bims-senagi 2022-02-06 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022‒02‒06
thirty-four papers selected by
Maria Grazia Vizioli
Mayo Clinic

Cellular senescence and the skeleton: pathophysiology and therapeutic implications.
The role of cellular senescence and SASP in tumor microenvironment.
The mechanotransduction of MLO-Y4 cells is disrupted by the senescence-associated secretory phenotype of neighboring cells.
Cellular Senescence in Cardiovascular Diseases: A Systematic Review.
Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age.
Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence.
Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock.
Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain.
Cellular senescence, inflammation, and cognition in aging and Alzheimer's disease: What's the connection?
Autophagy takes it all - autophagy inducers target immune aging.
Distinct profiles of cellular senescence-associated gene expression in the aged, diseased or injured central nervous system.
Cellular senescence in the cholangiopathies.
A new function for the serine protease HtrA2 in controlling radiation-induced senescence in cancer cells.
Atrial Fibrillation Underlies Cardiomyocyte Senescence and Contributes to Deleterious Atrial Remodeling during Disease Progression.
Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial.
Immune system aging and the aging-related diseases in the COVID-19 era.
White matter-associated microglia: New players in brain aging and neurodegenerative diseases.
Pharmacological Blockade of NLRP3 Inflammasome/IL-1β-Positive Loop Mitigates Endothelial Cell Senescence and Dysfunction.
Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?
Tetrahydroxy stilbene glycoside attenuates endothelial cell premature senescence induced by H2O2 through the microRNA-34a/SIRT1 pathway.
Canonical Wnt Signaling in the Pathology of Iron Overload-Induced Oxidative Stress and Age-Related Diseases.
p16 a biomarker of aging and tolerance for cancer therapy.
Protective Effects of Exercise Become Especially Important for the Aging Immune System in The Covid-19 Era.
Loss of circRNAs from the crh-1 gene extends the mean lifespan in Caenorhabditis elegans.
Interplay between K-RAS and miRNAs.
Novel insights from a multiomics dissection of the hayflick limit.
The various regulatory functions of long noncoding RNAs in apoptosis, cell cycle, and cellular senescence.
Continuous and intermittent ketogenic diets initiated in late middle-aged mice improves cognition and motor endurance at advanced age.
An open science study of ageing in companion dogs.
Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages.
Chronic low-grade inflammation is involved in TLR4 knockout-induced spontaneous obesity in aged mice.
The selection force weakens with age because ageing evolves and not vice versa.
SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage.
Emerging Roles of Ceramide in Cardiovascular Diseases.

J Clin Invest. 2022 Feb 01. pii: e154888. [Epub ahead of print]132(3):

Cellular senescence and the skeleton: pathophysiology and therapeutic implications.

Sundeep Khosla, Joshua N Farr, David G Monroe.

Cellular senescence is a fundamental aging mechanism that is currently the focus of considerable interest as a pathway that could be targeted to ameliorate aging across multiple tissues, including the skeleton. There is now substantial evidence that senescent cells accumulate in the bone microenvironment with aging and that targeting these cells prevents age-related bone loss, at least in mice. Cellular senescence also plays important roles in mediating the skeletal fragility associated with diabetes mellitus, radiation, and chemotherapy. As such, there are ongoing efforts to develop "senolytic" drugs that kill senescent cells by targeting key survival mechanisms in these cells without affecting normal cells. Because senescent cells accumulate across tissues with aging, senolytics offer the attractive possibility of treating multiple age-related comorbidities simultaneously.

DOI: https://doi.org/10.1172/JCI154888
FEBS J. 2022 Feb 02.

The role of cellular senescence and SASP in tumor microenvironment.

Masaki Takasugi, Yuya Yoshida, Eiji Hara, Naoko Ohtani.

  Cellular senescence refers to a state of irreversible cell cycle arrest that can be induced by various cellular stresses and is known to play a pivotal role in tumor suppression. While senescence-associated growth arrest can inhibit the proliferation of cancer-prone cells, the altered secretory profile of senescent cells, termed the senescence-associated secretory phenotype, can contribute to the microenvironment that promotes tumor development. Although the senescence-associated secretory phenotype and its effects on tumorigenesis are both highly context-dependent, mechanisms underlying such diversity are becoming better understood, thereby allowing the creation of new strategies to effectively target the senescence-associated secretory phenotype and senescent cells for cancer therapy. In this review, we discuss the current knowledge on cellular senescence and the senescence-associated secretory phenotype to develop a structural understanding of their roles in the tumor microenvironment and provide perspectives for future research, including the possibility of senotherapy for the treatment of cancer.

Keywords:  SASP; senescence surveillance; senolytics; senomorphics; tumor microenvironment

DOI:  https://doi.org/10.1111/febs.16381
J Cell Physiol. 2022 Feb 01.

The mechanotransduction of MLO-Y4 cells is disrupted by the senescence-associated secretory phenotype of neighboring cells.

Joseph D Gardinier, Amit Chougule, Chunbin Zhang.

  Age-related bone loss is attributed to the accumulation of senescent cells and their increasing production of inflammatory cytokines as part of the senescence-associated secretory phenotype (SASP). In otherwise healthy individuals, osteocytes play a key role in maintaining bone mass through their primary function of responding to skeletal loading. Given that osteocytes' response to loading is known to steadily decline with age, we hypothesized that the increasing presence of senescent cells and their SASP inhibit osteocytes' response to loading. To test this hypothesis, we developed two in vitro models of senescent osteocytes and osteoblasts derived from MLO-Y4 and MC3T3 cell lines, respectively. The senescent phenotype was unique to each cell type based on distinct changes in cell cycle inhibitors and SASP profile. The SASP profile of senescent osteocytes was in part dependent on nuclear factor-κB signaling and presents a new potential mechanism to target the SASP in bone. Nonsenescent MLO-Y4 cells cultured with the SASP of each senescent cell type failed to exhibit changes in gene expression as well as ERK phosphorylation and prostaglandin E2 release. The SASP of senescent osteocytes had the largest effect and neutralizing interleukin-6 (IL-6) as part of the SASP restored osteocytes' response to loading. The loss in mechanotransduction due to IL-6 was attributed to a decrease in P2X7 expression and overall sensitivity to purinergic signaling. Altogether, these findings demonstrate that the SASP of senescent cells have a negative effect on the mechanotransduction of osteocytes and that IL-6 is a key SASP component that contributes to the loss in mechanotransduction.

