Integrating Bulk and Single-cell Transcriptomics to Elucidate the Role and Potential Mechanisms of Autophagy in Aging Tissue

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2024 Oct 16

PMID 39414741

Authors

Zhenhua Zhu

Linsen Li

Youqiong Ye

Qing Zhong

Affiliations

Soon will be listed here.

Abstract

Purpose: Autophagy is frequently observed in tissues during the aging process, yet the tissues most strongly correlated with autophagy during aging and the underlying regulatory mechanisms remain inadequately understood. The purpose of this study is to identify the tissues with the highest correlation between autophagy and aging, and to explore the functions and mechanisms of autophagy in the aging tissue microenvironment.

Methods: Integrated bulk RNA-seq from over 7000 normal tissue samples, single-cell sequencing data from blood samples of different ages, more than 2000 acute myeloid leukemia (AML) bulk RNA-seq, and multiple sets of AML single-cell data. The datasets were analysed using various bioinformatic approaches.

Results: Blood tissue exhibited the highest positive correlation between autophagy and aging among healthy tissues. Single-cell resolution analysis revealed that in aged blood, classical monocytes (C. monocytes) are most closely associated with elevated autophagy levels. Increased autophagy in these monocytes correlated with a higher proportion of C. monocytes, with hypoxia identified as a crucial contributing factor. In AML, a representative myeloid blood disease, enhanced autophagy was accompanied by an increased proportionof C. monocytes. High autophagy levels in monocytes are associated with pro-inflammatory gene upregulation and Reactive Oxygen Species (ROS) accumulation, contributing to tissue aging.

Conclusion: This study revealed that autophagy is most strongly correlated with aging in blood tissue. Enhanced autophagy levels in C. monocytes demonstrate a positive correlation with increased secretion of pro-inflammatory factors and elevated production of ROS, which may contribute to a more rapid aging process. This discovery underscores the critical role of autophagy in blood aging and suggests potential therapeutic targets to mitigate aging-related health issues.

References

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

Goldman D, Cutler D, Rowe J, Michaud P, Sullivan J, Peneva D . Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff (Millwood). 2013; 32(10):1698-705. PMC: 3938188. DOI: 10.1377/hlthaff.2013.0052. View

Gasek N, Kuchel G, Kirkland J, Xu M . Strategies for Targeting Senescent Cells in Human Disease. Nat Aging. 2021; 1(10):870-879. PMC: 8612694. DOI: 10.1038/s43587-021-00121-8. View

Baker D, Childs B, Durik M, Wijers M, Sieben C, Zhong J . Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530(7589):184-9. PMC: 4845101. DOI: 10.1038/nature16932. View

Zhu Y, Tchkonia T, Pirtskhalava T, Gower A, Ding H, Giorgadze N . The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015; 14(4):644-58. PMC: 4531078. DOI: 10.1111/acel.12344. View

Kennedy B, Berger S, Brunet A, Campisi J, Cuervo A, Epel E . Geroscience: linking aging to chronic disease. Cell. 2014; 159(4):709-13. PMC: 4852871. DOI: 10.1016/j.cell.2014.10.039. View

Kirkland J, Tchkonia T . Cellular Senescence: A Translational Perspective. EBioMedicine. 2017; 21:21-28. PMC: 5514381. DOI: 10.1016/j.ebiom.2017.04.013. View

Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland J . Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013; 123(3):966-72. PMC: 3582125. DOI: 10.1172/JCI64098. View

Kirkland J, Tchkonia T . Clinical strategies and animal models for developing senolytic agents. Exp Gerontol. 2014; 68:19-25. PMC: 4412760. DOI: 10.1016/j.exger.2014.10.012. View

10.

Yang Z, Klionsky D . Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2009; 22(2):124-31. PMC: 2854249. DOI: 10.1016/j.ceb.2009.11.014. View

11.

Zhong Y, Wang Q, Li X, Yan Y, Backer J, Chait B . Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol. 2009; 11(4):468-76. PMC: 2664389. DOI: 10.1038/ncb1854. View

12.

Huang F, Wang B, Wang Y . Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. World J Gastroenterol. 2018; 24(41):4643-4651. PMC: 6224467. DOI: 10.3748/wjg.v24.i41.4643. View

13.

Nieto-Torres J, Hansen M . Macroautophagy and aging: The impact of cellular recycling on health and longevity. Mol Aspects Med. 2021; 82:101020. PMC: 8671213. DOI: 10.1016/j.mam.2021.101020. View

14.

Kang C, Elledge S . How autophagy both activates and inhibits cellular senescence. Autophagy. 2016; 12(5):898-9. PMC: 4854549. DOI: 10.1080/15548627.2015.1121361. View

15.

Rovira M, Sereda R, Pladevall-Morera D, Ramponi V, Marin I, Maus M . The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging Cell. 2022; 21(10):e13707. PMC: 9577959. DOI: 10.1111/acel.13707. View

16.

Beauvarlet J, Bensadoun P, Darbo E, Labrunie G, Rousseau B, Richard E . Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells. Nucleic Acids Res. 2019; 47(6):2739-2756. PMC: 6451122. DOI: 10.1093/nar/gkz095. View

17.

Hao X, Shiromoto Y, Sakurai M, Towers M, Zhang Q, Wu S . ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16 levels. Nat Cell Biol. 2022; 24(8):1202-1210. PMC: 9757154. DOI: 10.1038/s41556-022-00959-z. View

18.

Abdellatif M, Rainer P, Sedej S, Kroemer G . Hallmarks of cardiovascular ageing. Nat Rev Cardiol. 2023; 20(11):754-777. DOI: 10.1038/s41569-023-00881-3. View

19.

Zhu H, Li Q, Liao T, Yin X, Chen Q, Wang Z . Metabolomic profiling of single enlarged lysosomes. Nat Methods. 2021; 18(7):788-798. DOI: 10.1038/s41592-021-01182-8. View

20.

Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D . Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11(11):1305-14. DOI: 10.1038/ncb1975. View