Y chromosome unexpected effects on aging and disease in men

Y chromosome unexpected effects on aging and disease in men

Why losing the Y chromosome is more than genetics – it's a key to understanding male health disparities.

In a recent review article in the journalNature Reviews GeneticsThe researchers discussed current understanding regarding Y chromosome loss (LOY) and its impact on various diseases and the immune system. Their conclusions suggest that Loy is a dynamic mutation that significantly affects immune function, highlighting its role as a potential biomarker and treatment target.

background

Micronuclei and Y chromosome loss: The formation of micronuclei, small cellular structures containing chromosomes or fragments, plays a crucial role in Y chromosome decay and links LOY to genomic instability and aging processes.

LOY in human male cells was first identified over 60 years ago but has only recently received significant attention. Initially thought to have only minor effects on sexual differentiation and sperm production, LOY is now recognized as a common somatic mutation with broad effects.

Recent research has shown that Loy arises from mitotic errors and often involves trapping of the Y chromosome into micronuclei, which eventually disintegrates. Research since 2014 has linked LOY to increased risks of mortality, cancer and Alzheimer's disease, with environmental factors such as smoking contributing to its occurrence. Unlike other mutations, Loy is always a mosaic event and cannot be inherited.

Recent advances in Y chromosome sequencing have revitalized research and increased our understanding of Loy's role in health and disease. Furthermore, Loy is increasingly viewed as a marker of genome instability and a biological indicator of environmental stress.

Prevalence and underlying mechanisms

LOY occurs due to errors in cell division, causing the Y chromosome to break or be lost. The Y chromosome's unique structure and short ends (telomeres) make it more likely that they will eventually collapse into tiny structures called micronuclei. This process is associated with aging as older cells tend to have more micronuclei, leading to higher chances of LOY.

This condition is mainly associated with aging as the risk increases with age due to more cell divisions over time. Loy prevalence increases exponentially in men over 40 and can also be detected in young individuals, such as 19. Studies confirm a strong age-related correlation with Loy, which is also observed in other species.

Environmental triggers beyond smoking: Exposure to environmental toxins such as arsenic and glyphosate is associated with increased risk of LOY, suggesting that environmental pollutants may exacerbate genome instability and disease susceptibility in men.

In addition to age, environmental factors such as smoking and exposure to toxins such as arsenic and glyphosate contribute to Loy. Smoking, in particular, increases the risk of LOY, but quitting may reduce it. Genetic predisposition is another factor, with 156 genomic loci identified as being linked to LOY, many of which are involved in DNA repair and cell cycle regulation.

LOY is commonly found in blood cells, affecting immune function and contributing to disease risks, including certain cancers. It is less common in tissues such as buccal cells and atherosclerotic plaques. Loy's health effects include reduced life expectancy for men compared to women, with potential links to brain diseases such as Alzheimer's.

Additionally, Loy is predominantly present in high turnover cells such as hematopoietic cells, emphasizing its dynamic nature and relevance to aging.

Consequences and associated conditions

LOY in cells leads to deletion of Y chromosome-encoded genes, which influence leukocyte immune functions and can lead to gene hypomethylation during leukocyte differentiation. Dysregulation of immune checkpoint receptors such as PD1 and LAG3 has been linked to impaired immune responses, including reduced antitumor immunity.

Loy also affects platelet and red blood cell counts, potentially contributing to complications such as thrombosis in critically ill men with coronavirus disease 2019 (Covid-19).

The disease is dynamic, with loy-positive cells expanding and consolidating over time. Studies have shown a connection between Loy and sex hormones, including altered testosterone levels and higher sex hormone binding globulin (SHBG).

Sex hormone connection: Loy is associated with altered levels of testosterone and sex hormone binding globulin (SHBG), suggesting a complex interplay between genetic loss and hormonal regulation in aging and disease.

Affected cells may undergo positive selection and promote an immunosuppressive environment that may promote tumor growth. This selective advantage has been observed in monocytes, T cells and natural killer cells, with distinct effects on immune regulation varying across cell types. In some cells, Loy can impair immune responses in tumors, while its effects on monocytes differ.

Loy is linked to various diseases including cancer, cardiovascular disease (CVD), neurodegenerative diseases such as Alzheimer's and infectious diseases such as Covid-19. In Alzheimer's disease, Loy in microglia contributes to neuroinflammation, while in CVD, Loy-powered monocytes drive LOY cardiac fibrosis through TGFβ-mediated signaling.

Early studies have suggested that LOY in blood cells correlates with shorter life expectancy and increased susceptibility to diseases such as cancer, particularly in men.

During Covid-19, Loy in immune cells such as neutrophils is linked to worse outcomes in men. These results suggest that Loy may play a role in disease progression, particularly in men, by impairing immune responses, and further studies are needed to clarify the underlying mechanisms.

Conclusions

The study of the Y chromosome in humans has expanded beyond its critical role in sex determination to reveal its involvement in diseases such as bladder cancer, cardiac fibrosis, and Alzheimer's disease. Loy is linked to dysfunction, aging and genomic instability in the immune system, particularly in men, and could be a marker of chronic disease. Although the underlying mechanisms of LOY are still unclear, future research may identify specific mutations or factors that trigger LOY. For example, studies targeting TGFβ in animal models have shown promise in mitigating cardiac fibrosis caused by LOY, indicating its potential as a therapeutic target. This mutation could explain the shorter life expectancy in men as it affects gene expression and immune responses, suggesting that LOY is a key factor in male health disparities.

Further research is needed to understand its effects and potential therapeutic targets.

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