Keywords:  aging; cellular senescence; interleukin-6; mechanotransduction; osteocytes

DOI:  https://doi.org/10.1002/jcp.30690
Aging Dis. 2022 Feb;13(1): 103-128

Cellular Senescence in Cardiovascular Diseases: A Systematic Review.

Can Hu, Xin Zhang, Teng Teng, Zhen-Guo Ma, Qi-Zhu Tang.

  Aging is a prominent risk factor for cardiovascular diseases, which is the leading cause of death around the world. Recently, cellular senescence has received potential attention as a promising target in preventing cardiovascular diseases, including acute myocardial infarction, atherosclerosis, cardiac aging, pressure overload-induced hypertrophy, heart regeneration, hypertension, and abdominal aortic aneurysm. Here, we discuss the mechanisms underlying cellular senescence and describe the involvement of senescent cardiovascular cells (including cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts/myofibroblasts and T cells) in age-related cardiovascular diseases. Then, we highlight the targets (SIRT1 and mTOR) that regulating cellular senescence in cardiovascular disorders. Furthermore, we review the evidence that senescent cells can exert both beneficial and detrimental implications in cardiovascular diseases on a context-dependent manner. Finally, we summarize the emerging pro-senescent or anti-senescent interventions and discuss their therapeutic potential in preventing cardiovascular diseases.

Keywords:  Cardiac aging; Cardiomyocytes; Cardiovascular diseases; Cellular senescence; Senotherapy

DOI:  https://doi.org/10.14336/AD.2021.0927
Diabetes. 2022 Feb 02. pii: db210536. [Epub ahead of print]

Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age.

Fabiola Marino, Mariangela Scalise, Nadia Salerno, Luca Salerno, Claudia Molinaro, Donato Cappetta, Michele Torella, Marta Greco, Daniela Foti, Ferdinando C Sasso, Pasquale Mastroroberto, Antonella De Angelis, Georgina M Ellison-Hughes, Maurilio Sampaolesi, Marcello Rota, Francesco Rossi, Konrad Urbanek, Bernardo Nadal-Ginard, Daniele Torella, Eleonora Cianflone.

Diabetes Mellitus (DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. We assessed the hypothesis that senescence and senescence-associated secretory phenotype (SASP) are a main mechanism of cardiac degenerative defect in DM. Accordingly, we tested whether that ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from non-aged (50-64 years old) DM type 2 (T2DM) and non-diabetic (NDM) patients with post-infarct cardiomyopathy undergoing cardiac surgery. A higher ROS production in T2DM associated with an increased number of senescent/dysfunctional T2DM-human(h)CSCs with reduced proliferation, clonogenesis/spherogenesis and myogenic differentiation vs. NDM-hCSCs in vitro. T2DM-hCSCs show a defined pathologic SASP. A combination of two senolytics, Dasatinib (D) and Quercetin (Q), clears senescent T2DM-hCSCs in vitro restoring their expansion and myogenic differentiation capacities. In a T2DM model in young mice, diabetic status per se (independently of ischemia and age) causes CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D+Q treatment efficiently eliminates senescent cells, rescuing CSC function, which results in functional myocardial repair/regeneration improving cardiac function in murine DM. In conclusions, DM hampers CSC biology inhibiting their regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence abrogating the SASP restoring a fully proliferative-/differentiation- competent hCSC pool in T2DM with normalization of cardiac function.

DOI: https://doi.org/10.2337/db21-0536
Aging (Albany NY). 2022 Jan 30. 14(undefined):

Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence.

Yun Haeng Lee, Doyoung Choi, Geonhee Jang, Ji Yun Park, Eun Seon Song, Haneur Lee, Myeong Uk Kuk, Junghyun Joo, Soon Kil Ahn, Youngjoo Byun, Joon Tae Park.

  Senescence is a distinct set of changes in the senescence-associated secretory phenotype (SASP) and leads to aging and age-related diseases. Here, we screened compounds that could ameliorate senescence and identified an oxazoloquinoline analog (KB1541) designed to inhibit IL-33 signaling pathway. To elucidate the mechanism of action of KB1541, the proteins binding to KB1541 were investigated, and an interaction between KB1541 and 14-3-3ζ protein was found. Specifically, KB1541 interacted with 14-3-3ζ protein and phosphorylated of 14-3-3ζ protein at serine 58 residue. This phosphorylation increased ATP synthase 5 alpha/beta dimerization, which in turn promoted ATP production through increased oxidative phosphorylation (OXPHOS) efficiency. Then, the increased OXPHOS efficiency induced the recovery of mitochondrial function, coupled with senescence alleviation. Taken together, our results demonstrate a mechanism by which senescence is regulated by ATP synthase 5 alpha/beta dimerization upon fine-tuning of KB1541-mediated 14-3-3ζ protein activity.

Keywords:  14–3–3ζ; ATPase synthase 5; KB1541; OXPHOS; senescence amelioration

DOI:  https://doi.org/10.18632/aging.203858
Aging Cell. 2022 Feb 01. e13553

Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock.

Christopher Minteer, Marco Morselli, Margarita Meer, Jian Cao, Albert Higgins-Chen, Sabine M Lang, Matteo Pellegrini, Qin Yan, Morgan E Levine.

  Aging is associated with dramatic changes to DNA methylation (DNAm), although the causes and consequences of such alterations are unknown. Our ability to experimentally uncover mechanisms of epigenetic aging will be greatly enhanced by our ability to study and manipulate these changes using in vitro models. However, it remains unclear whether the changes elicited by cells in culture can serve as a model of what is observed in aging tissues in vivo. To test this, we serially passaged mouse embryonic fibroblasts (MEFs) and assessed changes in DNAm at each time point via reduced representation bisulfite sequencing. By developing a measure that tracked cellular aging in vitro, we tested whether it tracked physiological aging in various mouse tissues and whether anti-aging interventions modulate this measure. Our measure, termed CultureAGE, was shown to strongly increase with age when examined in multiple tissues (liver, lung, kidney, blood, and adipose). As a control, we confirmed that the measure was not a marker of cellular senescence, suggesting that it reflects a distinct yet progressive cellular aging phenomena that can be induced in vitro. Furthermore, we demonstrated slower epigenetic aging in animals undergoing caloric restriction and a resetting of our measure in lung and kidney fibroblasts when re-programmed to iPSCs. Enrichment and clustering analysis implicated EED and Polycomb group (PcG) factors as potentially important chromatin regulators in translational culture aging phenotypes. Overall, this study supports the concept that physiologically relevant aging changes can be induced in vitro and used to uncover mechanistic insights into epigenetic aging.

