Most longevity treatments were tested on one sex — and that’s a serious problem
Women live longer than men, but spend more years in poor health. Many anti-ageing interventions work better in one sex than the other. Yet most research barely looks at the difference.
The sex gap in lifespan is one of the most consistent findings in biology. Across dozens of countries and across many animal species, females outlive males. But the picture is more complicated than a simple survival advantage: women suffer higher rates of autoimmune disease, dementia, and chronic disability in later life. Men die younger but often remain healthier until closer to death. Understanding why this happens — and what it means for longevity interventions — turns out to be surprisingly difficult. A review published on Fight Aging! surveys what is actually known, and the answer is: less than the field tends to assume.
In mice, the evidence is clearest. Caloric restriction extends lifespan substantially in females but produces much smaller gains in males. Rapamycin — a drug that inhibits the mTOR pathway, a key regulator of cellular growth and ageing — shows stronger effects in female mice. Metformin, the diabetes drug currently being trialled as a longevity intervention in humans, produces more consistent benefits in male mice. The pattern repeats across intervention after intervention: the treatment works, but who it works for depends heavily on sex.
Beyond hormones
The obvious explanation is hormonal. Oestrogen confers well-documented protective effects on the cardiovascular system, immune function, and possibly the brain. After menopause, that protection disappears and female health trajectories change sharply. But hormones don’t explain everything. Even in castrated mice — stripped of sex hormones — lifespan differences between sexes persist, pointing to deeper mechanisms.
One alternative hypothesis focuses on mitochondria, the cell’s energy-generating structures. Mitochondrial DNA is inherited exclusively through the maternal line, which means mitochondrial mutations that harm males never get ‘tested’ in male bodies and can accumulate across generations unchecked. This so-called maternal inheritance hypothesis remains contested, but it hasn’t been ruled out either.
A methodological blind spot with real consequences
The practical problem is structural. Many ageing studies use only male animals to avoid hormonal variability. Clinical trials in humans rarely stratify results by sex. And the interventions now entering human trials — including rapamycin, senolytic drugs that clear out damaged cells, and NAD+ precursors — were rarely designed with sex differences in mind.
If the sex-specific differences observed in mice translate to humans at anything like the same magnitude, it means a substantial portion of any population might be receiving suboptimal treatment — or worse. The review does not resolve why these differences exist. What it makes plain is that the question has been underprioritised for far too long, and that any serious longevity programme that ignores sex as a biological variable is likely to produce recommendations that don’t work equally well for everyone.