bims-senagi 2022-10-09 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–10–09
twenty-six papers selected by
Maria Grazia Vizioli, Mayo Clinic

Restoration of lysosomal and mitochondrial function through p38 MAPK inhibition ameliorates senescence.
COVID-19 and cellular senescence.
Adipose tissue aging: An update on mechanisms and therapeutic strategies.
Epigenetic clock: a promising biomarker and practical tool in aging.
Muscle injury induces a transient senescence-like state that is required for myofiber growth during muscle regeneration.
Single-Cell Analyses of Heterotopic Ossification: Characteristics of Injury-Related Senescent Fibroblasts.
Accelerated aging phenotypes in the retinal pigment epithelium of Zmpste24-deficient mice.
Far-red Fluorescent Senescence-associated β-Galactosidase Probe for Identification and Enrichment of Senescent Tumor Cells by Flow Cytometry.
Cathepsin L was involved in vascular aging by mediating phenotypic transformation of vascular cells.
Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance.
Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy.
Aberrant methylation of Serpine1 mediates lung injury in neonatal mice prenatally exposed to intrauterine inflammation.
Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization.
Cellular senescence and abdominal aortic aneurysm: From pathogenesis to therapeutics.
Fusion and expansion of vitellogenin vesicles during Caenorhabditis elegans intestinal senescence.
AgeAnno: a knowledgebase of single-cell annotation of aging in human.
Long-term dietary restriction ameliorates ageing-related renal fibrosis in male mice by normalizing mitochondrial functions and autophagy.
SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.
Single-cell epigenome analysis reveals age-associated decay of heterochromatin domains in excitatory neurons in the mouse brain.
Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites.
Gut microbiota as a promising therapeutic target for age-related sarcopenia.
Dicer1 deficient mice exhibit premature aging and metabolic perturbations in adipocytes.
11β-HSD1 contributes to age-related metabolic decline in male mice.
Aging attenuates diurnal lipid uptake by brown adipose tissue.
Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice.
Aging compromises human islet beta cell function and identity by decreasing transcription factor activity and inducing ER stress.

Rejuvenation Res. 2022 Oct 07.

Restoration of lysosomal and mitochondrial function through p38 MAPK inhibition ameliorates senescence.

Ji Yun Park, Haneur Lee, Eun Seon Song, Yun Haeng Lee, Myeong Uk Kuk, Gahyun Ko, Hyung Wook Kwon, Youngjoo Byun, Joon Tae Park.

Oncogene-induced senescence (OIS), characterized by irreversible cell cycle arrest by oncogene activation, plays an important role in the pathogenesis of aging and age-related diseases. Recent research indicates that OIS is driven by activation of mitogen-activated protein kinase (MAPK). However, it is not apparent whether MAPK inhibition helps to recover senescence. In our previous study, we uncovered p38 MAPK inhibitor, SB203580, as an effective agent to reduce ROS and increase proliferation in premature senescent cells. In this study, we evaluated whether SB203580 could ameliorate senescence in normal senescent cells. The senescence-improving effect was observed in the results that SB203580 treatment restored lysosomal function, as evidenced by a decrease in lysosomal mass and an increase in autophagic vacuoles. Then, SB203580-mediated lysosomal function restoration triggered the clearance of damaged mitochondria, leading to metabolic reprogramming necessary for amelioration of senescence. Indeed, p38 MAPK inhibition by SB203580 improved key senescent phenotypes. Our findings suggest a novel mechanism by which modulation of p38 MAPK activity leads to senescence improvement through functional restoration of lysosome and mitochondria.

DOI: https://doi.org/10.1089/rej.2022.0043
Nat Rev Immunol. 2022 Oct 05.

COVID-19 and cellular senescence.

Clemens A Schmitt, Tamar Tchkonia, Laura J Niedernhofer, Paul D Robbins, James L Kirkland, Soyoung Lee.

The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a 'cytokine storm', tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.

DOI: https://doi.org/10.1038/s41577-022-00785-2
Metabolism. 2022 Oct 03. pii: S0026-0495(22)00206-2. [Epub ahead of print] 155328

Adipose tissue aging: An update on mechanisms and therapeutic strategies.

Zhaohua Cai, Ben He.

  Aging is a complex biological process characterized by a progressive loss of physiological integrity and increased vulnerability to age-related diseases. Adipose tissue plays central roles in the maintenance of whole-body metabolism homeostasis and has recently attracted significant attention as a biological driver of aging and age-related diseases. Here, we review the most recent advances in our understanding of the molecular and cellular mechanisms underlying age-related decline in adipose tissue function. In particular, we focus on the complex inter-relationship between metabolism, immune, and sympathetic nervous system within adipose tissue during aging. Moreover, we discuss the rejuvenation strategies to delay aging and extend lifespan, including senescent cell ablation (senolytics), dietary intervention, physical exercise, and heterochronic parabiosis. Understanding the pathological mechanisms that underlie adipose tissue aging will be critical for the development of new intervention strategies to slow or reverse aging and age-related diseases.

