Y Chromosome Role in Aging & Disease Unveiled

In a recent review article published in the journal Nature Reviews Genetics, experts examined their current understanding of the loss of the Y chromosome (LOY) and its consequences on numerous disorders and the immune system. Their findings suggest that LOY is a dynamic mutation that has a major impact on immune function, underlining its potential as a biomarker and therapeutic target.

Background

LOY in human male cells was discovered more than 60 years ago, although it has only recently received widespread attention. Originally thought to have little impact beyond sex differentiation and sperm production, LOY is now recognized as a frequent somatic mutation with far-reaching implications.

Recent study has indicated that LOY is caused by mitotic mistakes, most commonly the entrapment of the Y chromosome in micronuclei that eventually disintegrate. Since 2014, studies have connected LOY to an increased risk of mortality, cancer, and Alzheimer’s disease, with environmental factors such as smoking leading to its prevalence. Unlike other mutations, LOY occurs as a mosaic event and cannot be inherited.

Recent breakthroughs in Y chromosome sequencing have revived research, allowing us to better understand the role of LOY in health and disease. Furthermore, LOY is becoming recognized as a marker of genomic instability and a biological sign of environmental stress.

Prevalence and Underlying Mechanisms
LOY occurs when cells divide incorrectly, leading the Y chromosome to break apart or be lost. The Y chromosome’s unusual structure and short ends (telomeres) make it more prone to become stuck in tiny structures known as micronuclei, which eventually break down. This process is associated to aging, as older cells have more micronuclei, which increases the likelihood of LOY.

This disorder is primarily related with aging, as the risk increases with age as cells divide more frequently. LOY prevalence increases dramatically in men over 40 and can be identified in people as young as 19. Studies confirm a high age-related association with LOY, which has been reported in other animals.

Aside from aging, smoking and exposure to chemicals like arsenic and glyphosate contribute to LOY. Smoking, in particular, raises LOY risk, but quitting can help reduce it. Another aspect is genetic predisposition, with 156 chromosomal loci related to LOY, many of which play a role in DNA repair and cell cycle regulation.

LOY is widely found in blood cells, which affects immunological function and increases the risk of illness, including various malignancies. It is less prevalent in tissues such as buccal cells and atherosclerotic plaques. LOY’s influence on health includes a lower life expectancy for men compared to women, with suspected linkages to brain illnesses such as Alzheimer’s.

Furthermore, LOY is primarily found in cells with rapid turnover, such as hematopoietic cells, highlighting its dynamic character and importance to aging.

Consequences and associated conditions
LOY in cells causes the loss of Y chromosome-encoded genes, affecting leukocyte immunological activities and perhaps resulting in gene hypomethylation during leukocyte differentiation. immunological checkpoint receptor dysregulation, such as PD1 and LAG3, has been related to weakened immunological responses, including decreased antitumor immunity.

LOY also affects platelet and red blood cell counts, which may contribute to problems including thrombosis in critically ill males with coronavirus illness 2019 (COVID-19).

The disease is dynamic, with LOY-positive cells growing and contracting over time. Studies have found a link between LOY and sex hormones, such as altered testosterone levels and increased sex hormone-binding globulin (SHBG) levels.
Affected cells may experience positive selection, creating an immunosuppressive environment that can encourage tumor growth. This selective advantage has been found in monocytes, T cells, and natural killer cells, with different implications on immune regulation for each cell type. In some cells, LOY may decrease immunological responses in malignancies, however its effects on monocytes differ.
LOY has been related to a variety of disorders, including cancer, cardiovascular disease (CVD), neurological diseases such as Alzheimer’s, and infections like COVID-19. In Alzheimer’s illness, LOY in microglia contributes to neuroinflammation; in CVD, monocytes expressing LOY drive cardiac fibrosis through TGFβ-mediated signaling.

Early research has found that LOY in blood cells is associated with a lower life expectancy and a greater vulnerability to illnesses such as cancer, particularly in men.

During COVID-19, LOY in immune cells such as neutrophils is associated with worse results in men. These findings show that LOY may play a role in disease progression, particularly in males, by weakening immunological responses, and more research is needed to explain the underlying mechanisms.

Conclusions
Human Y chromosome research has moved beyond its important role in determining sex to discover its participation in disorders such as bladder cancer, cardiac fibrosis, and Alzheimer’s. LOY is associated with immune system failure, aging, and genomic instability, especially in men, and may be a marker for chronic illnesses. Although the fundamental mechanisms of LOY are yet unknown, future study may reveal specific mutations or variables that cause LOY. Targeting TGFβ in animal models has showed promise in treating LOY-induced heart fibrosis, indicating its potential as a therapeutic target. This mutation, which alters gene expression and immunological responses, may explain men’s shorter life expectancy, implying that LOY is a major component in male health disparities.

More research is needed to better understand the impacts and potential treatment targets.

For more information: Markljung, E., Sarkisyan, D., Filipowicz, N., & Dumanski, J. P. (2025). The effects of loss of Y chromosome on male health. Nature Reviews Genetics, 1-16. DOI: 10.1038/s41576-024-00805-y, https://www.nature.com/articles/s41576-024-00805-y