Keywords:  DNA methylation; aging; calorie restriction; epigenome; in vitro techniques; longevity; oxidative stress; replicative senescence

DOI:  https://doi.org/10.1111/acel.13553
Geroscience. 2022 Jan 31.

Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain.

Tamas Kiss, Ádám Nyúl-Tóth, Jordan DelFavero, Priya Balasubramanian, Stefano Tarantini, Janet Faakye, Rafal Gulej, Chetan Ahire, Anna Ungvari, Andriy Yabluchanskiy, Graham Wiley, Lori Garman, Zoltan Ungvari, Anna Csiszar.

  There is strong evidence that aging is associated with an increased presence of senescent cells in the brain. The finding that treatment with senolytic drugs improves cognitive performance of aged laboratory mice suggests that increased cellular senescence is causally linked to age-related cognitive decline. The relationship between senescent cells and their relative locations within the brain is critical to understanding the pathology of age-related cognitive decline and dementia. To assess spatial distribution of cellular senescence in the aged mouse brain, spatially resolved whole transcriptome mRNA expression was analyzed in sections of brains derived from young (3 months old) and aged (28 months old) C57BL/6 mice while capturing histological information in the same tissue section. Using this spatial transcriptomics (ST)-based method, microdomains containing senescent cells were identified on the basis of their senescence-related gene expression profiles (i.e., expression of the senescence marker cyclin-dependent kinase inhibitor p16INK4A encoded by the Cdkn2a gene) and were mapped to different anatomical brain regions. We confirmed that brain aging is associated with increased cellular senescence in the white matter, the hippocampi and the cortical grey matter. Transcriptional analysis of the senescent cell-containing ST spots shows that presence of senescent cells is associated with a gene expression signature suggestive of neuroinflammation. GO enrichment analysis of differentially expressed genes in the outer region of senescent cell-containing ST spots ("neighboring ST spots") also identified functions related to microglia activation and neuroinflammation. In conclusion, senescent cells accumulate with age in the white matter, the hippocampi and cortical grey matter and likely contribute to the genesis of inflammatory foci in a paracrine manner.

Keywords:  Ageing; Data analysis; Image processing; Neuroinflammation; Senescence; Spatial transcriptomics; Transcriptomics; Visualization

DOI:  https://doi.org/10.1007/s11357-022-00521-7
Alzheimers Dement. 2021 Dec;17 Suppl 3 e055688

Cellular senescence, inflammation, and cognition in aging and Alzheimer's disease: What's the connection?

Kevin N Hascup, Mackenzie R Peck, Yimin Fang, Nahayo Esperant-Hilaire, Caleigh A Findley, Samuel McFadden, Andrzej Bartke, Erin R Hascup.

BACKGROUND: Cellular senescence and inflammation may contribute to the pathogenesis of Alzheimer's disease (AD). We sought to define their inter-relationship in cell culture and animal models of AD and determine if senolytic compounds could alleviate these conditions thereby improving cognition.METHOD: Male and female C57BL/6 mice received monthly oral treatment with fisetin (100 mg/kg BW), dasatinib+quercertin (D+Q; 5 mg/kg BW and 50 mg/kg BW, respectively), or vehicle control from 4 to 12 months of age followed by cognitive assessment with Morris water maze and novel object recognition. Hippocampal tissue from untreated 12 month old male AβPP/PS1 and C57BL/6 mice underwent RNA sequencing (RNAseq) to assess cellular senescence and inflammation. Primary neurons were treated with Aβ42 (10µM) and fisetin (15µM), dasatinib (1µM), quercetin (10µM), D+Q, or vehicle control. Cell viability, senescent cell burden, and cytokine profiles were assessed.
RESULT: Long-term memory in mice treated with senolytic compounds was improved in males, but not in females. RNAseq results revealed elevated senescent and inflammatory markers in the hippocampus of AβPP/PS1 mice compared to C57BL/6 mice. Preliminary cell culture data indicate that primary neurons receiving senolytic treatment tended to have decreased senescence and inflammatory markers compared to controls.
CONCLUSION: Preliminary results support elevated cellular senescence and inflammation in the hippocampus of an AD mouse and treatment with senolytic compounds may improve cognition in a sex-dependent manner. Senolytic treatments in primary neuronal cultures appeared to reduce Aβ42 -related cellular senescence. Together, our results support that elimination of senescent cells and the corresponding inflammatory profile may be effective at treating impaired memory in AD. Supported by the National Institutes of Health (R01 AG057767, R01 AG061937), Center for Alzheimer's Research and trEatment (CARE), and the Kenneth Stark Endowment.

DOI: https://doi.org/10.1002/alz.055688
Dis Model Mech. 2022 01 01. pii: dmm049345. [Epub ahead of print]15(1):

Autophagy takes it all - autophagy inducers target immune aging.

Heidi Zinecker, Anna Katharina Simon.

  Autophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging. We examine how cutting-edge technologies, such as single-cell omics methods hold the promise to capture the complexity of molecular and cellular phenotypes associated with aging, driving the development of suitable putative biomarkers and clinical bioassays. Finally, we debate the urgency to initiate large-scale human clinical trials. We give special preference to small molecule probes and to dietary interventions that can extend healthy lifespan and are affordable for most of the world's population.

Keywords:  Aging; Autophagy; Autophagy inducer; Immune system

DOI:  https://doi.org/10.1242/dmm.049345
Neurosci Lett. 2022 Jan 29. pii: S0304-3940(22)00037-4. [Epub ahead of print]772 136480

Distinct profiles of cellular senescence-associated gene expression in the aged, diseased or injured central nervous system.

Robert S Pijewski, Pearl A Sutter, Victoria A Duszak, Neeraj Singh, Riqiang Yan, Phillip P Smith, Stephen J Crocker.

