TY - JOUR
T1 - Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance
AU - Zhang, Xu
AU - Pearsall, Vesselina M.
AU - Carver, Chase M.
AU - Atkinson, Elizabeth J.
AU - Clarkson, Benjamin D.S.
AU - Grund, Ethan M.
AU - Baez-Faria, Michelle
AU - Pavelko, Kevin D.
AU - Kachergus, Jennifer M.
AU - White, Thomas A.
AU - Johnson, Renee K.
AU - Malo, Courtney S.
AU - Gonzalez-Suarez, Alan M.
AU - Ayasoufi, Katayoun
AU - Johnson, Kurt O.
AU - Tritz, Zachariah P.
AU - Fain, Cori E.
AU - Khadka, Roman H.
AU - Ogrodnik, Mikolaj
AU - Jurk, Diana
AU - Zhu, Yi
AU - Tchkonia, Tamara
AU - Revzin, Alexander
AU - Kirkland, James L.
AU - Johnson, Aaron J.
AU - Howe, Charles L.
AU - Thompson, E. Aubrey
AU - LeBrasseur, Nathan K.
AU - Schafer, Marissa J.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-33226-8
DO - 10.1038/s41467-022-33226-8
M3 - Article
C2 - 36167854
AN - SCOPUS:85138907977
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5671
ER -