Women whose menopause came early showed older-looking DNA marks more than a decade later

The ovaries are among the first organs to wear out. Menopause, the point when periods stop for good, usually comes between 45 and 55. Researchers have long wondered whether the age at which it happens says something about how fast the rest of the body is aging, and whether menopausal hormone therapy (MHT, prescription estrogen with or without a progestin) changes that picture.

To measure “biological age”, scientists use epigenetic clocks. Our DNA carries small chemical tags, called methyl groups, whose pattern shifts as we age. A clock reads this pattern in a blood sample and estimates an age. If the clock says 65 for a 60-year-old, that person shows age acceleration. Some clocks, such as GrimAge and DunedinPACE, were built to track the risk of disease and death or the current speed of aging, and they tend to predict health better than older clocks.

What they did

The team reused data from the PLCO trial, a large US study run by the National Cancer Institute that enrolled healthy adults aged 55 to 74 in the 1990s to test cancer screening. Its 78,209 women reported when their menopause occurred and whether they had used hormone therapy. The researchers linked this to breast cancer diagnoses and deaths, adjusting for age, weight, education, smoking and the type of menopause (natural or after surgery).

In 1,503 of these women, blood taken at the start of the study had been tested for DNA methylation. On average, menopause had happened 13.5 years before that blood draw. The team ran six epigenetic measures on these samples. They also used genetic scores, built from large published studies, to ask whether early menopause speeds up aging, or whether the two simply share genes.

What they found

• Earlier menopause was linked to older-looking DNA. Each step earlier in age at menopause went with higher age acceleration on two clocks, most clearly GrimAge. Three other measures pointed the same way but fell just short of statistical significance. The link was stronger in women who went through menopause naturally.
• Faster aging went with worse survival after breast cancer. Among the 758 women who developed breast cancer, those with higher DunedinPACE or GrimAge readings were more likely to die during follow-up. Women with early menopause also had worse survival, and part of that link ran through these aging measures.
• Shared genes, not a clear cause. Genes that push toward later menopause also tended to go with slower epigenetic aging. But the more careful genetic tests did not show that one causes the other; the authors see “shared polygenic architecture”, meaning many genes influence both.
• Hormone therapy looked different. Ever using it showed little link to epigenetic age. Current use did go with many specific DNA-tag changes and different immune markers in the blood, but these barely overlapped with the changes seen for early menopause.
• Breast cancer. In the full group, women who had ever used hormone therapy were diagnosed with breast cancer more often (about 17% higher risk after adjustment), mainly the hormone-sensitive kind and only after natural menopause. Yet they were about 28% less likely to die of breast cancer, and those who got it survived longer overall.

What to keep in mind

• Not yet peer-reviewed. This is a preprint; other scientists have not checked it yet.
• Observational. The authors stress that unmeasured differences between women cannot be ruled out; the genetic methods help, but do not replace a randomized trial. The links above are associations, not proof that early menopause or hormone therapy causes anything.
• One blood sample. DNA tags were measured only once, so the team cannot tell whether hormone therapy changes the aging trajectory or just marks women who were already different.
• Old treatments, one group. The hormone products were those used before the 2000s, and the DNA subset included only White non-Hispanic women. The authors call for studies of modern regimens and more diverse, younger groups.
• Hormone therapy is a prescription treatment with known risks and benefits. Decisions about it belong with a doctor; nothing here is advice.

Why it matters

The study supports an old idea: menopause timing is not just about reproduction but may be a window on how the whole body ages, visible in the blood more than a decade later. The genetics suggest that early menopause partly marks a built-in tendency rather than simply causing faster aging. And the breast cancer numbers show why researchers argue that counting diagnoses alone can miss part of the story: in this group, more diagnoses came alongside fewer deaths.