Spatial Mapping Senescent Cells Across the Mouse Lifespan by Multiplex Transcriptomics and Epigenomics

PROJECT SUMMARY
Cellular senescence, characterized by stable proliferation arrest and secretion of pro-inflammatory factors,
is not only a hallmark of aging, but also a key contributor to age-associated diseases in humans. As the US
population is aging, there is an added urgency to gain a better understanding of cellular senescence in
different tissues over the lifespan. Unfortunately, we still lack the knowledge to unambiguously define
senescence at the molecular and cellular levels, due to its heterogeneous phenotypes. To address this major
gap in knowledge, we propose to establish a tissue mapping center that focuses on the identification and
characterization of senescent cells in healthy mouse brain, bone marrow, breast, colon and liver. Our
research strategy builds on recent advances in single cell epigenomics technologies that our team developed
and the knowledge that senescent cells exhibit characteristic changes in the chromatin landscapes and
histone modifications along with gene expression levels at marker genes of cellular senescence. We will
deploy cutting-edge single cell in situ and tissue dissociative multi-omic tools that have been well established
in our center to produce comprehensive single cell resolution maps of the transcriptome and epigenome in
male and female mouse brain, bone marrow, breast, colon and liver, and to provide qualitative and
quantitative spatial maps of the normal burden of senescent cells in these vital organs, across the lifespan of
two mouse strains. We will rigorously validate the newly defined senescent cell populations using
pharmacologic and genetic approaches to eradicate senescent cells or suppress their inflammatory
phenotype, and orthogonal state-of-the-art and conventional assays for cellular senescence. We will
generate whole genome single cell DNA methylation data to link our spatial atlas to measurement of
epigenetic age, a candidate predictor of beneficial versus detrimental effects of senescent cells. We expect
that comprehensive single cell atlases of epigenome and transcriptome will enable us to identify and
characterize cellular senescence in different tissue contexts and during aging.
We expect that the planned
research will provide a reference for future studies that seek to characterize and target senescent cells
associated with or preceding disease in
brain, bone marrow, breast, colon and liver.

Grant Number: 3U54AG079758-04S1
NIH Institute/Center: NIH
Principal Investigator: PETER ADAMS