Intracellular protons accelerate aging and switch on aging hallmarks in mice

• Published in: Journal of cellular biochemistry Vol. 119; no. 12; pp. 9825 - 9837
• Main Authors: Osanai, Tomohiro, Tanaka, Makoto, Izumiyama, Kei, Mikami, Kasumi, Kitajima, Maiko, Tomisawa, Toshiko, Magota, Koji, Tomita, Hirofumi, Okumura, Ken
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2018
• Subjects: Acetylation; Acidosis; Aging; Alopecia; ATP synthase; Autophagy; Bicarbonates; Body weight loss; Bone turnover; coupling factor 6; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Epigenetics; genomic instability; Heterochromatin; Histone deacetylase; Hypertension; Intracellular; intracellular acidosis; Kidney diseases; Kidneys; Life span; Lysine; Metabolic acidosis; Metabolism; Methylation; Mice; Na+/K+-exchanging ATPase; Phagocytosis; Phenotypes; Proteins; Protons; Regression analysis; salt; Salts; Senescence; Weight loss; ATP synthase; autophagy; salt; coupling factor 6; aging; intracellular acidosis; genomic instability; epigenetics
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27302

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‐F1Fo 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.