Chinese scientists have identified a pathway connecting the spleen to the brain that may in part explain why women are more susceptible than men to cognitive decline as they age.

The study, published Sept. 18 in the peer-reviewed journal Neuron, was led by Ma Huan, vice dean of the School of Brain Science and Brain Medicine at Zhejiang University, in eastern China.

Existing literature shows that although women live on average longer than men, they are more susceptible to cognitive impairment from midlife onwards. Scientists have lacked a clear biological explanation for this phenomenon, attributing it until now primarily to estrogen.

The new research, however, has found that the spleen may influence brain aging through a pathway involving a gene on the X chromosome, which becomes more active in women as they age.

Using gene-expression data from 11 major organs in a preexisting database, the team found that beginning around age 40, signs of cellular senescence — when cells stop dividing and begin to malfunction — rose sharply in women’s brains and spleens, exceeding levels observed in men of the same age. A similar pattern was confirmed in naturally aging mice and in donor human brain tissue. 

The researchers’ findings raise a key question: Is cognitive decline in part the result of the body sending a signal to the brain telling it to age? 

In searching for that signal, the researchers identified miR-10a-5p, a microRNA — a type of gene expression regulator — whose levels rose in the spleens and brains of middle-aged female mice but not in their male counterparts. 

The team then looked for proteins that regulate miR-10a-5p and discovered that RBMX, a protein encoded by a gene on the X chromosome, binds to, stabilizes, and allows the microRNA to accumulate. This process only occurred in female mice, as females carry two X chromosomes.

Next, the researchers injected mice with a compound to block miR-10a-5p, finding this lowered its levels in their brains, as did removing their spleens — indicating that the organ is a major source of the microRNA. Because the compound used does not efficiently cross the blood-brain barrier, the results imply that muting it elsewhere in the body may be enough to alter levels in the brain.

Once inside neurons in the brain, miR-10a-5p suppresses a protein called γCaMKII linked to calcium regulation within mitochondria — structures within the cell that generate its energy. When levels of this protein fall — which occurs during middle age in females — calcium signaling weakens and energy output declines, pushing neurons toward senescence. Restoring the protein in mice with reduced γCaMKII reversed these changes.

“We’ve tended to treat cognitive aging as something confined to the brain,” Qu Jing, the first author of the study, told Sixth Tone. “This work suggests the brain isn’t an isolated organ, and age-related changes in peripheral tissue may start shaping its condition much earlier than we assumed.”

The findings also suggest that because some of the brain’s miR-10a-5p originates elsewhere in the body, testing for it in patients’ blood could help assess brain-aging risk long before cognitive symptoms appear. Second, because reducing miR-10a-5p levels in the body affects the brain, it may be possible to protect against cognitive decline without developing a drug that crosses the blood-brain barrier.

“One important message from this work is that midlife isn’t just a stage where you wait for aging to happen, but a possible critical window for maintaining long-term brain health,” Qu said, adding that because the study points to a connection between the immune system and the brain, sustaining a well-functioning immune system may matter for cognitive health too. 

Editor: Marianne Gunnarsson.

(Header image: Amana/VCG)