A hidden DNA genome protector may explain why health and aging differ between men and women

How diseases develop and how the body ages can differ between females and males, but the biological reasons for these differences are not fully understood. Researchers are studying the role of sex chromosomes to better understand what may be driving these differences.

A collaboration between Jeannie Lee, MD, Ph.D., an investigator at Mass General Brigham (MGB-Boston), and Alejandro Vaquero, Ph.D., an investigator at Josep Carreras Leukemia Institute (Barcelona), has now made an advance toward understanding why there are such sex differences.

Working with MGB postdoctoral fellow Nicolas Simonet, Ph.D., the team found that SIRT7, a protein involved in how cells respond to stress and aging, plays a critical role in maintaining the health of the X chromosome. This is especially important in females, who have two X chromosomes, compared with males, who have one. The study is published in the journal Nature.

In female cells, one X chromosome is normally “turned off” to keep gene activity balanced. But the researchers found that when SIRT7 is missing, this balance breaks down. The inactive X chromosome becomes overly silenced. More surprisingly, the active X chromosome becomes too active. This overactivity disrupts normal gene regulation and makes the chromosome prone to DNA damage and genome instability.

These effects were strongest in females. In animal models, females lacking SIRT7 showed more DNA damage, poorer health and shorter life spans compared with males.

The findings suggest that SIRT7 acts like a genetic safeguard, keeping the active X chromosome stable and its gene activity in check. Without it, the delicate balance that cells rely on is lost.

This research provides new insight into why aging, disease risk and biological responses can differ between the sexes. By uncovering how the X chromosome is regulated, the study may help inform future approaches to treating conditions that affect females and males differently.

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Stephanie Baum

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Robert Egan

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