Keywords:  Adipose tissue; Aging; Inflammation

DOI:  https://doi.org/10.1016/j.metabol.2022.155328
Ageing Res Rev. 2022 Oct 04. pii: S1568-1637(22)00185-4. [Epub ahead of print] 101743

Epigenetic clock: a promising biomarker and practical tool in aging.

Ran Duan, Qiaoyu Fu, Yu Sun, Qingfeng Li.

  As a complicated process, aging is characterized by various changes at the cellular, subcellular and nuclear levels, one of which is epigenetic aging. With increasing awareness of the critical role that epigenetic alternations play in aging, DNA methylation patterns have been employed as a measure of biological age, currently referred to as the epigenetic clock. This review provides a comprehensive overview of the epigenetic clock as a biomarker of aging and a useful tool to manage healthy aging. In this burgeoning scientific field, various kinds of epigenetic clocks continue to emerge, including Horvath's clock, Hannum's clock, DNA PhenoAge, and DNA GrimAge. We hereby present the most classic epigenetic clocks, as well as their differences. Correlations of epigenetic age with morbidity, mortality and other factors suggest the potential of epigenetic clocks for risk prediction and identification in the context of aging. In particular, we summarize studies on promising age-reversing interventions, with epigenetic clocks employed as a practical tool in the efficacy evaluation. We also discuss how the lack of higher-quality information poses a major challenge, and offer some suggestions to address existing obstacles. Hopefully, our review will help provide an appropriate understanding of the epigenetic clocks, thereby enabling novel insights into the aging process and how it can be manipulated to promote healthy aging.

Keywords:  DNA methylation; Epigenetic clock; aging; chronological age; epigenetic age

DOI:  https://doi.org/10.1016/j.arr.2022.101743
FASEB J. 2022 Nov;36(11): e22587

Muscle injury induces a transient senescence-like state that is required for myofiber growth during muscle regeneration.

Laura V Young, Griffen Wakelin, Alasdair W R Cameron, Stevan A Springer, Joel P Ross, Grant Wolters, J Patrick Murphy, Michel G Arsenault, Sean Ng, Nicolás Collao, Michael De Lisio, Vladimir Ljubicic, Adam P W Johnston.

  Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a, and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single-cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are "transiently" present within regenerating skeletal muscle and within the muscles of D2-mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibrog-adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence-associated beta-gal (SA-β-gal) activity. Importantly, when these cells were removed with ABT-263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion. These results highlight that an "acute" senescent phenotype facilitates regeneration similar to skin and neonatal myocardium.

Keywords:  muscle; regeneration; senescence; single-cell RNA sequencing

DOI:  https://doi.org/10.1096/fj.202200289RR
J Inflamm Res. 2022 ;15 5579-5593

Single-Cell Analyses of Heterotopic Ossification: Characteristics of Injury-Related Senescent Fibroblasts.

Qiang Zhang, Dong Zhou, Yu Liang.

   Introduction: Injury-related cellular senescence may be involved in heterotopic ossification, and no research has been performed about this before.
Methods and Results: The study utilized integrated single-cell RNA-sequencing (scRNA-seq) data from heterotopic ossification samples. The number of senescent cells increased from day 3 and reached the highest level at day 21. However, the expression level of Cyclin Dependent Kinase Inhibitor 2A (Cdkn2a) has no such tendency as the change of cell amount, indicating that the expression level of Cdkn2a may be different in different types of senescent cells or the same time of senescent cell at different time points. The expression level of SASPs (senescence associated secret phenotypes) was also different in different types of senescent cells or at different time points. The GO (gene ontology) analysis revealed that the senescent cells were significantly correlated with the ossification processes, like ECM organization, cell adhesion, ossification, cartilage development, etc. Trajectory analysis showed that injury-related senescent fibroblasts (day 7 and 21) and age-related senescent fibroblasts (day 0 and 42) were in different branches. GO analysis demonstrated that injury-related senescent fibroblasts were mainly related to ossification and ECM remodeling. The KEGG (Kyoto Encyclopedia of Genes and Genomes) results revealed that the ossification was significantly corrected with protein processing in PI3K-Akt signaling, MAPK signaling, focal adhesion, etc.
Conclusion: Consequently, we demonstrated that, unlike age-related senescence, the injury-related senescence demonstrated significantly different SASP phenotypes. The injury-related senescence of fibroblasts is associated with heterotopic ossification formation and may act through PI3K/Akt-induced SASPs.