  The molecular process of cellular senescence, which is known to contribute to aging, has been implicated in several diseases of the central nervous system (CNS). The purpose of this study was to generate an unbiased survey of cellular senescence gene expression with whole brain tissues using a standardized, curated set of 88 genes associated with cellular senescence. We performed a comparative analysis of aged brains with two CNS disease models; the 5xFAD mouse model of Alzheimer's disease, and cuprizone-induced CNS demyelination. Each experimental group could be distinguished from the others by expression of unique subsets of cellular senescence genes, with minimal overlap between each group. Gene ontology analyses identified unique processes within cellular senescence among each group. To examine how these changes translate to the human condition, we interrogated gene expression data from publicly available databases of human aging and AD cases which also corroborated our finding that cellular senescence gene expression changes in AD differ significantly from healthy aging, although the changes in human did not always correlate with the murine models. These data provide important insight on the common and unique global changes in expression of cellular senescence genes in the CNS accompanying aging, injury or disease. Future studies may define, using more refined cellular assays, the specific cellular phenotype differences, and how disparate drivers of unique disease pathologies all seemingly culminate in a common activation of cellular senescence.

Keywords:  Alzheimer's disease; Cuprizone; Gene enrichment analysis; Plau; RNAseq

DOI:  https://doi.org/10.1016/j.neulet.2022.136480
Curr Opin Gastroenterol. 2022 Mar 01. 38(2): 121-127

Cellular senescence in the cholangiopathies.

Pamela S Bogert, Steven P O'Hara, Nicholas F LaRusso.

PURPOSE OF REVIEW: Cellular senescence (i.e. permanent withdrawal from the cell cycle) is increasingly recognized as a pathologic feature in a variety of inflammatory liver diseases, including primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and additional cholangiopathies. Herein, we provide an update on the interplay between cholangiocytes, cellular senescence and the cholangiopathies.RECENT FINDINGS: The themes covered by this review include novel models for studying the role of senescent cholangiocytes and the cholangiopathies, identification and modulation of key pathways or molecules regulating cholangiocyte senescence, and discovery of druggable targets to advance therapeutic options for the cholangiopathies. Most recent studies focused on PSC; however, the concepts and findings may be applied to additional cholangiopathies.
SUMMARY: Cholangiopathies present unique and divergent clinicopathological features, causes and genetic backgrounds, but share several common disease processes. Cholangiocyte senescence in the cholestatic cholangiopathies, primarily PSC and PBC, is regarded as a key pathogenetic process. Importantly, senescent cholangiocytes exhibit phenotypic features including the senescence-associated secretory phenotype (SASP) and resistance to apoptosis that provide new directions for basic research and new prognostic and therapeutic approaches for clinical practice.

DOI: https://doi.org/10.1097/MOG.0000000000000805
Mol Oncol. 2022 Feb 05.

A new function for the serine protease HtrA2 in controlling radiation-induced senescence in cancer cells.

Liat Hammer, Vered Levin-Salomon, Naama Yaeli-Slonim, Moria Weiss, Naama P Dekel-Bird, Tsviya Olender, Ziv Porat, Sabina Winograd-Katz, Alon Savidor, Yishai Levin, Shani Bialik, Benjamin Geiger, Adi Kimchi.

  Radiation therapy can induce cellular senescence in cancer cells, leading to short-term tumor growth arrest but increased long-term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation-induced senescence in cultured cancer cells. The irradiated cells exhibited a typical senescent phenotype, including upregulation of p53 and its main target, p21, followed by a sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence-associated beta-galactosidase activity. Mass spectrometry-based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy. A functional siRNA screen using a cell-death-related library identified mitochondrial serine protease HtrA2 as being necessary for sustained growth arrest of the senescent cells. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus, HtrA2 is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence and the continuous maintenance of proliferation arrest.

Keywords:  HtrA2/Omi; cellular senescence; radiation therapy; siRNA functional screen; vimentin

DOI:  https://doi.org/10.1002/1878-0261.13187
Aging Dis. 2022 Feb;13(1): 298-312

Atrial Fibrillation Underlies Cardiomyocyte Senescence and Contributes to Deleterious Atrial Remodeling during Disease Progression.

Ailiya Adili, Xiyu Zhu, Hailong Cao, Xinlong Tang, Yali Wang, Junxia Wang, Jian Shi, Qing Zhou, Dongjin Wang.

  Accelerated senescence is triggered by key mediators of arrhythmogenic substrates and contributes to atrial fibrillation (AF). We sought to understand senescence in AF and the extent to which it aggravates the AF process. Twenty-six AF patients undergoing open-heart surgery were included, and 12 patients with sinus rhythm served as controls. Another cohort included 120 consecutive persistent AF patients with valvular heart diseases. HL-1 atrial myocytes were tachypaced (TP) to simulate experimental AF. Compared with sinus rhythm, left atrial appendages (LAAs) with AF presented a significantly increased positive area of cellular senescence, with upregulated expression of p16, p21 and p53. Next, p21 mRNA was increased in patients with AF recurrence compared with that in patients without recurrence. In multivariate analysis, p21 (OR: 2.97; 95% CI: 1.65-5.34; P<0.001) was a significant independent predictor of AF early recurrence. Interestingly, TP induced HL-1 atrial myocyte senescence in vitro, accompanied by a marked increase in the senescence-associated secretory phenotype (SASP) and altered the expression of sarcoplasmic reticulum (SR)-related proteins. Suppression of p21 by siRNA reduced TP induced cell senescence and IL-1β, IL-6 elevation, and partly changed SR-related proteins expression. Moreover, we show that the level of γH2AX, a marker of DNA damage, was higher in AF patients than in sinus rhythm controls. Similarly, an increase in γH2AX levels was observed following TP. AF underlies cardiomyocyte senescence and contributes to deleterious atrial remodeling during disease progression. This finding may help facilitate the search for new therapeutic approaches for antiaging therapy for AF.

Keywords:  Atrial Cardiomyocyte Senescence; Atrial Fibrillation; Atrial Remolding; DNA Damage

DOI:  https://doi.org/10.14336/AD.2021.0619
J Prev Alzheimers Dis. 2022 ;9(1): 22-29

Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial.

M M Gonzales, V R Garbarino, E Marques Zilli, R C Petersen, J L Kirkland, T Tchkonia, N Musi, S Seshadri, S Craft, M E Orr.

  Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).

Keywords:  Alzheimer’s disease; Clinical trial; cellular senescence; senolytic therapy; tau

DOI:  https://doi.org/10.14283/jpad.2021.62
Immunol Lett. 2022 Jan 31. pii: S0165-2478(22)00019-0. [Epub ahead of print]243 19-27

Immune system aging and the aging-related diseases in the COVID-19 era.

Jacek M Witkowski.

  The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.

