As human beings age, we accumulate mutations in our DNA. These mutations can be harmless, or they can contribute to age-related conditions including neurodegenerative disorders, cardiovascular diseases, and some cancers. The most prevalent age-related mutation in males is the loss of the entire Y chromosome (LOY). Ken Walsh, PhD, Lockhart B. McGuire Professor of Internal Medicine and Resident Member of the Robert M. Berne Cardiovascular Research Center, is an expert in LOY. Over 40% of men show some loss of Y chromosomes by age 70, and previous work in Walsh’s lab has shown that LOY is an important factor in conditions with a strong male bias, such as cardiovascular disease. If fact, epidemiological data show that conditions stemming from LOY can explain much of the 6-year gap in life expectancy between males and females, who have no Y chromosome to lose. “This begs the question: ‘How does losing the Y chromosome in men cause earlier mortality?’,” says Walsh.
Walsh and his research team address a part of this question in their recent article, “Hematopoietic Loss of the Y Chromosome Activates Immune Checkpoints and Contributes to Impaired Senescent Cell Clearance and Renal Disease,” published in Science Translational Medicine. Having shown previously that LOY in immune cells leads to increased heart failure mortality, the team turned to other organs. The team, led by Yohei Arai, MD, PhD, a postdoctoral researcher in the Walsh lab, analyzed over 216,000 samples from the UK and determined that men with a high degree of Y chromosome loss were up to six times more likely to develop chronic kidney disease than those who had not lost their Y chromosomes. To understand why, Dr. Arai studied male mice with LOY. Like humans, these mice developed kidney failure as they aged and recovered poorly from kidney injuries, showing more scarring compared to their counterparts with an intact genome. “Interestingly, they also had more senescent cells—zombie-like cells that don’t grow, but secrete molecules that can promote tissue injury,” explains Walsh. When Dr. Arai treated the Y-less mice with drugs that target these zombie cells, the extra kidney damage the mice suffered from was reversed, suggesting that the senescent cells were an important part of the system.
Senescent cells are known to accumulate as we age because the body’s immune cells struggle to dispose of them as efficiently. It takes ten times longer for an old mouse to eliminate a senescent cell than a young mouse, for example. Dr. Arai suspected that male immune cells without Y chromosomes had a harder time eliminating these cells. His hypothesis was correct. When he compared immune cells with and without LOY, the ones with LOY were worse at destroying senescent cells. Looking deeper, Dr. Arai found that men and male mice who had lost their Y chromosomes send signals to immune cells that prevent them from killing dangerous cells. Blocking those signals restored normal function in both the kidneys and immune system.
Walsh and Dr. Arai hypothesize that LOY suppressing the immune system could explain why LOY is associated with a wide array of cancers in males—the body loses its ability to destroy tumors before they become established. Many tumors even use the same immune suppression molecules seen in this study to evade destruction, which could explain why men tend to respond better to cancer therapies that block those signals. Future work will continue to explore LOY, its consequences, and treatment options.