Intracellular protons accelerate aging and switch on aging hallmarks in mice

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 F_o 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.