Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice

Yu-Chiau Shyu; Po-Cheng Liao; Ting-Shou Huang; Chun-Ju Yang; Mu-Jie Lu; Shih-Ming Huang; Xin-Yu Lin; Cai-Cin Liou; Yu-Hsiang Kao; Chi-Huan Lu; Hui-Ling Peng; Jim-Ray Chen; Wen-Jin Cherng; Ning-I Yang; Yung-Chang Chen; Heng-Chih Pan; Si-Tse Jiang; Chih-Chin Hsu; Gigin Lin; Shin-Sheng Yuan; Paul Wei-Che Hsu; Kou-Juey Wu; Tung-Liang Lee; Che-Kun James Shen

doi:10.1002/advs.202201409

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice

Adv Sci (Weinh). 2022 Sep;9(25):e2201409. doi: 10.1002/advs.202201409. Epub 2022 Jul 13.

Authors

Yu-Chiau Shyu^{1

2}, Po-Cheng Liao¹, Ting-Shou Huang^{1

3

4}, Chun-Ju Yang¹, Mu-Jie Lu¹, Shih-Ming Huang⁵, Xin-Yu Lin¹, Cai-Cin Liou¹, Yu-Hsiang Kao¹, Chi-Huan Lu¹, Hui-Ling Peng¹, Jim-Ray Chen⁶, Wen-Jin Cherng⁷, Ning-I Yang⁸, Yung-Chang Chen^{9

10}, Heng-Chih Pan¹, Si-Tse Jiang^{3

11}, Chih-Chin Hsu^{10

12}, Gigin Lin^{13

14

15}, Shin-Sheng Yuan¹⁶, Paul Wei-Che Hsu¹⁷, Kou-Juey Wu¹⁸, Tung-Liang Lee^{19

20}, Che-Kun James Shen^{20

21}

Affiliations

¹ Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung branch, Keelung, 204, Taiwan.
² Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan.
³ Department of General Surgery, Chang Gung Memorial Hospital, Keelung branch, Keelung, 204, Taiwan.
⁴ School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
⁵ Department of Radiation Oncology, Chung-Gung Memorial Hospital, Keelung branch, Keelung, 204, Taiwan.
⁶ Department of Pathology, Chang Gung Memorial Hospital, Keelung branch, Keelung, 204, Taiwan.
⁷ Department of Cardiology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, 333, Taiwan.
⁸ Department of Cardiology, Chang Gung Memorial Hospital, Keelung branch, Keelung, 204, Taiwan.
⁹ Department of Nephrology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, 333, Taiwan.
¹⁰ Department of Medicine, School of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
¹¹ Department of Research and Development, National Laboratory Animal Center, Tainan, 741, Taiwan.
¹² Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital Keelung branch, Keelung, 204, Taiwan.
¹³ Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, 333, Taiwan.
¹⁴ Clinical Metabolomics Core Lab, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, 333, Taiwan.
¹⁵ Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, 333, Taiwan.
¹⁶ Institute of Statistical Science, Academia Sinica, Taipei, 115, Taiwan.
¹⁷ Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, 350, Taiwan.
¹⁸ Cancer Genome Research Center, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, 333, Taiwan.
¹⁹ Pro-Clintech Co. Ltd., Keelung, 204, Taiwan.
²⁰ Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan.
²¹ Ph.D. Program in Medical Neuroscience, Taipei Medical University, Taipei, 110, Taiwan.

Abstract

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1^K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1^K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8⁺ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1^K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1^K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Keywords: KLF1/EKLF; SUMOylation; aging; antiaging; hematopoietic stem cells (HSCs).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Hematopoietic Stem Cells
Longevity* / genetics
Mice
Sumoylation*

Abstract

Publication types

MeSH terms

Grants and funding