title: Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells.
abstract: Senescent cells (SCs) have been considered a source of age-related chronic sterile systemic inflammation and a target for anti-aging therapies. To understand mechanisms controlling the amount of SCs, we analyzed the phenomenon of rapid clearance of human senescent fibroblasts implanted into SCID mice, which can be overcome when SCs were embedded into alginate beads preventing them from immunocyte attack. To identify putative SC killers, we analyzed the content of cell populations in lavage and capsules formed around the SC-containing beads. One of the major cell types attracted by secretory factors of SCs was a subpopulation of macrophages characterized by p16(Ink4a) gene expression and β-galactosidase activity at pH6.0 (β-gal(pH6)), thus resembling SCs. Consistently, mice with p16(Ink4a) promoter-driven luciferase, developed bright luminescence of their peritoneal cavity within two weeks following implantation of SCs embedded in alginate beads. p16(Ink4a)/β-gal(pH6)-expressing cells had surface biomarkers of macrophages F4/80 and were sensitive to liposomal clodronate used for the selective killing of cells capable of phagocytosis. At the same time, clodronate failed to kill bona fide SCs generated in vitro by genotoxic stress. Old mice with elevated proportion of p16(Ink4a)/β-gal(pH6)-positive cells in their tissues demonstrated reduction of both following systemic clodronate treatment, indicating that a significant proportion of cells previously considered to be SCs are actually a subclass of macrophages. These observations point at a significant role of p16(Ink4a)/β-gal(pH6)-positive macrophages in aging, which previously was attributed solely to SCs. They require re-interpretation of the mechanisms underlying rejuvenating effects following eradication of p16(Ink4a)/β-gal(pH6)-positive cells and reconsideration of potential cellular target for anti-aging treatment.
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Hall
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Balan
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Anatoli S
authors.initials: AS
authors.lastname: Gleiberman
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Evguenia
authors.initials: E
authors.lastname: Strom
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Krasnov
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Virtuoso
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Rydkina
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Slavoljub
authors.initials: S
authors.lastname: Vujcic
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Balan
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Gitlin
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Leonova
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Polinsky
authors.affiliation: Everon Biosciences, Inc., Buffalo, NY 14203, USA.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Chernova
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D001616:beta-Galactosidase / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008081:Liposomes; D001616:beta-Galactosidase
keywords: chronological aging; clodronate; inflammaging; inflammation; p16INK4a; senescence-associated beta-galactosidase; senescence-associated secretory phenotype