Bioanalysis Core

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 male and female 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, histone modifications and expression of 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: 5U54AG079758-04
NIH Institute/Center: NIH
Principal Investigator: PETER ADAMS