As we age, our immune system is one of the biological systems that fails to function as well as it used to. This age-related decline results in a weakened response to vaccination, regained vulnerability to infections we previously had resistance to (loss of immunological memory) and increased susceptibility to infections.
To explore the reasons behind this decline, researchers at the Babraham Institute used a colony of aged mice maintained at the Institute to perform the first genome-wide mouse study into how ageing affects gene regulation in developing B cells. B cells are an essential part of our immune system, producing antibodies and regulating immune responses. B cells are made in bone marrow, acquiring maturity once they have passed through several precursor stages.
In the paper published today in Genome Biology, the researchers describe how they used a combination of techniques to gain a comprehensive insight into gene expression differences, gene accessibility, histone modification and chromosome conformation in B cell precursors from young and old mice. Comparing genome-wide gene expression levels between the two groups of mice showed that although the levels of expression of most genes are unchanged, some genes and microRNAs show age-specific changes. Within this group are genes that encode key components of the insulin/insulin-like growth factor signalling pathway and metabolic pathways linked to nutrient signalling.
Dr Patrick Varga-Weisz, affiliated group leader at the Babraham Institute and co-leader of the study said: “By identifying the genes that show age-related changes in expression and how they are affected by age, we can start to formulate explanations of what is happening during B cell development in older animals.
“Our analysis suggests that the processes regulating gene expression start to change with age. Altered expression of the genes required for B cell development is going to disrupt the biological balance, a bit like the individual members of an orchestra playing their parts too loudly, too quietly, or at the wrong times.”
Dr Anne Corcoran, group leader in the Institute’s Lymphocyte Signalling research programme and co-leader of the study said: “By looking into the genomic interactions that regulate gene expression, we were able to connect changes in the levels of gene expression to alterations in how the genetic information is packed and organised within the three-dimensional organisation of the genome. Our in-depth analysis identified that age-related changes in gene expression are often linked to a rewiring of how the genome interacts to control gene expression.”
The research identifies alterations in the insulin/ insulin-like growth factor signalling pathway at several points, suggesting a central role for this signalling system in the ageing process in B cell precursors. Analysis of ageing in other tissues and systems has also identified genes encoding parts of the insulin/IGF signalling system, pointing towards this as one of the conserved ageing-controlling pathways. In addition to what was already known about the feedback regulation of the insulin/IGF signalling system, this research uncovers a role for chromatin reorganisation of key genes.
“Looking forward to next steps, a key question to explore is whether similar regulatory mechanisms involving alterations in chromatin structure and the 3D organisation of the genome also play a role in other systems and tissues during ageing” concludes Patrick.
Main publication reference
Koohy, H., Bolland, D.J., and Matheson, L.S. et al. Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells. Genome Biology
This work was funded by the BBSRC as an Institute Strategic Programme Grant.
Dr Louisa Wood, Communications Manager, firstname.lastname@example.org
BioMed Central's On Biology blog post by Anne and Patrick: Aging and the intricacies of the immune system
Affiliated authors (in author order)
Hashem Koohy - affiliated scientist, Fraser and Spivakov groups
Daniel Bolland - Corcoran group, Lymphocyte Signalling Programme
Louise Matheson - affiliated scientist, Elderkin group at the time of this research. Now a member of Martin Turner’s lab in the Lymphocyte Signalling Programme
Stefan Schoenfelder - Career Progression Fellow, Epigenetics Programme
Claudia Stellato - affiliated scientist, Varga-Weisz group
Andrew Dimond - affiliated scientist, Fraser group
Csilla Varnai - affiliated scientist, Fraser group
Peter Chovanec - Corcoran group, Lymphocyte Signalling Programme
Tamara Chessa – Stephens group, Signalling Programme
Jeremy Denizot - affiliated scientist, Varga-Weisz group
Raquel Manzano Garcia - affiliated scientist, Varga-Weisz group
Steven Wingett - affiliated scientist, Fraser group
Paula Freire-Pritchett - affiliated scientist, Spivakov group
Takashi Nagano - affiliated scientist, Fraser group
Phill Hawkins - Group Leader, Signalling Programme
Len Stephens - Group Leader, Signalling Programme
Sarah Elderkin - affiliated group leader
Mikhail Spivakov - affiliated group leader
Peter Fraser - affiliated group leader
Anne Corcoran - Group Leader, Lymphocyte Signalling and Development Programme
Patrick Varga-Weisz - affiliated group leader
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.
This research used young (3 months) and old (19-22 months) mice as sources of bone marrow to study B cell precursor cell populations. Please follow the link for further details of the Institute’s animal research and our animal welfare practices.
About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
05 September 2018