Deprogramming senescence by genomic stabilizing molecules in vivo

Abstract

Aging is the inevitable, time-dependent, natural process in all living cells, resulting from the accumulation of cellular damage with insufficient cell repair. Global hypomethylation and Alu (B1) hypomethylation become aging indicators, which are commonly found not only in cellular aging but also in human clinical studies of age-related diseases. Much evidence indicates that Alu (B1) hypermethylation could promote both mammalian and yeast cell growth and considerably increase cell survival by reducing the susceptibility to DNA-damaging agents. Also, Box-A of high mobility group box 1 (HMGB1), a DNA chaperone protein with different roles, is reported to be a genomic stabilizing protein by promoting physiologic replication-independent endogenous DNA double-strand breaks (phy-RIND-EDSBs). Phy-RIND-EDSBs, also called youth-associated genome stabilizing DNA gaps (Youth-DNA-GAPs), are beneficial DNA gaps, releasing DNA tension to promote genomic stability. Box-A of HMGB1 protein increased cell proliferation and declined DNA damage in mammalian cells. The decrease in HMGB1 protein level results in the reduction of phy-RIND-EDSBs (Youth-DNA-GAPs) and the high frequency of DNA damage, found in aging cells. Recently, D-galactose (D-gal)-induced animal is widely used as a pre-clinical aging model, that exhibits cellular aging phenotypes and impaired aging organ functions in liver and brain, due to excessive oxidative stress. D-gal induction also contributes to systemic DNA damage accumulating in many organs as found in naturally aging. Consistently, a type 1 diabetic rat model induced by streptozotocin (STZ) is widely employed as a mimetic model for the study of diabetic wounds, which also demonstrates the defects in wound repair and the increased DNA damage. Herein, we reported that Box-A of HMGB1 treatment in D-gal-induced and naturally aging rats alleviated the age-related phenotypes; abnormal liver function parameters, a presence of senescence-associated β-galactosidase (SA-β-gal), the expressions of aging marker protein p16INK4A and p21, DNA damage marker γ-H2A.X protein in the aging rat liver. These led to the restoration the impaired aging liver functions and aging brain by showing the improved cognitive functions in two aging rat models. In addition, we also found that B1 siRNA or Box-A of HMGB1 treatment in diabetic wounds accelerate repair and demonstrated the significant decrease in DNA damage markers in the diabetic wound area. Furthermore, Box A of HMGB1 treatment in a baby porcine model, provides the important evidence of safety use in large animals, and also demonstrates an effect of growth acceleration in baby pigs. Hence, this study may show the possibility of using Box A of HMGB1 in future clinical implications. The findings in the study of Box A of HMGB1 and B1 siRNA underpin the importance of epigenetic reprogramming as a potential therapeutic target for diabetes and its complications