Men who lose their Y chromosome with age face higher cancer and dementia risk

Loss of the Y chromosome in blood cells is common enough that roughly 40 percent of men around age 70 show it, and a review in Science published October 1 pulls together what has been tied to it: cancers, heart disease, severe infections and Alzheimer’s disease. The review’s authors describe those as associations in men who lose the chromosome, with mechanisms still being worked out. It does not establish that the loss causes any of them.

The corresponding author is Dan Theodorescu of the University of Arizona Cancer Center, and the co-lead is Dena Dubal of the University of California, San Francisco, with Fabrisia Ambrosio of Harvard Medical School and Michael Stout of the Oklahoma Medical Research Foundation among the co-authors.

Mosaic loss in blood cells

Mosaic loss of the Y chromosome means some cells in a man’s body lack the chromosome while others keep it. The best-documented form is in white blood cells, where, according to ScienceAlert’s overview, about 40 percent of 70-year-old men show it and 57 percent of 93-year-olds. For most of the time since its discovery in 1963, it was treated as a benign marker of aging; a lifespan association was not reported until 2014, a timeline laid out by Big Think.

The new University release on the review frames the chromosomes more broadly. Theodorescu said the X and Y chromosomes carry genetic instructions that shape how cells age and how the body defends itself against major diseases. The review also covers women: loss of an X chromosome has been linked to a higher leukemia risk. Genes on the sex chromosomes influence disease risk independently of hormones, the release says, working both on their own and alongside them.

Four disease links and the evidence under each

The strength of the evidence differs by disease, and the review’s wording, “linked to” and “associated with,” reflects that. Heart disease has the most developed support. Kenneth Walsh’s group reported in Science that men losing the Y in more than 40 percent of their blood cells faced a 31 percent higher risk of dying from cardiovascular disease and a two- to threefold higher risk of dying from congestive heart failure, using U.K. Biobank data on about 500,000 people, and then used CRISPR to delete the Y from mouse blood cells and saw more scarring in the heart, according to Big Think’s account.

Cancer evidence runs along two lines. In tumors, Y loss may let cancer cells evade the immune system. In normal-looking tissue, a September JCI Insight study by Theodorescu’s team examined 1,000 tissue samples from 405 men across 11 organs and about 4.3 million cell nuclei and found Y loss highest in samples from colon, rectum, esophagus, pancreas and lung cancer cases. Theodorescu described a gradient: the closer a tissue sits to a cancer, the more Y chromosome loss it shows. He and his co-authors call the zone of affected normal tissue a pre-neoplastic field effect, a region of genetic vulnerability that may make cancer easier to start. The same team found earlier that Y loss inside cancer cells enables immune evasion, a possible explanation for higher mortality from carcinomas in men.

Alzheimer’s disease sits on the weakest rung of that ladder, with no tissue-level or large-cohort mortality figure of the kind cited for heart disease in the sources read here: a reported link, with the review calling Y loss something that “may be” a contributor to age-related disease rather than a proven driver. Dementia in general is not the measured outcome in the release; Alzheimer’s disease is.

Scientists who study the chromosome are not unanimous on what its loss costs. ScienceAlert quotes evolutionary biologist Hughes saying that genes retained on the Y serve crucial functions across the whole body, and evolutionary biologist Graves noting that important genes like these can always be picked up by other chromosomes. The first view supports a real cost to losing the Y; the second leaves room for cells that cope, which would help explain why many men with loss never develop the diseases in question.

Association against cause

Observational links leave an obvious loophole. Men whose cells lose the Y may be older, sicker or exposed to something, such as smoking, that damages chromosomes and causes disease independently. New Atlas’s report on the JCI Insight work describes a “field effect,” in which loss creates localized inflammation that predisposes cells to turning cancerous, and notes a dose-dependent pattern, but the language there is also one of predisposition, not demonstrated causation.

The mouse experiments carry the causal weight today, and they are limited to heart, kidney, lung and brain outcomes in animals. For men, the open item is what a Y-loss test would change in practice: no source read for this article describes a screening recommendation or a treatment.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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