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 4

Downregulation of senescence genes by eliminating p19ARF-expressing cells.

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Downregulation of senescence genes by eliminating p19ARF-expressing cell...
(A) Experimental design. Twelve-month-old female wild-type or ARF–diphtheria toxin receptor (ARF-DTR) mice were intraperitoneally injected with diphtheria toxin (DT) or PBS twice with a 2-week interval. Two weeks after the second DT injection, mice were sacrificed and their lungs were analyzed. (B) Luciferase signals in the lung area were measured in ARF-DTR mice using Living Image in vivo imaging software. Values represent the mean ± SEM of independent experiments. (C and D) Total RNA was extracted from the lungs of 2-month-old and 12-month-old female ARF-DTR mice treated with DT or not treated for 4 weeks (C) or 12-month-old wild-type mice treated or not treated with DT for 4 weeks (D). The expression of ARF, INK4a, and p21 was analyzed by real-time PCR. mRNA levels were normalized to GAPDH in each mouse. Values represent the mean ± SEM of independent experiments. Data were analyzed 1-way ANOVA followed by post-hoc Tukey-Kramer multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001.