Elimination of p19ARF-expressing cells enhances pulmonary function in mice
Michihiro Hashimoto, Azusa Asai, Hiroyuki Kawagishi, Ryuta Mikawa, Yuji Iwashita, Kazuki Kanayama, Kazushi Sugimoto, Tadashi Sato, Mitsuo Maruyama, Masataka Sugimoto
Michihiro Hashimoto, Azusa Asai, Hiroyuki Kawagishi, Ryuta Mikawa, Yuji Iwashita, Kazuki Kanayama, Kazushi Sugimoto, Tadashi Sato, Mitsuo Maruyama, Masataka Sugimoto
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Research Article Aging Cell biology

Elimination of p19ARF-expressing cells enhances pulmonary function in mice

Abstract

Senescent cells accumulate in many tissues as animals age and are considered to underlie several aging-associated pathologies. The tumor suppressors p19ARF and p16INK4a, both of which are encoded in the CDKN2A locus, play critical roles in inducing and maintaining permanent cell cycle arrest during cellular senescence. Although the elimination of p16INK4a-expressing cells extends the life span of the mouse, it is unclear whether tissue function is restored by the elimination of senescent cells in aged animals and whether and how p19ARF contributes to tissue aging. The aging-associated decline in lung function is characterized by an increase in compliance as well as pathogenic susceptibility to pulmonary diseases. We herein demonstrated that pulmonary function in 12-month-old mice was reversibly restored by the elimination of p19ARF-expressing cells. The ablation of p19ARF-expressing cells using a toxin receptor-mediated cell knockout system ameliorated aging-associated lung hypofunction. Furthermore, the aging-associated gene expression profile was reversed after the elimination of p19ARF. Our results indicate that the aging-associated decline in lung function was, at least partly, attributed to p19ARF and was recovered by eliminating p19ARF-expressing cells.

Authors

Michihiro Hashimoto, Azusa Asai, Hiroyuki Kawagishi, Ryuta Mikawa, Yuji Iwashita, Kazuki Kanayama, Kazushi Sugimoto, Tadashi Sato, Mitsuo Maruyama, Masataka Sugimoto

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Figure 2

A luciferase signal was detected in 12-month-old ARF-DTR transgenic mice.

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A luciferase signal was detected in 12-month-old ARF-DTR transgenic mice...
(A) D-luciferin (150 mg/kg body weight) was injected intraperitoneally into 2- or 12-month-old female ARF–diphtheria toxin receptor (ARF-DTR) or 12-month-old female wild-type mice. Ten minutes after the injection of luciferin, an in vivo imaging analysis was performed in order to detect luminescence with a 3-minute exposure. Mice were shaved before the injection. (B) Total RNA was extracted from wild-type mouse lung and perigonadal adipose tissues at the indicated ages. ARF and INK4a mRNA levels were analyzed by real-time PCR and normalized to that of 18S rRNA. Values represent mean ± SEM of at least 3 independent experiments. (C) Luciferase activity was monitored in 12-month-old female ARF-DTR mice before (left) and 2 days (right) after an intraperitoneal injection of diphtheria toxin (DT). Signals in the red circle indicate lung tissue luciferase activity. (D) Luciferin was injected intraperitoneally into 12-month-old female ARF-DTR mice treated or untreated with DT for 3 days. Ten minutes later, mice were sacrificed and subjected to laparotomy, and in vivo luciferase activity was analyzed. A light image (left) and superimposed image (right) are shown. Lu, lung; Ad, adipose tissue. Representative images of 3 independent experiments are shown.