p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli

Abstract

Constitutive p16Ink4a expression, along with senescence-associated β-galactosidase (SAβG), are commonly accepted biomarkers of senescent cells (SCs). Recent reports attributed improvement of the healthspan of aged mice following p16Ink4a-positive cell killing to the eradication of accumulated SCs. However, detection of p16Ink4a/SAβG-positive macrophages in the adipose tissue of old mice and in the peritoneal cavity of young animals following injection of alginate-encapsulated SCs has raised concerns about the exclusivity of these markers for SCs. Here we report that expression of p16Ink4a and SAβG in macrophages is acquired as part of a physiological response to immune stimuli rather than through senescence, consistent with reports that p16Ink4a plays a role in macrophage polarization and response. Unlike SCs, p16Ink4a/SAβG-positive macrophages can be induced in p53-null mice. Macrophages, but not mesenchymal SCs, lose both markers in response to M1- [LPS, IFN-α, Poly(I:C)] and increase their expression in response to M2-inducing stimuli (IL-4, IL-13). Moreover, interferon-inducing agent Poly(I:C) dramatically reduced p16Ink4a expression in vivo in our alginate bead model and in the adipose tissue of aged mice. These observations suggest that the antiaging effects following eradication of p16Ink4a-positive cells may not be solely attributed to SCs but also to non-senescent p16Ink4a/SAβG-positive macrophages.

Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

“…2C). The residual p53 expression in Adipoq-p53iKO mice may reflect the reported increases of p53 in adipose progenitor cells, macrophages, and endothelial cells (26,35,36), which are not affected by Adipoq promoter-driven Cre expression in differentiated adipocytes (38). RT-qPCR also confirmed reduced expression levels of known p53 target genes [Cdkn1a (or p21), Tigar, and Bax] in aged iWAT of Adipoq-p53iKO mice, compared to the control (Fig.…”

“…Like the WAT, p53 also increased in interscapular brown adipose tissue (iBAT; data not shown). It has been reported that p53 expression increases in macrophages and endothelial cells in aged tissues (35,36). To confirm p53 increased in adipocytes of aged iWAT/eWAT, we isolated SVF from iWAT of young and aged mice and examined p53 expression in cultured adipocytes differentiated in vitro.…”

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…Macrophages have been reported to express high levels of p16 INK4a and senescent‐associated β ‐galactosidase activity (Hall et al, 2017). Although p19 ARF expression in macrophages has not been documented, and no luciferase activity was detected in the BALF cells of ARF‐DTR mice (Hashimoto et al, 2016), it is still possible that DT acted through the macrophage depletion in PPE‐treated ARF‐DTR mice.…”

Measuring biological aging in humans: A quest

“…Conditions that trigger senescence include genomic instability, extreme telomere shortening, metabolic and proteostatic stress, reactive oxidative species (ROS), oncogene activation, mitochondrial dysfunction, epigenetic changes, and other mechanisms that have not been fully clarified (Childs, Durik, Baker, & van Deursen, ; Childs et al, ; López‐Otín et al, ). In general, these conditions trigger a response that activates the tumor suppressor genes p53, p16 Ink4a , and p21 that utilize different pathways to induce cell cycle arrest (Hall et al, ; Liu et al, ). Most studies indicate that senescence‐induced replication arrest acts as a tumor suppression mechanism, but other physiological roles are emerging, including fetal organ development, wound healing, and aging (Baker & Petersen, ; Pratsinis, Mavrogonatou, & Kletsas, ; Wiley & Campisi, ; Zhang, Chen, Liu, Chen, & Liu, ).…”