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Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians
Abstract
Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB , ATP6V0C , ATG4D , and WIPI1 , could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1 , Atg18a , extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.
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No significant changes were observed in transcriptional markers of the TFEB/TFE3 axis and lysosomal degradation, such as ATG7, ATG14, WIPI1, ULK1, ULK2, or SQSTM1.
“No significant changes were observed in transcriptional markers of this pathway, such as ATG7, ATG14, WIPI1, ULK1, ULK2, or SQSTM1 [44], supporting the interpretation that lysosomal biogenesis was not enhanced after R55 treatment.”
From Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model (2025) · cites this paper as [44]
The Results section on overexpression of autophagy-lysosomal genes identifies WIPI1 as an autophagosome component and SQSTM1 as a marker of autophagic degradation. The paper does not establish that the listed genes showed no significant transcriptional changes, nor does it assess their response to R55 treatment; its centenarian comparison instead reports up-regulation of autophagy-lysosomal genes. (LLM, conf=0.78)
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Metadata
- Authors
- Xiao, F.-H., Chen, X.-Q., Yu, Q., Ye, Y., Liu, Y.-W., Yan, D., Yang, L.-Q., Chen, G., Lin, R., Yang, L., Liao, X., Zhang, W., Zhang, W., Tang, N. L.-S., Wang, X.-F., Zhou, J., Cai, W.-W., He, Y.-H., & Kong, Q.-P.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2018-10-23
- Volume
- 28
- Issue
- 11
- Pages
- 1601-1610
- ISSN
- 1088-9051
- 1549-5469
- PMC
- PMC6211641
- Cited by
- 55
- References
- 13
- Language
- en
- Funders
- Key Research Program of Frontier Sciences (QYZDB-SSW-SMC020)
- International Partnership Program (152453KYSB20160006)
- Chinese Academy of Sciences
- National Natural Science Foundation of China (81671404, 81500670, 31460290, 81701394, 91749109, 81471966, 81672040, U1602226)
- National Program on Key Research and Development Project (2016YFA0100900)
- Yunnan Applied Basic Research Project (2017FA038, 2018FB121)
- State Key Laboratory of Genetic Resources and Evolution (GREKF16-10)
- Department of Science and Technology of Hainan Province (KJHZ2013-16)
- Youth Innovation Promotion Association of Chinese Academy of Sciences
- West Light Foundation of the Chinese Academy of Sciences
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