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 Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/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 Klf1K74R/K74R mice extends the lifespan of the wild‐type mice. The Klf1K74R/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.

Long-term Hematopoietic Transfer of the Anti-Cancer and Lifespan-Extending Capabilities of A Genetically Engineered Blood System by Transplantation of Bone Marrow Mononuclear Cells

“…Secondly, homozygosity of the K74R substitution was required for the higher cancer resistance of the Eklf(K74R) mice (Figure S1). Consistent with the previous study 21 , the Eklf(K74R) mice survived longer than the WT mice after the injection of B16-F10 cells.…”

“…The lower expression of ICGs would contribute to the anti-cancer capabilities of the Eklf(K74R) blood to fight against cancer (Figures. 1, 2, and 3) and to extension of the lifespan of cancer-bearing mice 21 . Given that EKLF is expressed in HSCs 16 , B cells, T cells 12 , NK cells and macrophages (bio-GPS database), and that RNAi knockdown of Eklf expression significantly reduced Pd-1 and Pd-l1 mRNA levels in splenic CD3 + T cells (Figure 4C), we assert that this protein is an upstream transcriptional regulator of the Pd-1 and Pd-l1 genes and, more generally, it regulates the transcriptomes of a diverse range of hematopoietic cells.…”

“…The anti-cancer capability of the Eklf(K74R) mice have rendered them relatively free from spontaneous cancer occurrence 21 , which is also reflected by their resistance to tumorigenesis of the B16-F10 cells and LLC1 cells in the cancer-growth inhibition assay 21 (Figures. 1 and 3).…”

“…Also, WT mice receiving BMMNC at 2-month-old Eklf(K74R) mice would live longer than those receiving WT BMMNC (Figure S2B). In interesting parallel, infusion of HSC(K74R) could extend the life span of aged WT recipient mice 21 . Hematopoietic stem cell remix, or adapt this material for any purpose without crediting the original authors.…”

“…The K74R substitution did not alter the expression levels of EKLF in the bone marrow, fetal liver 21 and the PB cells (Figure S1D), neither did it affect much the PB populations as shown by CBC analysis 21 . We further analyzed the PB populations by flow cytometry of WT and Eklf(K74R) mice of the ages 3 and 24 months, respectively.…”