Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance

Xu Zhang, Vesselina M. Pearsall, Chase M. Carver, Elizabeth J. Atkinson, Benjamin D. S. Clarkson, Ethan M. Grund, Michelle Baez-Faria, Kevin D. Pavelko, Jennifer M. Kachergus, Thomas A. White, Renee K. Johnson, Courtney S. Malo, Alan M. Gonzalez-Suarez, Katayoun Ayasoufi, Kurt O. Johnson, Zachariah P. Tritz, Cori E. Fain, Roman H. Khadka, Mikolaj Ogrodnik, Diana Jurk, Yi Zhu, Tamara Tchkonia, Alexander Revzin, James L. Kirkland, Aaron J. Johnson, Charles L. Howe, E. Aubrey Thompson, Nathan K. LeBrasseur and Marissa J. Schafer ()
Additional contact information
Xu Zhang: Mayo Clinic
Vesselina M. Pearsall: Mayo Clinic
Chase M. Carver: Mayo Clinic
Elizabeth J. Atkinson: Mayo Clinic
Benjamin D. S. Clarkson: Mayo Clinic
Ethan M. Grund: Mayo Clinic
Michelle Baez-Faria: Mayo Clinic
Kevin D. Pavelko: Mayo Clinic
Jennifer M. Kachergus: Mayo Clinic
Thomas A. White: Mayo Clinic
Renee K. Johnson: Mayo Clinic
Courtney S. Malo: Mayo Clinic
Alan M. Gonzalez-Suarez: Mayo Clinic
Katayoun Ayasoufi: Mayo Clinic
Kurt O. Johnson: Mayo Clinic
Zachariah P. Tritz: Mayo Clinic
Cori E. Fain: Mayo Clinic
Roman H. Khadka: Mayo Clinic
Mikolaj Ogrodnik: Mayo Clinic
Diana Jurk: Mayo Clinic
Yi Zhu: Mayo Clinic
Tamara Tchkonia: Mayo Clinic
Alexander Revzin: Mayo Clinic
James L. Kirkland: Mayo Clinic
Aaron J. Johnson: Mayo Clinic
Charles L. Howe: Mayo Clinic
E. Aubrey Thompson: Mayo Clinic
Nathan K. LeBrasseur: Mayo Clinic
Marissa J. Schafer: Mayo Clinic

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.

Date: 2022
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DOI: 10.1038/s41467-022-33226-8

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