Seven drugs that extended lifespan only in male mice share a probable molecular signature: in visceral fat, they shift the inflammatory protein IL-11 in opposite directions, lowering it in males and raising it in females
Seven drugs that extended lifespan only in male mice share a probable molecular signature: in visceral fat, they shift the inflammatory protein IL-11 in opposite directions, lowering it in males and raising it in females
In a paper published on September 16, the laboratory of Richard Miller (University of Michigan), one of the leaders of the national Interventions Testing Program (ITP), measured IL-11 protein levels in four tissues of old mice treated with seven ITP compounds already confirmed to extend lifespan only in males. Sex differences appeared in only one of those tissues.
Since 2004, the ITP has been testing compounds for lifespan extension in mice across three independent laboratories (Jackson Laboratory, the University of Michigan, and the University of Texas Health Science Center at San Antonio) and has repeatedly identified drugs with the same peculiarity: they extend lifespan only in males, and the reason has remained unknown.
A clue came from a separate result: in 2024, a study published in Nature showed that IL-11 protein itself accumulates in mouse tissues with age, and that blocking it extends lifespan in both sexes. Deletion of the IL-11 gene extended lifespan by an average of 24.9%; an anti-IL-11 antibody extended it by 22.5% in males and 25% in females. Since removing IL-11 benefits both sexes, a logical next step was to check whether the male-only ITP drugs work by lowering this protein, and whether that same mechanism might explain why females do not respond.
Miller and colleagues selected seven such compounds, including canagliflozin (a diabetes drug that has already extended lifespan in male mice by 14%), mitoglitazone, and 16α-hydroxyestradiol, and measured IL-11 in four tissues of old mice of both sexes: liver, muscle, subcutaneous fat, and visceral fat, the fat that surrounds internal organs. The two types of fat were chosen deliberately: earlier data indicated that they respond differently to estrogen, and visceral fat is separately considered a hub of systemic inflammation during aging. Liver showed no response to any of the seven drugs. Muscle was tested for only two compounds and likewise showed no effect. Subcutaneous fat IL-11 decreased equally in both sexes, which means this fat depot does not explain the lifespan difference.
The asymmetry appeared specifically in visceral fat. In males, six of the seven drugs reduced IL-11 there by a factor of 2.5 to 3. In females, five of those six instead raised it by a factor of 1.2 to 2, and halofuginone raised it nearly twofold. Only meclizine left IL-11 unchanged in either sex. Two drugs in that group of six, mitoglitazone and astaxanthin, had originally shown modest lifespan effects (8% and 12%) that did not replicate at different doses; for the remaining four, the IL-11 signal looks considerably more robust.
The hypothesis was tested against an independent case: a combination of rapamycin and 17α-estradiol, which, unlike these seven drugs, extends lifespan in both sexes (interim data: median survival increased by 15% in both). If the IL-11 asymmetry in visceral fat truly explains the sex difference, this universal combination should not produce the paradoxical IL-11 rise in females. It did not: IL-11 decreased in males, and in females it did not change significantly.
The finding shifts the ITP question from "why does this not work in females" to "what switches the sign of the IL-11 response by sex in this tissue": a hormonal signal, epigenetics, or another pathway. The answer provides a testable target: if blocking IL-11 specifically in visceral fat of females restores the same lifespan extension seen in males, the candidate mechanism becomes a proven cause.