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-galpH6), 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-galpH6-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-galpH6-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-galpH6-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-galpH6-positive cells and reconsideration of potential cellular target for anti-aging treatment.
Highlights
Understanding the underlying causes of aging in mammals is a prerogative for the rational development of prophylaxis and treatment of this condition and extension of healthy life
Initial development of www.impactaging.com this model involved generating reporter cells of human neonatal dermal fibroblast (NDF) expressing secreted Gaussia luciferase (GLuc), allowing for cell survival to be monitored in vivo via measurement of GLuc activity from collected plasma [43,44]
Mice implanted with quiescent and senescent NDFs exhibited a similar decrease in GLuc signal from plasma up to day 7 postinjection, where 30% of GLuc activity remained compared to the activity observed 24 hours after initial cell implantation
Summary
Understanding the underlying causes of aging in mammals is a prerogative for the rational development of prophylaxis and treatment of this condition and extension of healthy life. Accumulation of p16(Ink4a)-positive cells in tissues of mice occurs with age, and their pharmacological eradication was associated with changes in phenotype consistent with a reduction of biological age and increased longevity in mice genetically prone to accelerated aging [21] or in wild type mice [23], respectively. Eradication of p16(Ink4a)positive cells was accompanied by the reduction in the proportion of cells within tissues, fat, that express β-galpH6 – one of a few histologically applicable markers of SCs [24]. Accumulation of p16(Ink4a)/β-galpH6-positive cells with age, along with a simultaneous increase of inflammatory factors in tissues was convincingly interpreted as pro-aging activity of SCs
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