Keywords:  SASPs; fibroblasts; heterotopic ossification; scRNA; senescence; senescence associated secret phenotypes; single-cell RNA-sequencing

DOI:  https://doi.org/10.2147/JIR.S369376
Biochem Biophys Res Commun. 2022 Sep 25. pii: S0006-291X(22)01317-1. [Epub ahead of print]632 62-68

Accelerated aging phenotypes in the retinal pigment epithelium of Zmpste24-deficient mice.

Jae-Byoung Chae, Chul-Woo Park, Hyeong Min Lee, Leo Sungwong Choi, Chaehee Park, Junghoon Kim, Jaejin Shin, Jooseung Hyeon, Jihan Lee, Hyungwoo Lee, Hyung Soon Park, Chang-Hoon Nam, Hyewon Chung.

  Age-related macular degeneration (AMD) is a chronic and progressive disease characterized by degeneration of the retinal pigment epithelium (RPE) and retina that ultimately leads to loss of vision. The pathological mechanisms of AMD are not fully known. Cellular senescence, which is a state of cell cycle arrest induced by DNA-damage or aging, is hypothesized to critically affect the pathogenesis of AMD. In this study, we examined the relationship between cellular senescence and RPE/retinal degeneration in mouse models of natural aging and accelerated aging. We performed a bulk RNA sequencing of the RPE cells from adult (8 months old) and naturally-aged old (24 months old) mice and found that common signatures of senescence and AMD pathology - inflammation, apoptosis, and blood vessel formation - are upregulated in the RPE of old mice. Next, we investigated markers of senescence and the degree of RPE/retinal degeneration in Zmpste24-deficient (Zmpste24-/-) mice, which is a model for progeria and accelerated aging. We found that Zmpste24-/- mice display markedly greater level of senescence-related markers in RPE and significant RPE/retinal degeneration compared to wild-type mice, in a manner consistent with natural aging. Overall, these results provide support for the association between cellular senescence of RPE and the pathogenesis of AMD, and suggest the use of Zmpste24-/- mice as a novel senescent RPE model of AMD.

Keywords:  AMD; RPE; Retina; Senescence; Zmpste24

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.061
J Vis Exp. 2022 Sep 13.

Far-red Fluorescent Senescence-associated β-Galactosidase Probe for Identification and Enrichment of Senescent Tumor Cells by Flow Cytometry.

Amy Flor, Joanna Pagacz, DeShawn Thompson, Stephen Kron.

Cellular senescence is a state of proliferative arrest induced by biological damage that normally accrues over years in aging cells but may also emerge rapidly in tumor cells as a response to damage induced by various cancer treatments. Tumor cell senescence is generally considered undesirable, as senescent cells become resistant to death and block tumor remission while exacerbating tumor malignancy and treatment resistance. Therefore, the identification of senescent tumor cells is of ongoing interest to the cancer research community. Various senescence assays exist, many based on the activity of the well-known senescence marker, senescence-associated beta-galactosidase (SA-β-Gal). Typically, the SA-β-Gal assay is performed using a chromogenic substrate (X-Gal) on fixed cells, with the slow and subjective enumeration of "blue" senescent cells by light microscopy. Improved assays using cell-permeant, fluorescent SA-β-Gal substrates, including C12-FDG (green) and DDAO-Galactoside (DDAOG; far-red), have enabled the analysis of living cells and allowed the use of high-throughput fluorescent analysis platforms, including flow cytometers. C12-FDG is a well-documented probe for SA-β-Gal, but its green fluorescent emission overlaps with intrinsic cellular autofluorescence (AF) that arises during senescence due to the accumulation of lipofuscin aggregates. By utilizing the far-red SA-β-Gal probe DDAOG, green cellular autofluorescence can be used as a secondary parameter to confirm senescence, adding reliability to the assay. The remaining fluorescence channels can be used for cell viability staining or optional fluorescent immunolabeling. Using flow cytometry, we demonstrate the use of DDAOG and lipofuscin autofluorescence as a dual-parameter assay for the identification of senescent tumor cells. Quantitation of the percentage of viable senescent cells is performed. If desired, an optional immunolabeling step may be included to evaluate cell surface antigens of interest. Identified senescent cells can also be flow cytometrically sorted and collected for downstream analysis. Collected senescent cells can be immediately lysed (e.g., for immunoassays or 'omics analysis) or further cultured.

DOI: https://doi.org/10.3791/64176
Arch Gerontol Geriatr. 2022 Oct 04. pii: S0167-4943(22)00215-1. [Epub ahead of print]104 104828

Cathepsin L was involved in vascular aging by mediating phenotypic transformation of vascular cells.

Xin Pan, Yanping Yu, Yuxing Chen, Yanru Wang, Guoxiang Fu.

