [3]. The researchers hypothesized that 16α-hydroxyestriol might produce a similar lifespan extension in both sexes, but they were harshly proved wrong. The authors do not know what caused the significant reduction in female lifespan.

While estrogen supplementation might be beneficial for aging males, understanding the exact mechanisms and perfecting a therapy will take some time. 16α-hydroxyestriol is only the seventh ITP-tested drug to induce at least a 10% lifespan increase in one or both sexes.

Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor and is used to treat type 2 diabetes. Blocking SGLT2 in the kidneys reduces the reabsorption of glucose back into the blood and helps to lower blood sugar levels. Interestingly, the more famous anti-diabetes drug metformin failed to produce significant life extension [4].

Female mice had a much higher concentration of canagliflozin in the blood than males. The researchers speculate that “hypothetical benefits (of canagliflozin) that might accrue in females at younger ages are then countered by harmful effects at ages above 16 months, when blood levels of this drug are particularly high in females.” They plan a series of new experiments hoping to avoid this late-life toxic effect. Still, the success of a mid-life canagliflozin treatment in males is a great result. With this study, canagliflozin has become the fourth ITP-tested drug to increase lifespan when started later in life.

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…and the losers

The most high-profile failure was AKG, which has been touted as a potential geroprotector. AKG is involved in energy production in cells, and some research suggests that its supplementation can improve cellular function and reduce oxidative stress. “Our data on AKG,” the researchers wrote, “fail to confirm the published work in which this agent produced a small but significant lifespan benefit in female C57BL/6 mice” (those mice, widely known as B6, are inbred, as opposed to the genetically heterogenous mice used in the ITP). AKG is being tested by the ITP in another cohort, starting at an earlier age.

Sodium thiosulfate, a sulfur donor used as an antidote for cyanide poisoning, produced a 5% increase in median lifespan in males but not in females. This result fell just short of statistical significance, but the researchers haven’t given up on this inorganic molecule and plan to try other doses.

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Literature

[1] Miller, R. A., Harrison, D. E., Cortopassi, G. A., Dehghan, I., Fernandez, E., Garratt, M., … & Strong, R. (2024). Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin. GeroScience, 1-14.

[2] Strong, R., Miller, R. A., Cheng, C. J., Nelson, J. F., Gelfond, J., Allani, S. K., … & Harrison, D. E. (2022). Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice. Aging Cell, 21(12), e13724.

[3] Harrison, D. E., Strong, R., Allison, D. B., Ames, B. N., Astle, C. M., Atamna, H., … & Miller, R. A. (2014). Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging cell, 13(2), 273-282.

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[4] Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., … & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. Aging cell, 15(5), 872-884.

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About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.