Researchers identify new regulators of cellular aging

As we age, the risk for a wide range of diseases, including cancer and neurodegenerative conditions, increases. But while aging has been extensively studied, scientists don’t have a clear picture of the molecular changes that take place as we get older.

Now, researchers at the Broad Institute of MIT and Harvard and ETH Zürich in Switzerland have found key gene-expression regulators related to cellular aging that are tightly coupled to structural alterations of chromatin — the DNA-protein complex that forms chromosomes. The findings, published last month in Aging Cell, offer new insights into the biology of cellular aging. The research may also provide potential targets for aging reversal.

The study stems from a long-term collaboration between the laboratory of GV Shivashankar at ETH Zürich on the biological side and Caroline Uhler at the Broad Institute on the computational side.

“The explosion of biomedical data presents an exciting opportunity to develop novel machine learning methods to help answer important biological questions,” said study co-senior author Uhler, the director of the Eric and Wendy Schmidt Center at the Broad and a professor in the Department of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society at MIT. “In this work, the availability of large-scale sequencing data from many individuals in different age groups motivated us to develop methods to identify drivers of cellular aging,” she added.

Shivashankar’s lab has long been interested in understanding the relationship between a cell’s microenvironment, the three-dimensional structure of the genome, and gene expression in health and disease. Depending on how DNA is packed inside a cell’s nucleus, it may alter the expression of specific genes, which could in turn result in certain diseases, explained co-senior author Shivashankar, professor of Mechano-Genomics at ETH Zürich and head of the Laboratory of Nanoscale Biology at the Paul Scherrer Institute in Switzerland. “We’re very excited about understanding what may lead to healthy aging as opposed to cancer or neurodegeneration,” he added.

The study also aligns with the Eric and Wendy Schmidt Center’s goal of developing computational approaches for challenging biomedical questions. To this end, the Schmidt Center trains talented undergraduate, master’s, and PhD students as well as postdoctoral fellows with computational backgrounds on how to work with experimental biologists.

“As a graduate student in statistics, working closely with a biological lab allows me to gain a much deeper understanding of the kinds of questions and data that are most interesting to biologists,” said study co-first author Louis Cammarata, a PhD student at Harvard University and the Eric and Wendy Schmidt Center. “I’m able to design more useful computational methods because of this constant communication.”

Drivers of aging

In the nucleus of a cell, DNA coils around proteins to form chromatin. Other proteins bind along chromatin, creating complex three-dimensional structures that leave some genes accessible to transcription and others closed off.

Uhler, Shivashankar, and their teams analyzed gene expression data from skin cells of 133 individuals aged 1 to 96 years, who were divided in five age groups. The difference in gene expression was particularly prominent when comparing the two oldest groups, which included people aged 61 to 85 years and those aged 86 to 96 years. Differentially expressed genes tended to be involved in biological processes such as immune response and cell proliferation, which play important roles in aging.

Next, the researchers used statistical algorithms to combine these data with information from a database that lists protein-protein interactions. The analysis revealed key age-associated regulators of gene expression, which include transcription factors — proteins that control how other genes are expressed.

“Transcription factors may be post-translationally activated or they may benefit from changes in chromatin organization to activate their target genes at a later time point,” said study co-first author Jana Braunger, a former master’s student at the Eric and Wendy Schmidt Center and current PhD student at the University of Heidelberg.

Gene expression hubs

To analyze the coupling between chromatin organization and changes in gene expression, the researchers used an experimental method called Hi-C, which provides a proximity map of the DNA packing.

Comparing Hi-C data from old and young skin cells revealed that the structure of chromatin changes over time, either drawing apart genes that were close together or bringing together genes that were far apart in young cells.

In the cell’s nucleus, nearby genes are often expressed as a group, Cammarata explained. “There are specific hotspots where different chromosomes come together, along with other molecules that are useful for transcription, and within those hubs, you have active transcription and co-regulation of genes,” he said. “In aging, changes in how DNA is folded influence these hotspots of transcription.”

Mitigating aging

Although more work is needed to determine whether alterations in chromatin structure drive changes in gene expression or vice versa, some of the gene-expression regulators identified in this study could serve as potential targets to mitigate, prevent, or even reverse cellular aging. “Identifying the key transcriptional drivers of cellular aging is crucial to develop interventions for cellular reprogramming and rejuvenation,” Shivashankar said.

Uhler noted that the study is an example of how computational researchers can develop new methods to help answer important biological questions — a core mission of the Eric and Wendy Schmidt Center. “We place great importance on training the next generation of scientists — researchers who are strong on the computational side and understand the biological questions,”she said. “Merging computational science and biology can help us tackle some of medicine’s biggest challenges.”