  Vascular media and adventitia-induced remodeling plays an important role in vascular aging. However, the mechanism remains unclear. This study aims to investigate the mechanisms underlying vascular aging. Transcriptome analysis revealed that the expression of cathepsin L (CTSL) significantly decreased in arteries of old mice (24 months old) compared with that in arteries of young mice (4 months old), which was confirmed by immunohistochemistry and Western blot. The expression of CTSL in adventitia fibroblasts (AFs) and vascular smooth muscle cells (VSMCs) of aged mice was lower than that of young mice. Compared with wild-type control mice, CTSL knockout (CTSL - /-) mice had increased collagen deposition (fibrosis) and decreased telomerase activity and LC3Ⅱ/ LC3Ⅰratio. The expression of mammalian target of rapamycin (mTOR) and osteopontin (OPN) increased in aortas of CTSL-/-mice compared with that in aortas of wild-type control mice. In vitro, lentivirus-mediated CTSL knockdown induced VSMCs senescence and AFs transformed into myofibroblasts (MFs). Rapamycin, a mTOR inhibitor, inhibited CTSL deficiency induced VSMCs senescence, osteopontin (OPN) secretion and AFs migration. In conclusion, the decreased level of CTSL with age may participate in vascular aging by promoting the phenotypic transformation of vascular cells.

Keywords:  Cathepsin L; Osteopontin; Phenotypic transformation; Vascular aging; mTOR

DOI:  https://doi.org/10.1016/j.archger.2022.104828
Oncogene. 2022 Oct 06.

Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance.

Changxu Wang, Qilai Long, Qiang Fu, Qixia Xu, Da Fu, Yan Li, Libin Gao, Jianming Guo, Xiaoling Zhang, Eric W-F Lam, Judith Campisi, Yu Sun.

The tumor microenvironment (TME) represents a milieu enabling cancer cells to develop malignant properties, while concerted interactions between cancer and stromal cells frequently shape an "activated/reprogramed" niche to accelerate pathological progression. Here we report that a soluble factor epiregulin (EREG) is produced by senescent stromal cells, which non-cell-autonomously develop the senescence-associated secretory phenotype (SASP) upon DNA damage. Genotoxicity triggers EREG expression by engaging NF-κB and C/EBP, a process supported by elevated chromatin accessibility and increased histone acetylation. Stromal EREG reprograms the expression profile of recipient neoplastic cells in a paracrine manner, causing upregulation of MARCHF4, a membrane-bound E3 ubiquitin ligase involved in malignant progression, specifically drug resistance. A combinational strategy that empowers EREG-specific targeting in treatment-damaged TME significantly promotes cancer therapeutic efficacy in preclinical trials, achieving response indices superior to those of solely targeting cancer cells. In clinical oncology, EREG is expressed in tumor stroma and handily measurable in circulating blood of cancer patients post-chemotherapy. This study establishes EREG as both a targetable SASP factor and a new noninvasive biomarker of treatment-damaged TME, thus disclosing its substantial value in translational medicine.

DOI: https://doi.org/10.1038/s41388-022-02476-7
J Immunother Cancer. 2022 Oct;pii: e005020. [Epub ahead of print]10(10):

Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy.

Xia Liu, Fusheng Si, David Bagley, Feiya Ma, Yuanqin Zhang, Yan Tao, Emily Shaw, Guangyong Peng.

   BACKGROUND: Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.
METHODS: Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy.
RESULTS: We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.
CONCLUSIONS: These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.

Keywords:  Immunotherapy; Melanoma; T-Lymphocytes; Tumor Escape; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2022-005020
Cell Biosci. 2022 Oct 01. 12(1): 164

Aberrant methylation of Serpine1 mediates lung injury in neonatal mice prenatally exposed to intrauterine inflammation.

Dongting Yao, Jiuru Zhao, Qianqian Zhang, Tao Wang, Meng Ni, Sudong Qi, Qianwen Shen, Wei Li, Baihe Li, Xiya Ding, Zhiwei Liu.

   BACKGROUND: Intrauterine inflammation (IUI) alters epigenetic modifications in offspring, leading to lung injury. However, the epigenetic mechanism underlying IUI-induced lung injury remains uncertain. In the present study, we aim to investigate the effect of IUI on lung development, and to identify the key molecule involved in this process and its epigenetic regulatory mechanism.
RESULTS: Serpine1 was upregulated in the lung tissue of neonatal mice with IUI. Intranasal delivery of Serpine1 siRNA markedly reversed IUI-induced lung injury. Serpine1 overexpression substantially promoted cell senescence of both human and murine lung epithelial cells, reflected by decreased cell proliferation and increased senescence-associated β-galactosidase activity, G0/G1 cell fraction, senescence marker, and oxidative and DNA damage marker expression. IUI decreased the methylation level of the Serpine1 promoter, and methylation of the promoter led to transcriptional repression of Serpine1. Furthermore, IUI promoted the expression of Tet1 potentially through TNF-α, while Tet1 facilitated the demethylation of Serpine1 promoter. DNA pull-down and ChIP assays revealed that the Serpine1 promoter was regulated by Rela and Hdac2. DNA demethylation increased the recruitment of Rela to the Serpine1 promoter and induced the release of Hdac2.
CONCLUSION: Increased Serpine1 expression mediated by DNA demethylation causes lung injury in neonatal mice with IUI. Therefore, therapeutic interventions targeting Serpine1 may effectively prevent IUI-induced lung injury.

