Sex chromosomes shape ageing and disease risk
Men and women age differently. That has long been known, but the biological reason remained unclear. A review article in Science now highlights a long-underestimated connection: the sex chromosomes themselves, X and Y, directly influence how quickly cells age and what diseases arise as a result.
Every human carries two sex chromosomes: women typically have two X chromosomes (XX), men one X and one Y (XY). These chromosomes were long seen primarily as determining biological sex. The researchers show in this review that genes on the X and Y chromosomes directly contribute to ageing mechanisms, entirely independently of the hormonal differences between men and women.
One striking mechanism is the loss of the Y chromosome in body cells of older men. This loss occurs in blood cells and other tissues and is associated with a higher risk of cardiovascular disease, Alzheimer’s disease, and cancer. This is not a hereditary change but rather somatic mutations that accumulate with age.
X-inactivation and the cost of two X chromosomes
In women with two X chromosomes, one X is largely switched off in every cell, a process called X-inactivation. That sounds neutral, but as women age, this inactivation pattern can become uneven: some cells begin preferentially using the same X chromosome. This phenomenon, known as skewed X-inactivation, is tentatively associated with increased susceptibility to certain immune and cancer-related diseases, though a causal relationship has not yet been established.
At the same time, the X chromosome contains many regulators of DNA repair and immune function. Women may benefit from having two copies of some of those genes, which could partly explain their average longer life expectancy. But that protective effect also has a downside: a stronger immune response raises the risk of autoimmune diseases.
Implications for longevity research
This insight, published in Science, calls for greater attention to biological sex as a variable in ageing research. Until now, men and women have been grouped together in many studies. If the sex chromosomes themselves regulate ageing, the findings of combined analyses may be incomplete. That affects not only science, but also the development of drugs and prevention strategies.
Search terms to explore further: Y chromosome loss somatic ageing | X-inactivation immune regulation | sex-specific ageing mechanisms