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Hypertension is common in elderly population. We designed to search comprehensively for genes that are chronologically shifted in their expressions and to define their contributions to vascular aging and hypertension. RNA sequencing was conducted to search for senescence‐shifted transcripts in human umbilical vein endothelial cells (HUVECs). Small interfering RNA (siRNA), small‐molecule drugs, CRISPR/Cas9 techniques, and imaging were used to determine genes' function and contributions to age‐related phenotypes of the endothelial cell and blood vessel. Of 25 genes enriched in the term of "regulation of blood pressure," NPRA was changed most significantly. The decreased NPRA expression was replicated in aortas of aged mice. The knockdown of NPRA promoted HUVEC senescence and it decreased expressions of protein kinase cGMP‐dependent 1 (PKG), sirtuin 1 (SIRT1), and endothelial nitric oxide synthase (eNOS). Suppression of NPRA also decreased the phosphorylation of AMP‐activated protein kinase (AMPK) as well as the ratio of oxidized nicotinamide adenine dinucleotide (NAD+)/reduced nicotinamide adenine dinucleotide (NADH) but increased the production of reactive oxygen species (ROS). 8‐Br‐cGMP (analog of cGMP), or AICAR (AMPK activator), counteracted the observed changes in HUVECs. The Npr1+/− mice presented an elevated systolic blood pressure and their vessels became insensitive to endothelial‐dependent vasodilators. Further, vessels from Npr1+/− mice increased Cdkn1a but decreased eNos expressions. These phenotypes were rescued by intravenously administrated 8‐Br‐cGMP and viral overexpression of human PKG, respectively. In conclusion, we demonstrate NPRA/PKG/AMPK as a novel and critical signaling axis in the modulation of endothelial cell senescence, vascular aging, and hypertension. [ABSTRACT FROM AUTHOR]

Chromatin organization and transcriptional profiles undergo tremendous reordering during senescence. However, uncovering the regulatory mechanisms between chromatin reconstruction and gene expression in senescence has been elusive. Here, we depicted the landscapes of both chromatin accessibility and gene expression to reveal gene regulatory networks in human umbilical vein endothelial cell (HUVEC) senescence and found that chromatin accessibilities are redistributed during senescence. Particularly, the intergenic chromatin was massively shifted with the increased accessibility regions (IARs) or decreased accessibility regions (DARs), which were mainly enhancer elements. We defined AP‐1 transcription factor family as being responsible for driving chromatin accessibility reconstruction in IARs, where low DNA methylation improved binding affinity of AP‐1 and further increased the chromatin accessibility. Among AP‐1 transcription factors, we confirmed ATF3 was critical to reconstruct chromatin accessibility to promote cellular senescence. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program, we identified that AP‐1 was capable of reorganizing the chromatin accessibility profile to regulate senescence. [ABSTRACT FROM AUTHOR]

Objective: Human ABO blood groups are determined by the alleles A, B, and O (O01 and O02) of the ABO gene and have been linked to the risks for cardiovascular diseases and cancers that affect lifespan. We examined the genetic associations of the ABO gene and blood groups with longevity. Methods: We inspected the frequencies of the A, B, O, and O02 alleles in a large Chinese centenarian population (n = 2201) and in middle‐aged controls (n = 2330). The single nucleotide polymorphisms were selected as allele A (rs507666), B (rs8176743, rs8176746, and rs8176749), O (rs687289), and O02 (rs688976, rs549446, and rs512770). Results: Supported by allelic and genotypic association studies, the frequencies of blood types A, B, O, and AB in centenarian versus control participants were not statistically different: 0.2821 versus 0.2781 (χ2 = 0.09, P = 0.76), 0.2867 versus 0.3060 (χ2 = 2.03, P = 0.15), 0.3380 versus 0.3159 (χ2 = 2.52, P = 0.11), and 0.0859 versus 0.0910 (χ2 = 0.37, P = 0.54), respectively. Sex had little effect on these distributions. Conclusion: Integrated with other previous reports, we conclude from this large Chinese cohort that genetic variants of the ABO gene and blood groups are not associated with longevity. [ABSTRACT FROM AUTHOR]

β-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of β-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the β-adrenergic signaling pathway are associated with human longevity. We performed a 10-year follow-up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long-lived and 1028 geography-matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 ( C/A) and rs1042719 ( G/C), of ADRB2 in linkage disequilibrium (D' = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni-corrected P-values in a combined analysis were 0.00053-0.010. Men with haplotype A-C showed an increased probability to become centenarians (the frequency of A-C in long-lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI 95% = 1.17-1.88, P = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI 95% = 0.51-0.78, P = 0.000018). The permuted P-values were 0.00005 and 0.0009, respectively. ADRB2 encodes the β2-adrenergic receptor; the haplotype A-C markedly reduced its translational efficiency compared with C-G ( P = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of β2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan. [ABSTRACT FROM AUTHOR]

Sarcopenia, a leading cause for global disability and mortality, is an age‐related muscular disorder, characterized by accelerated muscle mass loss and functional decline. It is known that caloric restriction (CR), ketogenic diet or endurance exercise lessen sarcopenia and elevate circulating β‐hydroxybutyrate (β‐HB) levels. Whether the elevated β‐HB is essential to the reversal of sarcopenia, however, remains unclear. Here we show in both Caenorhabditis elegans and mouse models that an increase of β‐HB reverse myofiber atrophy and improves motor functions at advanced ages. β‐HB‐induced histone lysine β‐hydroxybutyrylation (Kbhb) is indispensable for the reversal of sarcopenia. Histone Kbhb enhances transcription of genes associated with mitochondrial pathways, including oxidative phosphorylation, ATP metabolic process and aerobic respiration. This ultimately leads to improve mitochondrial integrity and enhance mitochondrial respiration. The histone Kbhb are validated in mouse model with CR. Thus, we demonstrate that β‐HB induces histone Kbhb, increases mitochondrial function, and reverses sarcopenia. [ABSTRACT FROM AUTHOR]