TY - JOUR
T1 - Suppression of autophagic activity by Rubicon is a signature of aging
AU - Nakamura, Shuhei
AU - Oba, Masaki
AU - Suzuki, Mari
AU - Takahashi, Atsushi
AU - Yamamuro, Tadashi
AU - Fujiwara, Mari
AU - Ikenaka, Kensuke
AU - Minami, Satoshi
AU - Tabata, Namine
AU - Yamamoto, Kenichi
AU - Kubo, Sayaka
AU - Tokumura, Ayaka
AU - Akamatsu, Kanako
AU - Miyazaki, Yumi
AU - Kawabata, Tsuyoshi
AU - Hamasaki, Maho
AU - Fukui, Koji
AU - Sango, Kazunori
AU - Watanabe, Yoshihisa
AU - Takabatake, Yoshitsugu
AU - Kitajima, Tomoya S.
AU - Okada, Yukinori
AU - Mochizuki, Hideki
AU - Isaka, Yoshitaka
AU - Antebi, Adam
AU - Yoshimori, Tamotsu
N1 - Funding Information:
We thank Prof. Dr. Hansen and Dr. Kumsta (Sanford-Burnham Medical Research Institute) for let-363/TOR RNAi clone, bafilomycin injection protocol and MAH215 strain. We thank Prof. Grant for providing hTFR::GFP transgenic worms. Many thanks to C. elegans Genetic Center (CGC) at the University of Minnesota. S.N. is supported by AMED-PRIME (17gm6110003h0001), JSPS KAKENHI, the Senri Life Science Foundation, the Takeda Science Foundation, the Nakajima Foundation, and the MSD Life Science Foundation. M.S. is supported by JSPS KAKENHI and the Ichiro Kanehara Foundation. T.Y. is supported by AMED under grant number JP17gm5010001 and JP17gm0610005, MEXT/JSPS KAKENHI, JST CREST (JPMJCR17H6) and HFSP grant.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several organisms, but the underlying mechanism is unclear. Here, we show that the expression of Rubicon, a negative regulator of autophagy, increases in aged worm, fly and mouse tissues at transcript and/or protein levels, suggesting that an age-dependent increase in Rubicon impairs autophagy over time, and thereby curtails animal healthspan. Consistent with this idea, knockdown of Rubicon extends worm and fly lifespan and ameliorates several age-associated phenotypes. Tissue-specific experiments reveal that Rubicon knockdown in neurons has the greatest effect on lifespan. Rubicon knockout mice exhibits reductions in interstitial fibrosis in kidney and reduced α-synuclein accumulation in the brain. Rubicon is suppressed in several long-lived worms and calorie restricted mice. Taken together, our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging.
AB - Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several organisms, but the underlying mechanism is unclear. Here, we show that the expression of Rubicon, a negative regulator of autophagy, increases in aged worm, fly and mouse tissues at transcript and/or protein levels, suggesting that an age-dependent increase in Rubicon impairs autophagy over time, and thereby curtails animal healthspan. Consistent with this idea, knockdown of Rubicon extends worm and fly lifespan and ameliorates several age-associated phenotypes. Tissue-specific experiments reveal that Rubicon knockdown in neurons has the greatest effect on lifespan. Rubicon knockout mice exhibits reductions in interstitial fibrosis in kidney and reduced α-synuclein accumulation in the brain. Rubicon is suppressed in several long-lived worms and calorie restricted mice. Taken together, our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging.
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U2 - 10.1038/s41467-019-08729-6
DO - 10.1038/s41467-019-08729-6
M3 - Article
C2 - 30783089
AN - SCOPUS:85061766688
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 847
ER -