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AimCardiac aging, which causes cardiac diastolic dysfunction, frequently occurs in older people. The role of autophagy in cardiac aging is the subject of intensive research. Autophagy comprises steps called the autophagosome formation and autophagosome–lysosome fusion. Caloric restriction (CR) is the gold standard used to induce autophagosome formation, and autophagosome–lysosome fusion is reduced by aging. However, few studies are available that survey and compare signaling during CR (autophagosome formation induced status) and old (potentially autophagosome–lysosome fusion‐reduced status). Here we aimed to identify the rate‐limiting step of autophagic disorders during cardiac aging.MethodsWe employed bioinformatics to analyze publicly available DNA microarray datasets. The first dataset compared the hearts of young and old C57BL6 mice (OLD). The second dataset compared the hearts of young C57BL6 mice fed a normal diet with those of young C57BL6 mice subjected to CR.ResultsWe analyzed OLD‐upregulated genes that were significantly associated with the Gene Ontogeny term “Autophagy,” indicating that autophagic genes were upregulated in OLD mice. The autophagy‐related gene Atg5 and Atg5‐related genes were upregulated in OLD and CR mice. The identified hub and bottleneck genes are autophagic autophagosome formation suppressors such as Sirt2, Ilk and Islr, as well as the autophagosome–lysosome fusion inducer Snapin.ConclusionsAutophagosome formation genes were upregulated in aging mice subjected to CR, indicating that an upregulated autophagosome formation is not a change specific to cardiac aging. However, autophagosome–lysosome fusion genes, particularly the lysosome transportation‐related gene Snapin, were downregulated in aging, indicating that autophagosome–lysosome fusion may cause autophagic disorders in cardiac aging. Geriatr Gerontol Int 2021; 21: 108–115.

Background: Autophagy may contribute to the maintenance of atrial fibrillation (AF), but no previous study has concurrently surveyed all 3 phases of autophagy, namely autophagosome formation, lysosome formation, and autophagosome-lysosome fusion. Here we aimed to identify disorders involving various phases of autophagy during AF. Methods and Results: We used bioinformatic techniques to analyze publicly available DNA microarray datasets from the left atrium (LA) and right atrium (RA) of 7 patients with AF and 6 patients with normal sinus rhythm who underwent valvular surgeries. We compared gene expression levels in the LA (AF-LA) and RA of patients with AF with those in the LA and RA of patients with normal sinus rhythm. Several differentially expressed genes in the AF-LA sample were significantly associated with the Gene Ontogeny term ‘Autophagy’, indicating that the expression of autophagic genes was specifically altered in this dataset. In particular, the expression of genes known or suspected to be involved in autophagosome formation (autophagy related 5 [ ATG5 ], autophagy related 10 [ ATG10 ], autophagy related 12 [ ATG12 ], and light chain 3B [ LC3B ]), lysosome formation (lysosomal associated membrane protein 1 [ LAMP1 ] and lysosomal associated membrane protein 2 [ LAMP2 ]), and autophagosome-lysosome fusion (synaptosome associated protein 29 [ SNAP29 ], SNAP associated protein [ SNAPIN ], and syntaxin 17 [ STX17 ]) was significantly upregulated in the LA-AF dataset. Conclusions: Autophagy is activated excessively in, and may perpetuate, AF.

rier, 11 and dysfunction of the perivascular metabolite clearance system, 12 all of which are pathomechanistically related to reduced pulsation of the cerebral arterioles. 13,14 Previously, our group reported that left ventricular (LV) diastolic dysfunction, even without heart failure (HF), is associated with WMH, which, in turn, has been shown to be closely associated with cognitive decline in elderly patients without ischemic heart disease or stroke. 15 Similarly, Kokubo et al reported that higher night-time systolic blood pressure (BP) levels contribute to greater WMH volumes in older adults with hypertension. 16 However, both these studies were cross-sectional and did not investigate the

Background/Introduction Aging is known to be one of the primary causes of heart failure. Werner syndrome is one of the aging disorder that caused by dysfunction of DNA helicase-regulatory protein (WRN). However, there is little information whether WRN may cause any specific myocardial remodeling and vulnability for heart failure. More interestingly, ample evidences demonstrated DNA damage occurred in progeria causes autophagic disorder, contributing to aging phenotype, in short, autophagy may be a guardian of the genome. Although autophagic disorder has been implicated to cause cardiac remodeling in heart failure; however, it remains uncertain whether autophagic disorder may link to the mechanism of aging-induced cardiac remodeling. Purpose To elucidate whether autophagic disorder may be mechanistically responsible for cardiac aging we hypothesized whether aging-related DNA injury may affect autophagy that may lead to myocardial remodeling. Methods We employed progeria mouse model harboring amino acid (AA) substitution of WRN at position 577 (WRN-K577M), which were evaluated in terms of cardiac function and remodeling at the phase of adult (18 week-old). Results WRN-K577M exhibited diffuse left-ventricular (LV) hypertrophy, enhanced fibrosis, and diastolic LV dysfunction with preserved systolic ejection fraction. DNA microarray analysis of WRN-K577M heart revealed that the 253 genes were upregulated compared to age- and gender-matched wild-type counterpart. Sixteen genes were increased >4 fold higher than wild-type as follows: hypertrophy (Myh7, Klkb11), fibrosis (Fgf21, CTGF), inflammatory molecules (Ap1s3, Pla2g2e, Has1, MMP9), and oxidative stress (catalase). Cardiac aging markers (PARP-1, p53 and γH2AX) increased in heart of WRN-K577M with concomitant increase in oxidative stress (DHE staining) and apoptosis (TUNEL). Notably, autophagic turnover markers (i.e., increased on-rate of autophagy; p62 and LC3-II/I) were increased in myocardium of WRN-K577M, which was refractory to fasting-induced autophagic activation, indicating the on-rate step of autophagy is pathologically augmented under cardiac aging observed in WRN-K577M. In contrast, one of the key regulators of autophagy is the target of rapamycin, TOR kinase, which is the major inhibitory signal that shuts off autophagy with concomitant activation of Akt signaling. In contrast, blockade of the lysosomal fusion into autophagosome by systemic treatment with chloroquine (50 microg/g body weight) reduced LC3-II/I ratio, indicating the retarded off-rate of autophagy mediated by impaired lysosome fusion is presumably responsible for cardiac aging. Conclusion(s) DNA damage impairs autophagy in heart, leading to myocardial oxidative stress. In WRN-mutant progeria model, off-rate disorder of cardiac autophagy is, at least in part, the cause of increase in oxidative stress and inflammation in heart leading to HFpEF.