Aging of mice is associated with p16(Ink4a)- and ß-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells.
Aging (Albany NY)
; 8(7): 1294-315, 2016 07.
Article
in En
| MEDLINE
| ID: mdl-27391570
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 ß-galactosidase activity at pH6.0 (ß-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)/ß-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)/ß-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)/ß-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)/ß-gal(pH6)-positive cells and reconsideration of potential cellular target for anti-aging treatment.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Aging
/
Cellular Senescence
/
Beta-Galactosidase
/
Cyclin-Dependent Kinase Inhibitor p16
/
Macrophages
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
Aging (Albany NY)
Journal subject:
GERIATRIA
Year:
2016
Document type:
Article
Affiliation country:
United States
Country of publication:
United States