Keywords:  Adaptive immune system; Aging-related diseases; COVID-19; Immune system aging; Immunosenescence; Inflammaging; Innate immune system

DOI:  https://doi.org/10.1016/j.imlet.2022.01.005
Ageing Res Rev. 2022 Jan 28. pii: S1568-1637(22)00016-2. [Epub ahead of print]75 101574

White matter-associated microglia: New players in brain aging and neurodegenerative diseases.

Kyusik Ahn, Seung-Jae Lee, Inhee Mook-Jung.

  There has been growing interest in brain aging and rejuvenation. It is well known that brain aging is one of the leading causes of neurodegenerative diseases, such as Alzheimer's disease, but brain aging alone can cause cognitive decline. Microglia are thought to act as 'conductors' of white matter aging by modulating diverse glial cells and phagocytosing white matter-derived myelin debris. A recent study identified a specific subpopulation of microglia in the white matter of aged mice, termed white matter-associated microglia (WAM). Additionally, senescent microglia show impaired phagocytic function and altered lipid metabolism, which cause accumulation of lipid metabolites and eventually lead to myelin sheath degeneration. These results suggest that senescent WAM could be pivotal players in axonal loss during brain aging. The aim of this review is to assess the current state of knowledge on brain aging, with an emphasis on the roles of the white matter and microglia, and suggest potential approaches for rejuvenating the aged brain.

Keywords:  Aging; Brain; Microglia; Rejuvenation; White matter

DOI:  https://doi.org/10.1016/j.arr.2022.101574
Aging Dis. 2022 Feb;13(1): 284-297

Pharmacological Blockade of NLRP3 Inflammasome/IL-1β-Positive Loop Mitigates Endothelial Cell Senescence and Dysfunction.

Alejandra Romero, Pilar Dongil, Inés Valencia, Susana Vallejo, Álvaro San Hipólito-Luengo, Guillermo Díaz-Araya, José L Bartha, María M González-Arlanzón, Fernando Rivilla, Fernando de la Cuesta, Carlos F Sánchez-Ferrer, Concepción Peiró.

  The clinical relevance of IL-1β in chronic inflammation underlying atherosclerosis has been reinforced by recent evidence associating pharmacological inhibition of the cytokine with lower cardiovascular risk. Previously, we have demonstrated a direct involvement of IL-1β in endothelial senescence. Therefore, this can be a key mechanism contributing to the sterile inflammatory milieu associated with aging, termed inflammaging. In the present study, we have evaluated whether a positive feedback of IL-1β in the NLRP3 inflammasome via NF-κB could promote human endothelial senescence in vitro and murine endothelial dysfunction in vivo. Our results indicate that the NLRP3 inflammasome is pivotal in mediating the detrimental effects of IL-1β, showing that auto-activation is a crucial feature boosting endothelial cell senescence in vitro, which is paralleled by vascular dysfunction in vivo. Hence, the inhibitor of NLRP3 inflammasome assembly, MCC 950, was able to disrupt the aforementioned positive loop, thus alleviating inflammation, cell senescence and vascular dysfunction. Besides, we explored alternative NLRP3 inflammasome inhibitory agents such as the RAS heptapeptide Ang-(1-7) and the anti-aging protein klotho, both of which demonstrated protective effects in vitro and in vivo. Altogether, our results highlight a fundamental role for the hereby described NLRP3 inflammasome/IL-1β positive feedback loop in stress-induced inflammaging and the associated vascular dysfunction, additionally providing evidence of a potential therapeutic use of MCC 950, Ang-(1-7) and recombinant klotho to block this loop and its deleterious effects.

Keywords:  Interleukin-1β; NLRP3 inflammasome; angiotensin-(1-7); endothelial cell; klotho; senescence; vascular dysfunction

DOI:  https://doi.org/10.14336/AD.2021.0617
Aging Dis. 2022 Feb;13(1): 175-214

Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?

Chul-Kyu Kim, Perminder S Sachdev, Nady Braidy.

  Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.

Keywords:  NAD+; anti-ageing; brain health; caloric restriction; cellular energetics

DOI:  https://doi.org/10.14336/AD.2021.0705
Sci Rep. 2022 Feb 01. 12(1): 1708

Tetrahydroxy stilbene glycoside attenuates endothelial cell premature senescence induced by H2O2 through the microRNA-34a/SIRT1 pathway.

Lixuan Zhang, Yan Guo, Shennan Shi, Yani Zhuge, Nipi Chen, Zhishan Ding, Bo Jin.

Numerous studies have demonstrated that endothelial cell senescence plays a decisive role in the development and progression of cardiovascular diseases (CVD). Our previous results confirmed that Tetrahydroxy stilbene glycoside (TSG) can alleviate the human umbilical vein endothelial cells (HUVECs) senescence induced by H2O2 through SIRT1. It has been reported that miR-34a is a translational suppressor of SIRT1. In this study, we aimed to explore whether TSG regulates SIRT1 through miR-34a to ameliorate HUVECs senescence. H2O2 was used to induce premature senescence in HUVECs, and miR-34a mimic or inhibitor were transfected to over-express or suppress the expression level of miR-34a. Results revealed that TSG apparently decreased the miR-34a expression level in H2O2-induced premature senescence of HUVECs. When SIRT1 expression was inhibited by EX527, the attenuation of TSG on the expression level of miR-34a were abolished. When miR-34a expression was knockdown, the effect of TSG on HUVECs senescence could be enhanced. While miR-34a mimic could reverse the effect of TSG on HUVECs senescence. In conclusion, we demonstrated that TSG could attenuated endothelial cell senescence by targeting miR-34a/SIRT1 pathway.

DOI: https://doi.org/10.1038/s41598-022-05804-9
Oxid Med Cell Longev. 2022 ;2022 7163326

Canonical Wnt Signaling in the Pathology of Iron Overload-Induced Oxidative Stress and Age-Related Diseases.

Austin Armstrong, Ashok Mandala, Milan Malhotra, Jaya P Gnana-Prakasam.

Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.

DOI: https://doi.org/10.1155/2022/7163326
Transl Cancer Res. 2020 Sep;9(9): 5732-5742

p16 a biomarker of aging and tolerance for cancer therapy.

Hyman B Muss, Andrew Smitherman, William A Wood, Kirsten Nyrop, Sascha Tuchman, Paramjeet K Randhawa, Amy R Entwistle, Natalia Mitin, Shlomit S Shachar.

