Abstract 12831: Coupling Factor 6 Accelerates Aging by Synchronizing Primary Aging Hallmarks Such as Telomere Attrition and a Blocking Effect of Atpase Inhibitory Factor 1
Introduction: A transient low pH stressor gives great impacts to the nucleus, but little is known about the effect of chronic pH stressor on aging and lifespan. We identified that coupling factor 6 (CF6) induces long-term low pH in the cells by enhanced proton import through ecto-F1Fo complex and by reduced proton export through inhibition of Na+-K+ ATPase. We analyzed whether and how CF6-induced acidosis affects aging and lifespan, being focused on primary aging hallmarks of genomic instability, telomere attrition, epigenetic alterations, and defective proteostasis.
Methods and Results: CF6 overexpressing transgenic mice (TG, n=20) manifested early senescence-associated phenotypes such as signs of hair graying and sparseness, resulting in shortened lifespan compared with wild-type mice (WT, n=13) (median values; 108±2 vs 131±11 weeks, p<0.05). Long-term low pH disturbed nuclear envelope protein emerin as genomic instability and elevated aging-associated markers of global hypo-methylated DNA, histone 3 lysine 4 (H3K4) and H4K20 trimethylation, and H4K5 acetylation by decreased nucleoplasmic HDAC3, a binding partner of emerin. Leukocyte telomere length was shorter in TG compared with WT at the age of 100 weeks. Microarray analysis showed that a target molecule of three primary hallmarks was autophagy-related Atg7 that is commonly decreased in TG tissues. Chronic acidosis decreased and acetylated Atg7 protein in the TG heart and kidney without affecting insulin signaling. In TG cells, LC3 II and lysosome were located more weakly and diffusely in the cytoplasm compared with strong peri-nuclear staining in WT, being dependent on acetylation of LC3 II that inhibits cytoplasmic translocation. ATPase inhibitory factor 1 (IF1), an endogenous inhibitor for CF6, repaired subcellular localization of LC3 II and lamp1, and restored the decrease in Atg7 and emerin and the increase in H4K5ac. ChIP assay revealed that PCR in the repressor-binding region of Atg7 promoter at -441 through -763 was increased by CF6 after immuneprecipitated with anti-acetyl H4K5, anti-trimethyl H3K4, and H4K20 antibodies.
Conclusions: Long-term low pH switches on aging by onset and synchronization of primary aging hallmarks, and provides a novel target for anti-aging therapy.
Author Disclosures: T. Osanai: None. M. Tanaka: None. H. Tomita: None. A. Kobayashi: None. K. Okumura: None.
- © 2016 by American Heart Association, Inc.