Keywords:  Cell senescence; Hypomethylation; Intrauterine inflammation; Lung injury; Serpine1

DOI:  https://doi.org/10.1186/s13578-022-00901-8
Cell Chem Biol. 2022 Oct 03. pii: S2451-9456(22)00350-6. [Epub ahead of print]

Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization.

Yue Liu, Rick C Betori, Joanna Pagacz, Grant B Frost, Elena V Efimova, Ding Wu, Donald J Wolfgeher, Tracy M Bryan, Scott B Cohen, Karl A Scheidt, Stephen J Kron.

  Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.

Keywords:  DNA damage response; TERT; anti-tumor immunity; combination therapy; radiation; senescence

DOI:  https://doi.org/10.1016/j.chembiol.2022.09.002
Front Cardiovasc Med. 2022 ;9 999465

Cellular senescence and abdominal aortic aneurysm: From pathogenesis to therapeutics.

Ding Wang, Xinyu Hao, Longyuan Jia, Yuchen Jing, Bo Jiang, Shijie Xin.

  As China's population enters the aging stage, the threat of abdominal aortic aneurysm (AAA) mainly in elderly patients is becoming more and more serious. It is of great clinical significance to study the pathogenesis of AAA and explore potential therapeutic targets. The purpose of this paper is to analyze the pathogenesis of AAA from the perspective of cellular senescence: on the basis of clear evidence of cellular senescence in aneurysm wall, we actively elucidate specific molecular and regulatory pathways, and to explore the targeted drugs related to senescence and senescent cells eliminate measures, eventually improve the health of patients with AAA and prolong the life of human beings.

Keywords:  abdominal aortic aneurysm; cellular senescence; longevity; pathogenesis; therapeutics

DOI:  https://doi.org/10.3389/fcvm.2022.999465
Aging Cell. 2022 Oct 05. e13719

Fusion and expansion of vitellogenin vesicles during Caenorhabditis elegans intestinal senescence.

Chao Zhai, Nan Zhang, Xi-Xia Li, Xi Chen, Fei Sun, Meng-Qiu Dong.

  Some of the most conspicuous aging phenotypes of C. elegans are related to post-reproductive production of vitellogenins (Vtg), which form yolk protein (YP) complexes after processing and lipid loading. Vtg/YP levels show huge increases with age, and inhibition of this extends lifespan, but how subcellular and organism-wide distribution of these proteins changes with age has not been systematically explored. Here, this has been done to understand how vitellogenesis promotes aging. The age-associated changes of intestinal vitellogenin vesicles (VVs), pseudocoelomic yolk patches (PYPs), and gonadal yolk organelles (YOs) have been characterized by immuno-electron microscopy. We find that from reproductive adult day 2 (AD 2) to post-reproductive AD 6 and AD 9, intestinal VVs expand from 0.2 to 3-4 μm in diameter or by >3000 times in volume, PYPs increase by >3 times in YP concentration and volume, while YOs in oocytes shrink slightly from 0.5 to 0.4 μm in diameter or by 49% in volume. In AD 6 and AD 9 worms, mislocalized YOs found in the hypodermis, uterine cells, and the somatic gonadal sheath can reach a size of 10 μm across in the former two tissues. This remarkable size increase of VVs and that of mislocalized YOs in post-reproductive worms are accompanied by extensive fusion between these Vtg/YP-containing vesicular structures in somatic cells. In contrast, no fusion is seen between YOs in oocytes. We propose that in addition to the continued production of Vtg, excessive fusion between VVs and mislocalized YOs in the soma worsen the aging pathologies seen in C. elegans.

Keywords:   C. elegans ; Aging; Senescence; Vesicle fusion; Vitellogenin; Yolk

DOI:  https://doi.org/10.1111/acel.13719
Nucleic Acids Res. 2022 Oct 06. pii: gkac847. [Epub ahead of print]

AgeAnno: a knowledgebase of single-cell annotation of aging in human.

