Molecular atlas of senescent cells could chart way to therapies for age-related diseases and cancer – EurekAlert

image:Toren Finkel, M.D., Ph.D., distinguished professor of cardiology and director of the Aging Institute at the University of Pittsburgh and UPMC. view more

Credit: UPMC

PITTSBURGH,Oct. 20, 2021Most cells throughout the body can divide and multiply to replace old cells and repair damaged tissue, but in response to certain stresses, cells can lose their ability to proliferate. These so-called senescent cells accumulate with age and may contribute to cancer and age-related disorders,such aschronic lung disease, cardiovascular disease,frailtyand dementia,by pumping out signals that damage neighboring tissues.

But because these rare cells are tiny islands in the vast world of the human body, the molecular landscape of senescence has remained relatively uncharted.

With the goal of building an atlas of cellular senescence to understand how and why senescent cells develop and set the course for new therapies for age-related diseases, theNational Institutes of Healths Common Fundestablished theCellular Senescence Network (SenNet) Program. Today, the program announced it will award $125 million to16 teamsthatform the newSenNetConsortium. Two of the projects are led byUniversity of PittsburghSchool of MedicineandUPMCresearchers, who will receive a combined $31million overfive years.

In collaboration with researchers atCarnegie Mellon University,TheOhio State Universityand theUniversity of Rochester,TorenFinkel, M.D., Ph.D.,distinguished professor of cardiology and director of theAging Institute at Pitt and UPMC, is leading theTriStateSenNetTissue Mapping Center. Itwill contribute to this atlas by developing maps of senescence in heart and lung cells. Like molecular cartographers, the researchers will map gene expression and protein composition in senescent cells from human tissue slices and lab-grown mini organs, or organoids. Theyll compare different types of senescent cells from across the lifespan to characterize signposts, or biomarkers, of senescence.

We dont know if cellular senescence is one thing or many things, said Finkel. An analogy is cancer:Lung cancer, pancreatic cancer and lymphomas are all very different, even though we call them all cancer.We want to understand how senescent cells triggered by different stresses and occurring in different tissues are similar and how they are different.

According toMelanieKnigshoff, M.D.,Ph.D.,professorof medicine in thedivision ofPulmonary,Allergy andCriticalCareMedicine(PACCM)at Pitt,answeringthesequestionsis important for understanding the molecular mechanisms of senescence, which could point to new therapies calledsenolyticsthat seek and destroy senescent cells involved in age-related diseases.

In cancer, there are certain genetic changes in tumor cells, which allow you to develop targeted therapies, saidKnigshoff. Similarly,if we can define what is different between a senescent cell and adjacent normal cells, we might be able to devise therapies that eliminate these cells based on their molecular signatures.

These maps of senescent heart and lung cells combined with maps from different organs created by other teams in the consortium will contribute to a global atlas of cellular senescence spanning many tissues of the human body.

Tocreatean organized and navigable atlas,Jonathan Silverstein, M.D., professor in theDepartment of Biomedical Informaticsat Pitt and chief research informatics officer at Pitt and UPMCsInstitute for Precision Medicine, and researchers from Carnegie Mellon University and thePittsburgh Supercomputing Centerbuilding onprevioussuccess in managingThe HumanBioMolecularAtlas Program(HubMAP), a similar programthat aims to map healthy human tissues at a cellular levelare leading theSenNetConsortium Organization and Data Coordination Center (CODCC).

The CODCC will act like a library for the consortium, developing something like the Dewey Decimal System to annotate and organize the vast collection of maps produced by the other teams.

Eventually, the atlas of cellular senescence will be published online in an open-source repository so that other researchers can explore these data to make new discoveries about senescent cells and how they contribute to human health.

I think that the science of senescent cells is tremendously exciting because of their potential impact on a whole variety of diseases, said Silverstein. By doing the basic science of collecting all of this information and presenting it throughSenNet, there is incredible potential to learn more about the role these cells play in disease and develop pharmaceuticals that target them.

The principal investigators of theTriStateSenNET(Lung and Heart) Tissue Map and Atlas consortium (U54AG075931) are Toren Finkel and MelanieKnigshoff, Pitt; Irfan Rahman, Ph.D.,University of Rochester; and Ana Mora, M.D.,TheOhio State University. Other co-investigators on the project are OliverEickelberg,M.D.,Pitt; Mauricio Rojas, M.D.,TheOhio State University; and Ziv Bar-Joseph, Ph.D.,Carnegie Mellon University.

The principal investigators of theCellular Senescence Network (SenNet) Consortium Organization and Data Coordinating Center(U24CA268108)areJonathan Silverstein,M.D.,Pitt;Ziv Bar-Joseph, Ph.D., Carnegie Mellon Universityand Philip Blood, Pittsburgh Supercomputing Center.

To read this release online or share it, visithttps://www.upmc.com/media/news/102021-sennet-grant[when embargo lifts].

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Molecular atlas of senescent cells could chart way to therapies for age-related diseases and cancer - EurekAlert