Age-Related Y Chromosome Loss Correlates With Mortality

Cells accumulate all sorts of mutations and other damage, and the damage load rises over the years despite the best efforts of our evolved repair systems. This is the basis of aging: degeneration and disease is driven by damage and reactions to damage.

The research community has cataloged this damage, and can make strong arguments as to what is fundamental and what is a secondary effect. Our biology is enormously complex, however, and so many specific forms of damage and their progression are far from fully understood. The research community doesn't have a solid case for what exactly it is that some forms of amyloid - clumps of misfolded proteins that accumulate with age - are actually doing to cause harm, for example. Many other examples can be found in the specifics of nuclear DNA damage, the innumerably stochastic mutations scattered about the cells of the body. What are all of these different mutations really actually doing, individually and in aggregate? To answer that question comprehensively would involve generations of study with today's technology.

So it shouldn't be terribly surprising to find that comparatively little is known about the consequences of the loss of the Y chromosome in a small proportion of male cells that occurs with aging. Chromosome loss is a form of DNA damage that occurs in both genders, but for the purposes of this post we'll restrict ourselves to considering just the Y chromosome. If you go digging around for articles and papers you'll find that most work on this topic is coming from the cancer research community, and thus don't have a great deal to say on what this might mean outside of the context of cancer tissue and cancer patients, who are not a representative sample of the population at large.

The paper below, however, goes further and shows an association between Y chromosome loss and all-cause mortality in men. This is a starting point, though it doesn't say anything about why this might be the case. The cancer link is evident, as DNA damage is firmly established as a cause of cancer, but the rest is an open question. As for all associations with age-related damage, it is always possible that this is just a case of aging being a global phenomenon in the body. If there is more of any one measured type of damage, then mortality rates will tend to be higher in that population because there is also more of all the other unmeasured forms of damage.

Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer

Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive.

From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91) and non-hematological cancer mortality (HR = 3.62). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter.

Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.


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