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Aging Cell 2022 May 22:e13622. Epub 2022 May 22.

Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Read More

Aging Cell 2022 May 18:e13625. Epub 2022 May 18.

Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.

Mutation in Werner (WRN) RECQL helicase is associated with premature aging syndrome (Werner syndrome, WS) and predisposition to multiple cancers. In patients with solid cancers, deficiency of the WRN RECQL helicase is paradoxically associated with enhanced overall survival in response to treatment with TOP1 inhibitors, which stabilize pathological TOP1-DNA-covalent-complexes (TOP1cc) on the genome. However, the underlying mechanism of WRN in development of chemoresistance to TOP1 inhibitors is not yet explored. Read More

Aging Cell 2022 May 15:e13629. Epub 2022 May 15.

Department of Biology, Orentreich Foundation for the Advancement of Science, Cold Spring, New York, USA.

A sustained state of methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, continuously methionine-restricted rodents have less age-related pathology and are up to 45% longer-lived than controls. Promisingly, MR is feasible for humans, and studies have suggested that methionine-restricted individuals may receive similar benefits to rodents. Read More

Aging Cell 2022 May 15:e13628. Epub 2022 May 15.

School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.

Age-related memory impairment (AMI) is a common phenomenon across species. Vulnerability to interfering stimuli has been proposed to be an important cause of AMI. However, the molecular mechanisms underlying this vulnerability-related AMI remain unknown. Read More

Aging Cell 2022 May 14:e13617. Epub 2022 May 14.

Departments of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.

Alzheimer's disease (AD) is a pervasive neurodegeneration disease with high heritability. In this study, we employed CRISPR-Cas9-engineered technology to investigate the effects of a rare mutation (rs144662445) in the A kinase anchoring protein 9 (AKAP9) gene, which is associated with AD in African Americans (AA), on tau pathology and the tau interactome in SH-SY5Y P301L neuron-like cells. The mutation significantly increased the level of phosphorylated tau, specifically at the site Ser396/Ser404. Read More

Aging Cell 2022 May 13:e13624. Epub 2022 May 13.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA.

One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymus microenvironment. Thymic T-cell export continues into adulthood, yet the impact of thymus involution on the quality of newly generated T-cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue-restricted antigens (TRAs) decline with age, suggesting the involuting thymus may not promote efficient central tolerance. Read More

Aging Cell 2022 May 12:e13608. Epub 2022 May 12.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). Read More

Aging Cell 2022 May 10:e13627. Epub 2022 May 10.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center College of Medicine, College Station, Texas, USA.

Objectively diagnosing age-related cognitive impairment (ACI), mild cognitive impairment (MCI), and early-stage Alzheimer's disease (AD) is a difficult task, as most cognitive impairment is clinically established via questionnaires, history, and physical examinations. A recent study has suggested that monitoring a miRNA triad, miR-181a-5p, miR-146a-5p, and miR-148a-3p can identify ACI and its progression to MCI and AD (Islam et al., EMBO Mol Med. Read More

Aging Cell 2022 May 10:e13616. Epub 2022 May 10.

Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.

Accumulation of oxidative stress is highly intertwined with aging process and contributes to aging-related diseases, such as neurodegenerative diseases. Deciphering the molecular machinery that regulates oxidative stress is fundamental to further uncovering the pathogenesis of these diseases. Chaperone-mediated autophagy (CMA), a highly selective lysosome-dependent degradation process, has been proven to be an important maintainer of cellular homeostasis through multiple mechanisms, one of which is the attenuation of oxidative stress. Read More

Aging Cell 2022 May 8:e13626. Epub 2022 May 8.

Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.

The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie-and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Read More

Aging Cell 2022 May 4:e13621. Epub 2022 May 4.

Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.

For women, menopausal transition is a time of significant hormonal changes, which may contribute to altered body composition and regional adipose tissue accumulation. Excess adiposity, and especially adipose tissue accumulation in the central body region, increases women's risk of cardiovascular and metabolic conditions and affects physical functioning. We investigated the associations between menopausal progression and total and regional body adiposity measured with dual-energy X-ray absorptiometry and computed tomography in two longitudinal cohort studies of women aged 47-55 (n = 230 and 148, mean follow-up times 1. Read More

Aging Cell 2022 Apr 30:e13598. Epub 2022 Apr 30.

Chronobiology and Sleep Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Read More

Aging Cell 2022 05 27;21(5):e13623. Epub 2022 Apr 27.

Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.

Neuroinflammation is considered one of major factors in the pathogenesis of Alzheimer's disease (AD). In particular, inflammasome activation, including NLRP3 inflammasome in microglia, is regarded as fundamental for the pro-inflammatory response of immune cells. However, the precise molecular mechanism through which the NLRP3 inflammasome is associated with AD pathologies remains unclear. Read More

Aging Cell 2022 05 20;21(5):e13619. Epub 2022 Apr 20.

Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.

Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). Read More

Aging Cell 2022 05 20;21(5):e13618. Epub 2022 Apr 20.

Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.

Accumulating evidence suggests that ATP-sensitive potassium (K ) channels play an important role in the selective degeneration of dopaminergic neurons in the substantia nigra (SN). Furthermore, the expression of the K channel subunit sulfonylurea receptor 1 (SUR1) is upregulated in the remaining nigral dopaminergic neurons in Parkinson's disease (PD). However, the mechanism underlying this selective upregulation of the SUR1 subunit and its subsequent roles in PD progression are largely unknown. Read More

Aging Cell 2022 05 20;21(5):e13614. Epub 2022 Apr 20.

Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.