Kexin Huang, Hoaran Gong, Jingjing Guan, Lingxiao Zhang, Changbao Hu, Weiling Zhao, Liyu Huang, Wei Zhang, Pora Kim, Xiaobo Zhou.

Aging is a complex process that accompanied by molecular and cellular alterations. The identification of tissue-/cell type-specific biomarkers of aging and elucidation of the detailed biological mechanisms of aging-related genes at the single-cell level can help to understand the heterogeneous aging process and design targeted anti-aging therapeutics. Here, we built AgeAnno (https://relab.xidian.edu.cn/AgeAnno/#/), a knowledgebase of single cell annotation of aging in human, aiming to provide comprehensive characterizations for aging-related genes across diverse tissue-cell types in human by using single-cell RNA and ATAC sequencing data (scRNA and scATAC). The current version of AgeAnno houses 1 678 610 cells from 28 healthy tissue samples with ages ranging from 0 to 110 years. We collected 5580 aging-related genes from previous resources and performed dynamic functional annotations of the cellular context. For the scRNA data, we performed analyses include differential gene expression, gene variation coefficient, cell communication network, transcription factor (TF) regulatory network, and immune cell proportionc. AgeAnno also provides differential chromatin accessibility analysis, motif/TF enrichment and footprint analysis, and co-accessibility peak analysis for scATAC data. AgeAnno will be a unique resource to systematically characterize aging-related genes across diverse tissue-cell types in human, and it could facilitate antiaging and aging-related disease research.

DOI: https://doi.org/10.1093/nar/gkac847
Biogerontology. 2022 Oct 02.

Long-term dietary restriction ameliorates ageing-related renal fibrosis in male mice by normalizing mitochondrial functions and autophagy.

Chun-Hsien Chiang, Sin-Jin Li, Ting-Rui Zhang, Ching-Yi Chen.

  As the kidneys age, gradual changes in the structures and functions of mitochondria occur. Dietary restriction (DR) can play a protective role in ageing-associated renal decline, however the exact mechanisms involved are still unclear. This study aims to clarify the beneficial effects of long-term DR on renal ageing and to explore the potential mechanisms of mitochondrial homeostasis. Eight-week-old C57BL/6 male mice (n = 30) were randomly divided into three groups, Young-AL (AL, ad libitum), Aged-AL, and Aged-DR (60% intake of AL). Mice were sacrificed at age of 7 months (Young) or 22 months (Aged). Heavier body and kidney weights were associated with ageing, but DR reduced these increases in aged mice. Ageing caused extensive tubulointerstitial fibrosis and glomerulosclerosis in the kidney. Giant mitochondria with looser and irregular crista were observed in Aged-AL kidneys. DR retarded these morphological alterations in aged kidneys. In addition, DR reversed the increase of MDA caused by ageing. Renal ATP level was elevated by DR treatment. Mitochondrial-related proteins were analysed to elucidate this association. Ageing downregulated the renal levels of VDAC, FOXO1, SOD2, LC3I and II, and upregulated the renal levels of MFN2 and PINK1. In contrast, DR elevated the levels of VDAC, FOXO1, and LC3I and reduced the ratio of LC3II to LC3I in aged kidneys. To conclude, impaired mitochondria, increased oxidative stress, and severe fibrosis were noticed in the aged kidneys, and DR improved these changes by increasing functional mitochondria and promoting autophagic clearance.

Keywords:  Autophagy; Dietary restriction; Kidney; Mitochondrial functions

DOI:  https://doi.org/10.1007/s10522-022-09993-8
Aging Cell. 2022 Oct 05. e13721

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.

Rashpal S Dhillon, Yiming Amy Qin, Paul R van Ginkel, Vivian X Fu, James M Vann, Alexis J Lawton, Cara L Green, Fúlvia B Manchado-Gobatto, Claudio A Gobatto, Dudley W Lamming, Tomas A Prolla, John M Denu.

  Mitochondrial NAD+ -dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/- ) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

Keywords:  aerobic fitness; calorie restriction; fatty acid oxidation; fuel switching; lifespan; mitochondrial acetylation; mitochondrial respiration; sirtuins

DOI:  https://doi.org/10.1111/acel.13721
Cell Res. 2022 Oct 07.

Single-cell epigenome analysis reveals age-associated decay of heterochromatin domains in excitatory neurons in the mouse brain.

Yanxiao Zhang, Maria Luisa Amaral, Chenxu Zhu, Steven Francis Grieco, Xiaomeng Hou, Lin Lin, Justin Buchanan, Liqi Tong, Sebastian Preissl, Xiangmin Xu, Bing Ren.

