The ovary keeps changing for decades after menopause, a protein study suggests

The ovary ages early. Women are born with a fixed supply of follicles, the small sacs that hold egg cells, and when that supply runs out, periods stop for good: menopause, usually around age 50. Many women then live several decades more. What happens to the ovary during those years has had little attention. The usual textbook picture is of a shrunken organ made mostly of scar-like connective tissue that has gone quiet.

A new study in the journal Aging Cell questions that picture. By measuring thousands of proteins in healthy ovaries from women aged 50 to 75, the team found that the make-up of the tissue differs steadily with age, long after menopause. The study is small and looks at different women of different ages rather than following anyone over time, so it describes differences between age groups, not what drives them.

What they did

The researchers, led from the Buck Institute for Research on Aging, used ovarian tissue from the Northwestern University Reproductive Tissue Library. It came from 28 postmenopausal women (average age about 63) whose ovaries had been removed during surgery for various non-cancerous gynaecological conditions, most often problems of the womb lining such as endometriosis. A specialist in tissue diagnosis confirmed that every ovary looked normal under the microscope. The women were split into three age groups: 50–59 (11 women), 60–69 (10) and 70 or older (7).

The team then measured the tissue's proteome, the full set of proteins present, with mass spectrometry, a machine that breaks proteins into small fragments and identifies them by their weight.

They analysed the data in several ways: comparing the age groups pairwise, letting a statistical model try to tell the groups apart, and testing which proteins rose or fell steadily with age while taking body weight and self-reported ethnicity into account. Two of the most interesting proteins were also checked by staining thin slices of tissue with antibodies that colour a chosen protein.

What they found

The team measured 5,812 protein groups.

• Bigger gaps with more years. Between the 50–59 and 60–69 groups, 40 proteins differed clearly (34 higher in the older group, 6 lower). Between the 50–59 and 70-plus groups, 117 differed (33 higher, 84 lower).
• A shift in what the tissue is doing. Proteins linked to reading genes and processing RNA were more prominent in the youngest group. In the oldest group the balance moved towards metabolism, fat transport, and the innate immune system, the body's fast, general defences, including the complement proteins that tag invaders and damaged cells.
• Remodelling of the scaffold. Much of the change involved the extracellular matrix, the mesh of proteins between cells that gives tissue its structure. Collagens, its main building blocks, tended to fall with age, while secreted factors rose. Structural proteins such as keratins, which help cells keep their shape, were lower in older ovaries.
• A 26-protein signature. Combining the analyses, the team picked 26 proteins that changed most consistently. A score built from them rose closely with age across the 28 women.
• Checked in tissue slices. Staining confirmed two of these proteins: WNT4, a signalling protein, was more abundant in older ovaries (10 women stained), and fibromodulin, which helps organise collagen fibres, was less abundant (8 women).
• Overlap with other signatures. Some age-linked proteins matched those released by cells that have stopped dividing in lab experiments on ovarian tissue. A panel of proteins associated with ovarian cancer was, on average, highest in the 60–69 group. The authors stress that all the ovaries were normal, so this is a shared pattern, not cancer.

What to keep in mind

• The authors' own limits. The age at menopause, the years since menopause and whether the women had used hormone therapy were not known. These could all shape how the ovary changes, so the study speaks about age after menopause, not about menopause itself.
• Small numbers. Only 28 women took part, with just 7 aged 70 or over. When age was treated as a smooth scale and other factors were accounted for, only two proteins passed the strict significance test; many others were weaker candidates.
• One snapshot. Each woman gave tissue once. Differences between age groups may partly reflect differences between the women, not changes within one person's ovary.
• Not a random sample. All the ovaries were removed for medical reasons. The team found that the reasons for surgery were not linked to age group, but these women may still differ from others.
• Lab comparisons. The cell-ageing comparison used tissue in which ageing was triggered with a drug, which the authors note does not fully mirror natural ageing.
• No health outcomes. The study was not designed to show whether these protein changes affect women's health.

Why it matters

Women spend a large part of their lives after menopause, yet the ovary in those years is barely studied. This work offers what the team calls a reference map of how a normal postmenopausal ovary differs with age, and it argues against seeing the organ as an inert leftover. Changes in the tissue scaffold and in immune and inflammatory signalling are seen in many ageing organs, so the ovary may follow a similar path. Whether these changes matter for health elsewhere in the body, and how they relate to time since menopause or hormone therapy, are questions the authors say need larger studies that follow women over time.