Lars Forsberg's research on Loss of chromosome Y – why men live shorter lives?
Somatic genetic variation
I am fascinated by the fact that throughout life, the DNA content and sequences within the cells of our bodies change. These changes can be as small as point mutations or indels, larger as structural or copy-number variants, or involve entire chromosomes. Depending on where and when they occur, such somatic genetic mutations can be neutral or have profound impact on cellular functions and disease processes. As a consequence of their accumulation during life, it is now established that the somata of normally aging people is composed of genetically differentiated cells. The emerging view is that we are all mosaics and thus, that a normal human body contain a myriad of genomes!
What is LOY?
The research in the group is focused on the most common human somatic mutation: the mosaic loss of chromosome Y, or just LOY. Somatic loss of chromosome Y has been reported in cells from many different organs and cell types, but it can only occur in men, not in women. Men with LOY in blood carry a fraction of circulating leukocytes without the Y chromosome due to its loss from hematopoietic progenitor cells during lifetime. The hematological Y loss typically occurs by chromosomal mis-segregation during mitoses in the bone marrow and thus, for a single cell LOY is a binary event. Within individuals with LOY, however, a part of the blood cell progenitors will still carry a Y chromosome, creating a somatic mosaicism among circulating leukocytes.
Prevalence of LOY in blood and known risk factors
The most recent results suggest that LOY might be an inescapable result of living and that all men that survive long enough will likely be affected.
Using sensitive single cell analyses, we can identify LOY-cells in the majority of blood samples and in cells collected from other organs in aging men. Remarkably, the latest work shows that LOY in fact occurs multiple times and in many hematopoietic progenitors within individuals during lifetime, and not only in the elderly, but also in younger men. Using standard DNA-based technologies, LOY is detectable in at least 5% of peripheral blood cells among about 5%, 20%, 40% and 60% of normally aging men around 50, 60, 70 and 90 years of age, respectively. These numbers of prevalence observed in several studies would translate into hundreds of millions of men globally that might be unknowingly affected by Y loss in blood at a level detectable using standard DNA-based methods.
In addition to increasing age, the main replicated risk factors for LOY in blood include germline genetic susceptibility, smoking and various toxic exposures. Is has been known for over 60 years that LOY is a frequent event in cells of the hematopoietic system of aging men, but for a long time LOY was viewed as a neutral phenomenon. In contrast to this belief, current discoveries tells a quite different story, as outlined below.
LOY is associated with diseases and death
About ten years ago, I made the serendipitous discovery that LOY in blood leukocytes is associated with increased risk for cancer and all-cause mortality among elderly men. We published this paradigm-shifting finding 2014, in a paper that sparked new interest in LOY and initiated a decade of progress in fields such as oncology, geriatrics and cardiovascular research.
Hence, studies by us and many others have now established that hematological Y loss is associated with increased risk for all major causes of death, including the biggest killer of all: cardiovascular diseases, but also dementias such as Alzheimer’s disease and many different forms of cancer, i.e. both hematological malignancies (blood cancers) and non-hematological cancers (solid tumors).
Given associations between LOY in blood and increased risk for a variety of lethal diseases, it is not surprising that LOY in blood is also associated with all-cause mortality, i.e. men with high levels of LOY in blood die on average at younger ages compared with other men. Thus, these associations are dose-sensitive, implying that a higher percentage of circulating leukocytes with LOY is linked with greater exacerbation of diseases.
How can LOY in blood cells increase the risk for disease in other organs?
It has been heavily debated if LOY in blood is just a neutral passenger event or actually causal of disease, and several non-mutually exclusive disease mechanisms have been considered. For example, recent publications show that LOY-leukocytes display differential gene expression of hundreds of autosomal genes, is associated with genomewide epigenetic dysregulation and affect the differentiation of hematopoietic cells. These results show that Y loss has profound effects on leukocyte biology and cellular functions of affected immune cells on many levels, but they don’t demonstrate direct causality with disease.
To address this fundamental question, we generated mouse models with LOY in blood leukocytes using CRISPR-Cas9 and observed that LOY-mice had a reduced lifespan compared with controls. In addition to this vital result of direct causality, LOY was found to be associated with enhanced fibrosis of internal organs such as heart, lung and kidney.
By analyses of tissue resident leukocytes, a LOY-driven profibrotic disease mechanism could be identified. Briefly, circulating LOY-leukocytes have a propensity to differentiate into profibrotic LOY-macrophages in other organs, triggering the canonical TGFβ-signalling pathway leading to activation of tissue resident fibroblasts and scarring of tissues known as fibrosis, and eventually organ failure. Of relevance in a translational perspective, clinically available TGFβ-inhibitors reduced fibrosis caused by LOY in mice models.
In can also be noted that fibrosis is a component of many types of disease, and the LOY-driven profibrotic disease mechanism helps explain how LOY in blood can be associated with so many and diverse diseases. Thus, we have begun to learn how LOY in leukocytes can exacerbate disease manifesting in other organs, and ongoing studies continue to unravel fascinating LOY biology on many levels.
Significance of LOY
Based on effect sizes observed in epidemiological investigations and global demographics, it is reasonable to suspect that LOY contributes to millions of male deaths annually. This is a mind-blowing number that could solve a long-lasting conundrum in medicine; the fact that men in the entire world live on average about 5–6 years shorter lives than women. Thus, as a male-specific and common genetic risk factor, LOY sheds new light on the higher incidence of many common diseases in men compared with women, and in the end, the profound sex bias in longevity.
The progress in LOY research in recent years has the potential to improve male health, by facilitating the clinical utility of LOY. Hence, a stratification of men with LOY for tailored treatment strategies might benefit patients in various medical disciplines. For example, given the profibrotic and TGFβ-driven action of LOY, it is likely that patients with LOY would display improved response to TGFβ inhibition-based treatments in various diseases. Furthermore, translational applicability can be envisioned within personalized immune therapies against cancer and other disease.
Ongoing research in the Forsberg lab
The overarching purpose of our ongoing research projects is to explore associations between LOY in blood and disease risks, to further explore and understand how LOY in blood causes diseases in various organs. Eventually, we aim to identify mitigation strategies to improve male health.
In addition to our groundbreaking research on LOY in blood, we also invested in projects related to other forms of clonal hematopoiesis, methods development and spatial biology. The research group is situated in a vibrant research environment at Uppsala Biomedical Centre (BMC) and includes skills in bioinformatics as well as the wet lab.
If you are still reading this, you are probably as fascinated as we are about this new field in medical genetics and molecular epidemiology, and might be open for collaboration or working with us? Just send an email to lars.forsberg@ipg.uu.se =)