Loss of heterochromatin has been implicated as a cause of pre-mature aging and age-associated decline in organ functions in mammals; however, the specific cell types and gene loci affected by this type of epigenetic change have remained unclear. To address this knowledge gap, we probed chromatin accessibility at single-cell resolution in the brains, hearts, skeletal muscles, and bone marrows from young, middle-aged, and old mice, and assessed age-associated changes at 353,126 candidate cis-regulatory elements (cCREs) across 32 major cell types. Unexpectedly, we detected increased chromatin accessibility within specific heterochromatin domains in old mouse excitatory neurons. The gain of chromatin accessibility at these genomic loci was accompanied by the cell-type-specific loss of heterochromatin and activation of LINE1 elements. Immunostaining further confirmed the loss of the heterochromatin mark H3K9me3 in the excitatory neurons but not in inhibitory neurons or glial cells. Our results reveal the cell-type-specific changes in chromatin landscapes in old mice and shed light on the scope of heterochromatin loss in mammalian aging.

DOI: https://doi.org/10.1038/s41422-022-00719-6
Aging (Albany NY). 2022 Oct 03. 14(undefined):

Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites.

Antoine Daunay, Lise M Hardy, Yosra Bouyacoub, Mourad Sahbatou, Mathilde Touvier, Hélène Blanché, Jean-François Deleuze, Alexandre How-Kit.

  Aging is a progressive time-dependent biological process affecting differentially individuals, who can sometimes present exceptional longevity. Epigenetic alterations are one of the hallmarks of aging, which comprise the epigenetic drift and clock at DNA methylation level. In the present study, we estimated the DNA methylation-based age (DNAmage) using four epigenetic clocks based on a small number of CpGs in French centenarians and semi-supercentenarians (CSSC, n=214) as well as nonagenarians' and centenarians' offspring (NCO, n=143) compared to individuals from the French general population (CG, n=149). DNA methylation analysis of the nine CpGs included in the epigenetic clocks showed high correlation with chronological age (-0.66>R>0.54) and also the presence of an epigenetic drift for four CpGs that was only visible in CSSC. DNAmage analysis showed that CSSC and to a lesser extend NCO present a younger DNAmage than their chronological age (15-28.5 years for CSSC, 4.4-11.5 years for NCO and 4.2-8.2 years for CG), which were strongly significant in CSSC compared to CG (p-values<2.2e-16). These differences suggest that epigenetic aging and potentially biological aging are slowed in exceptionally long-lived individuals and that epigenetic clocks based on a small number of CpGs are sufficient to reveal alterations of the global epigenetic clock.

Keywords:  DNA methylation; DNAmage; centenarians; epigenetic clock; longevity; pyrosequencing

DOI:  https://doi.org/10.18632/aging.204316
Ageing Res Rev. 2022 Sep 28. pii: S1568-1637(22)00181-7. [Epub ahead of print]81 101739

Gut microbiota as a promising therapeutic target for age-related sarcopenia.

Ting Zhang, Jin-Ke Cheng, Yao-Min Hu.

  Sarcopenia is characterized by a progressive loss of skeletal muscle mass and function with aging. Recently, sarcopenia has been shown to be closely related with gut microbiota. Strategies such as probiotics and fecal microbiota transplantation have shown potential to ameliorate the muscle loss. This review will focus on the age-related sarcopenia, in particular on the relationship between gut microbiota and age-related sarcopenia, how gut microbiota is engaged in sarcopenia, and the potential role of gut microbiota in the treatment of age-related sarcopenia.

Keywords:  Aging; Gut microbiota; Microbiota; Probiotics; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1016/j.arr.2022.101739
iScience. 2022 Oct 21. 25(10): 105149

Dicer1 deficient mice exhibit premature aging and metabolic perturbations in adipocytes.

Aurore De Cauwer, Thomas Loustau, William Erne, Angélique Pichot, Anne Molitor, Tristan Stemmelen, Raphael Carapito, Gertraud Orend, Seiamak Bahram, Philippe Georgel.

  Age-related diseases are major concern in developed countries. To avoid disabilities that accompany increased lifespan, pharmaceutical approaches are considered. Therefore, appropriate animal models are required for a better understanding of aging processes and potential in vivo assays to evaluate the impact of molecules that may delay the occurrence of age-related diseases. Few mouse models exhibiting pathological aging exist, but currently, none of them reproducibly mimics human diseases like osteoporosis, cognitive dysfunctions or sarcopenia that can be seen in some, but not all, elders. Here, we describe the premature aging phenotypes of Dicer-deficient mature animals, which exhibit an overall deterioration of many organs and tissues (skin, heart, and adipose tissue) ultimately leading to a significant reduction of their lifespan. Molecular characterization of transcriptional responses focused on the adipose tissue suggested that both canonical and non-canonical functions of DICER are involved in this process and highlight potential actionable pathways to revert it.

Keywords:  Model organism; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2022.105149
J Endocrinol. 2022 Dec 01. 255(3): 117-129

11β-HSD1 contributes to age-related metabolic decline in male mice.