  There is great variability in life-expectancy, physical, cognitive, and functional domains in cancer patients of similar chronologic age. Nowhere is this more apparent than among middle-aged and older patients. However, even in younger patients of similar age, extensive exposure to environmental stressors can cause great variability in health status. A biomarker that would reflect biologic age and any and all health deficits in a cancer patient at a distinct point in time might help predict long term outcomes related to treatment, especially toxicity and overall survival. p16INK4a (hereafter referred to as p16) expression represents an ideal biomarker that reflects both cellular senescence and biologic aging. In murine models, p16 expression reflects biologic aging in almost all organs. Preliminary findings in patients with cancer support p16 measurement as a marker of physiologic aging and predictor of toxicity in patients treated with chemotherapy. This review describes the role of p16 in cell senescence, the methodology of p16 measurement in humans, preliminary studies of p16 in humans, and the potential clinical utility of p16 in guiding treatment for cancer patients.

Keywords:  aging; biomarker; cancer; p16; senescence

DOI:  https://doi.org/10.21037/tcr.2020.03.39
Aging Dis. 2022 Feb;13(1): 129-143

Protective Effects of Exercise Become Especially Important for the Aging Immune System in The Covid-19 Era.

Katarzyna Domaszewska, Michał Boraczyński, Yi-Yuan Tang, Joanna Gronek, Krystian Wochna, Tomasz Boraczyński, Dariusz Wieliński, Piotr Gronek.

  Aging is a complex, multietiological process and a major risk factor for most non-genetic, chronic diseases including geriatric syndromes that negatively affect healthspan and longevity. In the scenario of "healthy or good aging", especially during the COVID-19 era, the proper implementation of exercise as "adjuvant" or "polypill" to improve disease-related symptoms and comorbidities in the general population is a top priority. However, there is still a gap concerning studies analyzing influence of exercise training to immune system in older people. Therefore, the aim of this review is to provide a brief summary of well-established findings in exercise immunology and immunogerontology, but with a focus on the main exercise-induced mechanisms associated with aging of the immune system (immunosenescence). The scientific data strongly supports the notion that regular exercise as a low-cost and non-pharmacological treatment approach, when adjusted on an individual basis in elderly, induce multiple rejuvenating mechanisms: (1) affects the telomere-length dynamics (a "telo-protective" effect), (2) promote short- and long-term anti-inflammatory effects (via e.g., triggering the anti-inflammatory phenotype), 3) stimulates the adaptive immune system (e.g., helps to offset diminished adaptive responses) and in parallel inhibits the accelerated immunosenescence process, (4) increases post-vaccination immune responses, and (5) possibly extends both healthspan and lifespan.

Keywords:  COVID-19; aging process; exercise; immune system; immunosenescence

DOI:  https://doi.org/10.14336/AD.2021.1219
Aging Cell. 2022 Jan 31. e13560

Loss of circRNAs from the crh-1 gene extends the mean lifespan in Caenorhabditis elegans.

David Knupp, Brian G Jorgensen, Hussam Z Alshareef, Jaffar M Bhat, Jeremy J Grubbs, Pedro Miura, Alexander M van der Linden.

  Accumulation of circular RNAs (circRNAs) during aging occurs on a genome-wide level for multiple organisms, but its significance is unknown. Generating circRNA loss-of-function mutants is difficult because the vast majority of these RNAs are comprised of exons shared with protein-coding mRNAs. In Caenorhabditis elegans, most circRNAs were previously found to accumulate during aging. Two of the most abundant, age-accumulating circRNAs are generated from exon 4 of the crh-1 gene (circ-crh-1). Here, we found that the biogenesis of circ-crh-1 was regulated by the double-stranded RNA-binding protein ADR-1. We identified Reverse Complementary Match (RCM) sequences in introns flanking circ-crh-1. Using CRISPR-Cas9, we deleted the downstream RCM and found that this completely eliminated expression of the circRNA without affecting linear mRNA expression from the crh-1 gene. Remarkably, worms lacking circ-crh-1 exhibited a significantly longer mean lifespan. Lifespan was partially restored to wild type by expression of circ-crh-1 in neural tissues. Widespread transcriptome alterations in circ-crh-1 mutants were identified using RNA-Seq. Moving forward, intronic RCM deletion using CRISPR should be a widely applicable method to identify lifespan-regulating circRNAs in C. elegans.

Keywords:   Caenorhabditis elegans ; crh-1 ; aging; circRNA; reverse complementary match

DOI:  https://doi.org/10.1111/acel.13560
Trends Cancer. 2022 Jan 26. pii: S2405-8033(22)00002-4. [Epub ahead of print]

Interplay between K-RAS and miRNAs.

Bing Shui, Gaspare La Rocca, Andrea Ventura, Kevin M Haigis.

  K-RAS is frequently mutated in cancers, and its overactivation can lead to oncogene-induced senescence (OIS), a barrier to cellular transformation. Feedback onto K-RAS limits its signaling to avoid senescence while achieving the appropriate level of activation that promotes proliferation and survival. Such regulation could be mediated by miRNAs, as aberrant RAS signaling and miRNA activity coexist in several cancers, with miRNAs acting both up- and downstream of K-RAS. Several miRNAs both regulate and are regulated by K-RAS, suggesting a noncoding RNA-based feedback mechanism. Functional interactions between K-RAS and the miRNA machinery have also begun to unfold. This review comprehensively surveys the state of knowledge connecting K-RAS to miRNA function and proposes a model for the regulation of K-RAS signaling by noncoding RNAs.

Keywords:  K-RAS; cancer; feedback regulation; miRNA

DOI:  https://doi.org/10.1016/j.trecan.2022.01.002
Elife. 2022 Feb 04. pii: e70283. [Epub ahead of print]11

Novel insights from a multiomics dissection of the hayflick limit.

Michelle Chan, Han Yuan, Ilya Soifer, Tobias M Maile, Rebecca Y Wang, Andrea Ireland, Jonathon J O'Brien, Jérôme Goudeau, Leanne Jg Chan, Twaritha Vijay, Adam Freund, Cynthia Kenyon, Bryson D Bennett, Fiona E McAllister, David R Kelley, Margaret Roy, Robert L Cohen, Arthur D Levinson, David Botstein, David G Hendrickson.

  The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick's original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by the transcription factors YAP1/TEAD1 and TGF-𝛽2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.

Keywords:  chromosomes; gene expression; genetics; genomics; human

DOI:  https://doi.org/10.7554/eLife.70283
J Cell Biochem. 2022 Feb 02.

The various regulatory functions of long noncoding RNAs in apoptosis, cell cycle, and cellular senescence.

