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

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.

SUBMITTER: Shyu YC

PROVIDER: S-EPMC9443461 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Shyu Yu-Chiau YC Liao Po-Cheng PC Huang Ting-Shou TS Yang Chun-Ju CJ Lu Mu-Jie MJ Huang Shih-Ming SM Lin Xin-Yu XY Liou Cai-Cin CC Kao Yu-Hsiang YH Lu Chi-Huan CH Peng Hui-Ling HL Chen Jim-Ray JR Cherng Wen-Jin WJ Yang Ning-I NI Chen Yung-Chang YC Pan Heng-Chih HC Jiang Si-Tse ST Hsu Chih-Chin CC Lin Gigin G Yuan Shin-Sheng SS Hsu Paul Wei-Che PW Wu Kou-Juey KJ Lee Tung-Liang TL Shen Che-Kun James CJ

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220713 25

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<sup ...[more]

PMID: 35822667

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Project description:ObjectiveThe gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates beta cell function and improves glycemia through its incretin actions. GIP also regulates endothelial function and suppresses adipose tissue inflammation through control of macrophage activity. Activation of the GIP receptor (GIPR) attenuates experimental atherosclerosis and inflammation in mice, however whether loss of GIPR signaling impacts the development of atherosclerosis is uncertain.MethodsAtherosclerosis and related metabolic phenotypes were studied in Apoe-/-:Gipr-/- mice and in Gipr+/+ and Gipr-/- mice treated with an adeno-associated virus expressing PCSK9 (AAV-PCSK9). Bone marrow transplantation (BMT) studies were carried out using donor marrow from Apoe-/-:Gipr-/-and Apoe-/-:Gipr+/+mice transplanted into Apoe-/-:Gipr-/- recipient mice. Experimental endpoints included the extent of aortic atherosclerosis and inflammation, body weight, glucose tolerance, and circulating lipid levels, the proportions and subsets of circulating leukocytes, and tissue gene expression profiles informing lipid and glucose metabolism, and inflammation.ResultsBody weight was lower, circulating myeloid cells were reduced, and glucose tolerance was not different, however, aortic atherosclerosis was increased in Apoe-/-:Gipr-/- mice and trended higher in Gipr-/- mice with atherosclerosis induced by AAV-PCSK9. Levels of mRNA transcripts for genes contributing to inflammation were increased in the aortae of Apoe-/-:Gipr-/- mice and expression of a subset of inflammation-related hepatic genes were increased in Gipr-/- mice treated with AAV-PCSK9. BMT experiments did not reveal marked atherosclerosis, failing to implicate bone marrow derived GIPR + cells in the control of atherosclerosis or aortic inflammation.ConclusionsLoss of the Gipr in mice results in increased aortic atherosclerosis and enhanced inflammation in aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings extend concepts of GIPR in the suppression of inflammation-related pathophysiology beyond its classical incretin role in the control of metabolism.

Dataset Information

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

Publications

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

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