Stuart A Morgan, Laura L Gathercole, Zaki K Hassan-Smith, Jeremy Tomlinson, Paul M Stewart, Gareth G Lavery.

  The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing's syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1-/-) following 4 months high-fat feeding. We found that high fat-fed 11β-HSD1-/- mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11β-HSD1-/- mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11β-HSD1-/- mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11β-HSD1-/- animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11β-HSD1-/- mice had an age-related increase in morning corticosterone. Surprisingly, 11β-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11β-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.

Keywords:  11β-HSD1; Cushing’s syndrome; ageing; glucocorticoids; insulin resistance; obesity

DOI:  https://doi.org/10.1530/JOE-22-0169
Aging (Albany NY). 2022 Oct 04. 14(undefined):

Aging attenuates diurnal lipid uptake by brown adipose tissue.

Wietse In Het Panhuis, Milena Schönke, Ricky Siebeler, Salwa Afkir, Rianne Baelde, Amanda C M Pronk, Trea C M Streefland, Hetty C M Sips, Reshma A Lalai, Patrick C N Rensen, Sander Kooijman.

  Brown adipose tissue (BAT) contributes to cardiometabolic health by taking up glucose and lipids for oxidation, a process that displays a strong diurnal rhythm. While aging has been shown to reduce thermogenic characteristics of BAT, it is as yet unknown whether this reduction is specific to the time of day. Therefore, we assessed whole-body and BAT energy metabolism in young and middle-aged male and female C57BL/6J mice and studied the consequences for lipid metabolism in humanized APOE*3-Leiden.CETP mice (also on a C57BL/6J background). We demonstrate that in middle-aged versus young mice body temperature is lower in both male and female mice, while uptake of triglyceride (TG)-derived fatty acids (FAs) by BAT, reflecting metabolic activity, is attenuated at its peak at the onset of the dark (wakeful) phase in female mice. This coincided with delayed plasma clearance of TG-rich lipoproteins and TG-depleted lipoprotein core remnants, and elevated plasma TGs at the same time point. Furthermore, middle-aged female mice showed increased adiposity, accompanied by lipid accumulation, increased expression of genes involved in lipogenesis, and reduced expression of genes involved in fat oxidation and the intracellular clock machinery in BAT. Peak abundance of lipoprotein lipase (LPL), a crucial regulator of FA uptake, was attenuated in BAT. Our findings suggest that LPL is a potential therapeutic target for restoring diurnal metabolic BAT activity, and that efficiency of strategies targeting BAT may be improved by including time of day as an important factor.

Keywords:  APOE*3-Leiden.CETP mice; aging; brown adipose tissue; diurnal rhythm; lipoprotein metabolism

DOI:  https://doi.org/10.18632/aging.204318
Nat Commun. 2022 Oct 05. 13(1): 5655

Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice.

Takayoshi Sasako, Toshihiro Umehara, Kotaro Soeda, Kazuma Kaneko, Miho Suzuki, Naoki Kobayashi, Yukiko Okazaki, Miwa Tamura-Nakano, Tomoki Chiba, Domenico Accili, C Ronald Kahn, Tetsuo Noda, Hiroshi Asahara, Toshimasa Yamauchi, Takashi Kadowaki, Kohjiro Ueki.

Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1/4, but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan.

DOI: https://doi.org/10.1038/s41467-022-33008-2
Sci Adv. 2022 Oct 07. 8(40): eabo3932

Aging compromises human islet beta cell function and identity by decreasing transcription factor activity and inducing ER stress.

Shristi Shrestha, Galina Erikson, James Lyon, Aliya F Spigelman, Austin Bautista, Jocelyn E Manning Fox, Cristiane Dos Santos, Maxim Shokhirev, Jean-Philippe Cartailler, Martin W Hetzer, Patrick E MacDonald, Rafael Arrojo E Drigo.

Pancreatic islet beta cells are essential for maintaining glucose homeostasis. To understand the impact of aging on beta cells, we performed meta-analysis of single-cell RNA sequencing datasets, transcription factor (TF) regulon analysis, high-resolution confocal microscopy, and measured insulin secretion from nondiabetic donors spanning most of the human life span. This revealed the range of molecular and functional changes that occur during beta cell aging, including the transcriptional deregulation that associates with cellular immaturity and reorganization of beta cell TF networks, increased gene transcription rates, and reduced glucose-stimulated insulin release. These alterations associate with activation of endoplasmic reticulum (ER) stress and autophagy pathways. We propose that a chronic state of ER stress undermines old beta cell structure function to increase the risk of beta cell failure and type 2 diabetes onset as humans age.

DOI: https://doi.org/10.1126/sciadv.abo3932