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J Cell Biochem. 2018 Dec;119(12):9825-9837. doi: 10.1002/jcb.27302. Epub 2018 Aug 20.

Intracellular protons accelerate aging and switch on aging hallmarks in mice.

Author information

1
Department of Nursing Science, Hirosaki University Graduate School of Health Science, Hirosaki, Japan.
2
Department of Hypertension and Stroke Internal Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
3
Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
4
Daiichi Sankyo Co, Ltd, Biologics Technology Research Laboratories Group 1, Pharmaceutical Technology Division, Gunma, Japan.
5
Saiseikai Kumamoto Hospital, Division of Cardiology, Kumamoto, Japan.

Abstract

Diet-induced metabolic acidosis is associated with the impairment of bone metabolism and an increased risk of a number of chronic noncommunicable diseases, such as type 2 diabetes mellitus and hypertension. The serum bicarbonate level is an independent predictor of chronic kidney disease progression. We investigated whether proton accelerates aging by analyzing both coupling factor 6-overexpressing transgenic (TG) and high salt-fed mice which display sustained intracellular acidosis, due to enhanced proton import through ecto-F1 Fo complex and/or reduced proton export through Na+ -K+ ATPase inhibition. Both types of mice displayed shortened lifespan and early senescence-associated phenotypes such as signs of hair greying and alopecia, weight loss, and/or reduced organ mass. In chronic intracellular acidosis mice, autophagy was impaired by regression of Atg7, an increase in nuclear acetylated LC3 II, and acetylation of Atg7. The increase in histone 3 trimethylation at lysine 4 (H3K4me3) and H4K20me3 and the decrease in H3K9me3 and H3K27me3 were observed in the heart and kidney obtained from both TG and high salt-fed mice. The decrease in lamin A/C, emerin, and heterochromatin protein 1α without changes in barrier-to-autointegration factor and high-mobility group box 1 was confirmed in TG and high salt-fed mice. Suppression of nuclear histone deacetylase 3-emerin system is attributable to epigenetic regression of Atg7 and H4K5 acetylation. These findings will shed light on novel aging and impaired autophagy mechanism, and provide implications in a target for antiaging therapy.

KEYWORDS:

ATP synthase; aging; autophagy; coupling factor 6; epigenetics; genomic instability; intracellular acidosis; salt

PMID:
30129099
DOI:
10.1002/jcb.27302

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