Mohammad Heydarnezhad Asl, Faezeh Pasban Khelejani, Seyedeh Zahra Bahojb Mahdavi, Leila Emrahi, Asiyeh Jebelli, Ahad Mokhtarzadeh.

  Long noncoding RNAs (lncRNAs) are a group of noncoding cellular RNAs involved in significant biological phenomena such as differentiation, cell development, genomic imprinting, adjusting the enzymatic activity, regulating chromosome conformation, apoptosis, cell cycle, and cellular senescence. The misregulation of lncRNAs interrupting normal biological processes has been implicated in tumor formation and metastasis, resulting in cancer. Apoptosis and cell cycle, two main biological phenomena, are highly conserved and intimately coupled mechanisms. Hence, some cell cycle regulators can influence both programmed cell death and cell division. Apoptosis eliminates defective and unwanted cells, and the cell cycle enables cells to replicate themselves. The improper regulation of apoptosis and cell cycle contributes to numerous disorders such as neurodegenerative and autoimmune diseases, viral infection, anemia, and mainly cancer. Cellular senescence is a tumor-suppressing response initiated by environmental and internal stress factors. This phenomenon has recently attained more attention due to its therapeutic implications in the field of senotherapy. In this review, the regulatory roles of lncRNAs on apoptosis, cell cycle, and senescence will be discussed. First, the role of lncRNAs in mitochondrial dynamics and apoptosis is addressed. Next, the interaction between lncRNAs and caspases, pro/antiapoptotic proteins, and also EGFR/PI3K/PTEN/AKT/mTORC1 signaling pathway will be investigated. Furthermore, the effect of lncRNAs in the cell cycle is surveyed through interaction with cyclins, cdks, p21, and wnt/β-catenin/c-myc pathway. Finally, the function of essential lncRNAs in cellular senescence is mentioned.

Keywords:  apoptosis; cell cycle; cellular senescence; lncRNA

DOI:  https://doi.org/10.1002/jcb.30221
Alzheimers Dement. 2021 Dec;17 Suppl 3 e052443

Continuous and intermittent ketogenic diets initiated in late middle-aged mice improves cognition and motor endurance at advanced age.

Zeyu Zhou, Jon J Ramsey, Michelle Long, Regina Wang, Kyoungmi Kim, James Graham, Jennifer Rutkowsky.

BACKGROUND: Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, and an effective therapeutic strategy that promotes healthy aging may lower age-related risks of AD and ameliorate AD associated cognitive dysfunctions. There has been substantial interest in the application of ketogenic diets (KD) to manage neurological disorders associated with aging, and studies have also shown KDs started from early middle age improved cognition and longevity in mice. Thus, KDs might be used to reduce risk of cognitive declines at old age. KDs started later in life or intermittently administered may be more feasible and promote compliance in an older population. Therefore, this study sought to test if continuous or intermittent KDs started in late-middle-aged mice would improve measures of cognitive and motor function at advanced ages.METHOD: 18-month-old male C57BL/6J mice were randomly assigned to an isocaloric control (CD), ketogenic (KD), or intermittent ketogenic (IKD, 3 days of KD/week) diet. Continuous or intermittent ketosis was induced at a constant level of energy intake. At 20, 23, and 26 months of age, a panel of behavior tests were performed to assess cognitive (novel object recognition, Y-maze, and Barnes-maze) and motor (grid-wire hang, grip strength, open field, and rearing) functions.
RESULT: Y-maze alternation rate was significantly higher for both IKD and KD mice at 23 months of age and for KD mice at 26 months indicating an improved working memory. 26-month-old KD mice also showed better spatial learning memory as measured by time spent in target quadrant in Barnes-maze. Improved motor endurance and strength was observed in aged IK and KD mice as tested by grid wire hang. A significantly increased composite score of all the behavior parameters was observed in KD mice at 26 months of age, and IK mice showed a trend toward increased score compared to CD mice.
CONCLUSION: KD and IKD initiated in late-middle-aged mice improved cognition and motor endurance in aged mice. KD had a more potent effect on overall heath span in aged mice shown as a higher composite score of all the tests performed with IKD showing results intermediate to other diet groups.

DOI: https://doi.org/10.1002/alz.052443
Nature. 2022 02;602(7895): 51-57

An open science study of ageing in companion dogs.

Dog Aging Project Consortium

The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan. To take advantage of this opportunity, the Dog Aging Project will collect extensive survey data, environmental information, electronic veterinary medical records, genome-wide sequence information, clinicopathology and molecular phenotypes derived from blood cells, plasma and faecal samples. Here, we describe the specific goals and design of the Dog Aging Project and discuss the potential for this open-data, community science study to greatly enhance understanding of ageing in a genetically variable, socially relevant species living in a complex environment.

DOI: https://doi.org/10.1038/s41586-021-04282-9
Biochem Pharmacol. 2022 Jan 29. pii: S0006-2952(22)00029-6. [Epub ahead of print] 114935

Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages.

Libin Ni, Zhen Lin, Sunli Hu, Yifeng Shi, Zhichen Jiang, Jiayi Zhao, Yifei Zhou, Yaosen Wu, Naifeng Tian, Liaojun Sun, Aimin Wu, Zongyou Pan, Xiaolei Zhang, Xiangyang Wang.

  Osteoarthritis (OA) is a progressive joint disease characterized by the degradation and destruction of articular cartilage, which is involved with pathological microenvironmental alterations induced by damaged chondrocytes and inflammatory macrophages. However, the current therapies cannot effectively alleviate the progression of OA. Our previous studies have shown that the pathological process of OA progression is accompanied by DNA damage, and inhibition of STING, a key molecule in DNA damage, may become a potential method for the treatment of OA. Itaconate, a metabolite highly expressed in macrophages under inflammatory conditions, has shown a wide range of anti-inflammatory effects, but its effect on OA and its underlying mechanism has not yet been studied. In this study, we found that exogenous supplementation of itaconate can activate Nrf2, and accordingly inhibit the STING-dependent NF-κB pathway, thereby alleviating the inflammation, ECM degeneration and senescence of chondrocytes stimulated by IL-1β. In addition, itaconate can regulate the polarization of RAW264.7 macrophages, further reducing the apoptosis of chondrocytes. In vivo, intra-articular injection of itaconate reduces the degradation of cartilage and inflammation of synovial membrane in the mouse OA model. In conclusion, the present work suggests that exogenous supplementation of itaconate inhibits the inflammation, senescence and ECM degeneration of chondrocytes through the Nrf2/STING/NF-κB axis and regulates the polarization of synovial macrophages, thereby ameliorating the progression of OA, which supports that itaconate as a potential drug for the treatment of OA.