Telomerase levels in most human cells are insufficient to prevent loss of telomeric DNA with each replication cycle. The resulting "Hayflick" limit may have allowed lifespan to increase by suppressing the development of tumors early in life be it at the expense of compromised cellular responses late in life. At any given age, the average telomere length in leukocytes shows considerably variation between individuals with females having, on average, longer telomeres than males. Read More

Aging Cell 2022 05 18;21(5):e13613. Epub 2022 Apr 18.

Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.

Aging is accompanied by the progressive accumulation of permanent changes to the genomic sequence, termed somatic mutations. Small mutations, including single-base substitutions and insertions/deletions, are key determinants of the malignant transformations leading to cancer, but their role as initiators of other age-related phenotypes is controversial. Here, we present recent advances in the study of somatic mutagenesis in aging tissues and posit that the current uncertainty about its causal effects in the aging process is due to technological and methodological weaknesses. Read More

Aging Cell 2022 05 15;21(5):e13609. Epub 2022 Apr 15.

Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health Intramural Research Program, Baltimore, Maryland, USA.

Changes in the proteome of different human tissues with advancing age are poorly characterized. Here, we studied the proteins present in primary skin fibroblasts collected from 82 healthy individuals across a wide age spectrum (22-89 years old) who participated in the GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing) study of the National Institute on Aging, NIH. Proteins were extracted from lysed fibroblasts and subjected to liquid chromatography-mass spectrometry analysis, and the expression levels of 9341 proteins were analyzed using linear regression models. Read More

Aging Cell 2022 05 15;21(5):e13612. Epub 2022 Apr 15.

Department of Genetics, Eötvös Loránd University (ELTE), Budapest, Hungary.

In high-income countries, women tend to give birth at increasingly advanced ages. Despite its physiological, developmental, and medical consequences, why this tendency significantly affects genetic stability of the offspring remains largely unresolved. Accumulating evidence indicates that the higher the age of the mother at fertilization, the more intense the activity of transposable elements causing insertional mutations in functional DNA stretches in her oocyte involved in zygote formation. Read More

Aging Cell 2022 05 14;21(5):e13610. Epub 2022 Apr 14.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.

Sleep has been associated with aging and relevant health outcomes, but the causal relationship remains inconclusive. In this study, we investigated the associations of sleep behaviors with biological ages (BAs) among 363,886 middle and elderly adults from UK Biobank. Sleep index (0 [worst]-6 [best]) of each participant was retrieved from the following six sleep behaviors: snoring, chronotype, daytime sleepiness, sleep duration, insomnia, and difficulties in getting up. Read More

Aging Cell 2022 05 12;21(5):e13588. Epub 2022 Apr 12.

Key Laboratory of Functional Proteomics of Guangdong Province, Key Laboratory of Mental Health of the Ministry of Education, School of Basic Medical Sciences, Pediatric Center of Zhujiang Hospital, Center for Orthopaedic Surgery of the Third Affiliated Hospital, Southern Medical University, Guangzhou, China.

Substantial spine loss in striatal medium spiny neurons (MSNs) and abnormal behaviors are common features of Parkinson's disease (PD). The caudate putamen (CPu) mainly contains MSNs expressing dopamine D1 receptor (dMSNs) and dopamine D2 receptor (iMSNs) exerting critical effects on motor and cognition behavior. However, the molecular mechanisms contributing to spine loss and abnormal behaviors in dMSNs and iMSNs under parkinsonian state remain unknown. Read More

Aging Cell 2022 05 9;21(5):e13607. Epub 2022 Apr 9.

Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

Age-related changes in human T-cell populations are important contributors to immunosenescence. In particular, terminally differentiated CD8 effector memory CD45RA TEMRA cells and their subsets have characteristics of cellular senescence, accumulate in older individuals, and are increased in age-related chronic inflammatory diseases. In a detailed T-cell profiling among individuals over 65 years of age, we found a high interindividual variation among CD8 TEMRA populations. Read More

Aging Cell 2022 05 6;21(5):e13606. Epub 2022 Apr 6.

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. Read More

Aging Cell 2022 05 7;21(5):e13604. Epub 2022 Apr 7.

Unit of Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan.

Methionine restriction (MetR) can extend lifespan and delay the onset of aging-associated pathologies in most model organisms. Previously, we showed that supplementation with the metabolite S-adenosyl-L-homocysteine (SAH) extends lifespan and activates the energy sensor AMP-activated protein kinase (AMPK) in the budding yeast Saccharomyces cerevisiae. However, the mechanism involved and whether SAH can extend metazoan lifespan have remained unknown. Read More

Aging Cell 2022 05 2;21(5):e13601. Epub 2022 Apr 2.

Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.

Alzheimer's disease (AD) is age-related progressive neurological dysfunction. Limited clinical benefits for current treatments indicate an urgent need for novel therapeutic strategies. Previous transcriptomic analysis showed that DMP1 expression level was increased in AD model animals whereas it can induce cell-cycle arrest in several cell lines. Read More

Aging Cell 2022 05 31;21(5):e13600. Epub 2022 Mar 31.

Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD-like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg-AD mice. Read More

Aging Cell 2022 05 30;21(5):e13593. Epub 2022 Mar 30.

Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China.

Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully understood. Voltage-gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD-related abnormal neuronal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Read More

Aging Cell 2022 05 29;21(5):e13603. Epub 2022 Mar 29.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin-proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Read More

Aging Cell 2022 05 29;21(5):e13599. Epub 2022 Mar 29.

Department of Nuclear Medicine and Medical PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Aging is an inevitable process that all individuals experience, of which the extent differs among individuals. It has been recognized as the risk factor of neurodegenerative diseases by affecting gut microbiota compositions, microglia, and cognition abilities. Aging-induced changes in gut microbiota compositions have a critical role in orchestrating the morphology and functions of microglia through the gut-brain axis. Read More