Why men and women age differently, and why anti-aging therapies are ignoring that gap
Most anti-aging interventions that work in mice work better in females than males, or the other way around. Yet the vast majority of studies barely examine that difference. A new review exposes just how large our blind spot really is.
Women live longer than men on average, but they spend more of those extra years dealing with chronic illness. Men die sooner, yet they tend to be healthier in the period leading up to death. This pattern holds across dozens of countries and cultures. The biological explanation, however, remains surprisingly murky. A review published on Fight Aging! pulls together what research has established so far.
In mice, sex differences are well documented. Caloric restriction extends lifespan substantially in female mice, but far less so in males. Rapamycin, a drug that inhibits the mTOR pathway and influences aging processes, works better in females. Metformin, a diabetes medication also being studied as an anti-aging agent, shows positive effects primarily in male mice. The pattern is consistent: many interventions work, but who benefits most varies sharply by sex.
Hormones, mitochondria, and something else
The obvious explanation is hormonal: estrogen has protective effects on the cardiovascular system, the immune system, and possibly the brain. After menopause, that protection disappears and aging accelerates for women on several fronts. But that alone does not explain everything. Even in castrated mice, stripped of sex hormones, lifespan differences between the sexes persist. That points to mechanisms running deeper than hormones.
Another hypothesis focuses on mitochondria, the energy-generating organelles of the cell. Mitochondrial DNA is passed down exclusively through the mother. Because mitochondria are never ‘tested’ inside a male body, mutations that are harmful to males can accumulate undetected across generations. This idea, known as the ‘mother’s curse hypothesis’, remains controversial but has not been disproved.
What this means for research happening right now
The most pressing problem is methodological. Many aging studies use only male animals to avoid hormonal variability. Clinical trials in humans rarely break out results by sex. And the interventions currently being tested in human trials, including rapamycin, senolytic drugs that clear out aged cells, and NAD+ boosters, have seldom been designed with sex differences in mind.
If the sex differences in humans are anywhere near as large as those seen in mice, that means roughly half the population may get less benefit from certain interventions, or may even be harmed by them. The review does not answer why these differences exist. What it makes clear is that finding the answer is urgent.