Keywords:  Chondrocytes; Itaconate; Macrophages; Osteoarthritis; STING

DOI:  https://doi.org/10.1016/j.bcp.2022.114935
Biomed Pharmacother. 2022 Jan 29. pii: S0753-3322(22)00025-7. [Epub ahead of print]147 112637

Chronic low-grade inflammation is involved in TLR4 knockout-induced spontaneous obesity in aged mice.

Zhi-Yong Zhou, Yan Deng, Ying-Ling Wen, Yun-Qi Cheng, Kuang-Xun Li, Hong-Ping Chen.

  Chronic inflammation plays an important role in obesity-related complications, including insulin resistance, type 2 diabetes, and cardiovascular disease. The imbalances between T helper (Th)1/Th2 cells and Th17/regulatory T (Treg) cells participate in the pathogenesis of inflammation. Previously it was demonstrated that Toll-like receptor (TLR) 4 knockout (KO) prevents high-fat diet (HFD)-induced obesity of young mice (6 months of age), however the effect of TLR4 KO on spontaneous obesity in aged mice (18 month of age) is still unknown. To further study this, TLR4 KO and WT mice were fed with a standard chow diet from weaning to the endpoint of the experiment. We found that TLR4-/- mice were thinner compared with WT mice at 6 months (M) old. However, TLR4-/- mice spontaneously developed obesity with increased weight and adiposity in both subcutaneous and visceral fat depots by 18 M old. Our results also indicated that TLR4 KO activated TRIF/IRF3 signalling, induced inflammation, and repolarised alternatively-activated (M2) macrophages to classically-activated (M1) macrophages. In addition, TLR4 KO resulted in an increased spleen index and induced imbalances of Th1/Th2 and Th17/Treg cells which indicated the occurrence of chronic low-grade inflammation. In conclusion, chronic low-grade inflammation induced by TLR4 KO was involved in spontaneous obesity in aged mice. An emerging link was established among the TRIF/IRF3 pathway, chronic low-grade inflammation, and obesity. We hope that these novel findings will provide a potential preventive strategy for obesity and build a spontaneous obesity mouse model.

Keywords:  Aged mice; Inflammation factors; Obesity; T helper cell; TLR4

DOI:  https://doi.org/10.1016/j.biopha.2022.112637
Nat Commun. 2022 Feb 03. 13(1): 686

The selection force weakens with age because ageing evolves and not vice versa.

Stefano Giaimo, Arne Traulsen.

According to the classic theory of life history evolution, ageing evolves because selection on traits necessarily weakens throughout reproductive life. But this inexorable decline of the selection force with adult age was shown to crucially depend on specific assumptions that are not necessarily fulfilled. Whether ageing still evolves upon their relaxation remains an open problem. Here, we propose a fully dynamical model of life history evolution that does not presuppose any specific pattern the force of selection should follow. The model shows: (i) ageing can stably evolve, but negative ageing cannot; (ii) when ageing is a stable equilibrium, the associated selection force decreases with reproductive age; (iii) non-decreasing selection is either a transient or an unstable phenomenon. Thus, we generalize the classic theory of the evolution of ageing while overturning its logic: the decline of selection with age evolves dynamically, and is not an implicit consequence of certain assumptions.

DOI: https://doi.org/10.1038/s41467-022-28254-3
Mol Cell. 2022 Jan 27. pii: S1097-2765(22)00001-6. [Epub ahead of print]

SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage.

Karla F Meza-Sosa, Rui Miao, Francisco Navarro, Zhibin Zhang, Ying Zhang, Jun Jacob Hu, Corrine Corrina R Hartford, Xiao Ling Li, Gustavo Pedraza-Alva, Leonor Pérez-Martínez, Ashish Lal, Hao Wu, Judy Lieberman.

  p53, master transcriptional regulator of the genotoxic stress response, controls cell-cycle arrest and apoptosis following DNA damage. Here, we identify a p53-induced lncRNA suicidal PARP-1 cleavage enhancer (SPARCLE) adjacent to miR-34b/c required for p53-mediated apoptosis. SPARCLE is a ∼770-nt, nuclear lncRNA induced 1 day after DNA damage. Despite low expression (<16 copies/cell), SPARCLE deletion increases DNA repair and reduces DNA-damage-induced apoptosis as much as p53 deficiency, while its overexpression restores apoptosis in p53-deficient cells. SPARCLE does not alter gene expression. SPARCLE binds to PARP-1 with nanomolar affinity and causes apoptosis by acting as a caspase-3 cofactor for PARP-1 cleavage, which separates PARP-1's N-terminal (NT) DNA-binding domain from its catalytic domains. NT-PARP-1 inhibits DNA repair. Expressing NT-PARP-1 in SPARCLE-deficient cells increases unrepaired DNA damage and restores apoptosis after DNA damage. Thus, SPARCLE enhances p53-induced apoptosis by promoting PARP-1 cleavage, which interferes with DNA-damage repair.

Keywords:  PARP-1; apoptosis; genotoxic stress; lncRNA; miR-34; p53

DOI:  https://doi.org/10.1016/j.molcel.2022.01.001
Aging Dis. 2022 Feb;13(1): 232-245

Emerging Roles of Ceramide in Cardiovascular Diseases.

Hongyang Shu, Yizhong Peng, Weijian Hang, Na Li, Ning Zhou, Dao Wen Wang.

  Ceramide is a core molecule of sphingolipid metabolism that causes selective insulin resistance and dyslipidemia. Research on its involvement in cardiovascular diseases has grown rapidly. In resting cells, ceramide levels are extremely low, while they rapidly accumulate upon encountering external stimuli. Recently, the regulation of ceramide levels under pathological conditions, including myocardial infarction, hypertension, and atherosclerosis, has drawn great attention. Increased ceramide levels are strongly associated with adverse cardiovascular risks and events while inhibiting the synthesis of ceramide or accelerating its degradation improves a variety of cardiovascular diseases. In this article, we summarize the role of ceramide in cardiovascular disease, investigate the possible application of ceramide as a new diagnostic biomarker and a therapeutic target for cardiovascular disorders, and highlight the remaining problems.

Keywords:  cardiovascular disease; ceramide; diagnostic biomarker; sphingolipid metabolism; therapeutic target

DOI:  https://doi.org/10.14336/AD.2021.0710