bims-senagi 2022-03-13 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–03–13
forty papers selected by
Maria Grazia Vizioli, Mayo Clinic

Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development.
Synergistic Anti-Ageing through Senescent Cells Specific Reprogramming.
Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis.
Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence.
CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts.
Senescent CD4+CD28- T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis.
Age Related Osteoporosis: Targeting Cellular Senescence.
Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence.
Bone marrow adiposity in models of radiation- and aging-related bone loss is dependent on cellular senescence.
AAV-mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice.
Biological mechanisms of aging predict age-related disease co-occurrence in patients.
Altered p16Ink4a, IL-1β, and Lamin b1 Protein Expression Suggest Cellular Senescence in Deep Endometriotic Lesions.
CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging.
Role of senescent cells in the motile behavior of active, non-senescent cells in confluent populations.
Dynamic regulation of myofibroblast phenotype in cellular senescence.
DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.
Brain cellular senescence in mouse models of Alzheimer's disease.
Attenuation of intrinsic aging of the skin via elimination of senescent dermal fibroblasts with senolytic drugs.
mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a.
Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.
Immunosenescence: the role of age in multiple sclerosis.
Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis.
Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts.
Maintenance of Chronological Aging Features in Culture of Normal Human Dermal Fibroblasts from Old Donors.
Fluorometholone inhibits high glucose-induced cellular senescence in human retinal endothelial cells.
Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
The Complicated Nature of Somatic mtDNA Mutations in Aging.
Escape from senescence: revisiting cancer therapeutic strategies.
Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart.
Metabolic Regulation of Stem Cells in Aging.
Pseudotime Analysis Reveals Exponential Trends in DNA Methylation Aging with Mortality Associated Timescales.
Activating PGC-1α-mediated signaling cascades in the aorta contributes to the amelioration of vascular senescence and atherosclerosis by 2,3,4',5-tetrahydroxystilbene-2-O-β-d-glycoside.
Partial reprogramming strategy for intervertebral disc rejuvenation by activating energy switch.
Effects of dietary macronutrients on the hepatic transcriptome and serum metabolome in mice.
Distinct and diverse chromatin-proteomes of ageing mouse organs reveal protein signatures that correlate with physiological functions.
Aging of intestinal stem cells.
Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.
Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns.
The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging.
DNA Damage and Activation of cGAS/STING Pathway Induce Tumor Microenvironment Remodeling.

Front Cell Dev Biol. 2022 ;10 822816

Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development.

Li Hu, Huiqin Li, Meiting Zi, Wen Li, Jing Liu, Yang Yang, Daohong Zhou, Qing-Peng Kong, Yunxia Zhang, Yonghan He.

  Cellular senescence is a process that leads to a state of irreversible cell growth arrest induced by a variety of intrinsic and extrinsic stresses. Senescent cells (SnCs) accumulate with age and have been implicated in various age-related diseases in part via expressing the senescence-associated secretory phenotype. Elimination of SnCs has the potential to delay aging, treat age-related diseases and extend healthspan. However, once cells becoming senescent, they are more resistant to apoptotic stimuli. Senolytics can selectively eliminate SnCs by targeting the SnC anti-apoptotic pathways (SCAPs). They have been developed as a novel pharmacological strategy to treat various age-related diseases. However, the heterogeneity of the SnCs indicates that SnCs depend on different proteins or pathways for their survival. Thus, a better understanding of the underlying mechanisms for apoptotic resistance of SnCs will provide new molecular targets for the development of cell-specific or broad-spectrum therapeutics to clear SnCs. In this review, we discussed the latest research progresses and challenge in senolytic development, described the significance of regulation of senescence and apoptosis in aging, and systematically summarized the SCAPs involved in the apoptotic resistance in SnCs.

Keywords:  aging; apoptosis; resistance; senescent cell; senolytic

DOI:  https://doi.org/10.3389/fcell.2022.822816
Cells. 2022 Feb 28. pii: 830. [Epub ahead of print]11(5):

Synergistic Anti-Ageing through Senescent Cells Specific Reprogramming.

Rui Chen, Thomas Skutella.

  In this review, we seek a novel strategy for establishing a rejuvenating microenvironment through senescent cells specific reprogramming. We suggest that partial reprogramming can produce a secretory phenotype that facilitates cellular rejuvenation. This strategy is desired for specific partial reprogramming under control to avoid tumour risk and organ failure due to loss of cellular identity. It also alleviates the chronic inflammatory state associated with ageing and secondary senescence in adjacent cells by improving the senescence-associated secretory phenotype. This manuscript also hopes to explore whether intervening in cellular senescence can improve ageing and promote damage repair, in general, to increase people's healthy lifespan and reduce frailty. Feasible and safe clinical translational protocols are critical in rejuvenation by controlled reprogramming advances. This review discusses the limitations and controversies of these advances' application (while organizing the manuscript according to potential clinical translation schemes) to explore directions and hypotheses that have translational value for subsequent research.

Keywords:  SASP; ageing; p16Ink4a; p19Arf; p21Waf1/Cip1; senescence; senolytics/senostatics

DOI:  https://doi.org/10.3390/cells11050830
Cells. 2022 Mar 03. pii: 877. [Epub ahead of print]11(5):

Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis.

Xiaojing Hong, Lihui Wang, Kexiong Zhang, Jun Liu, Jun-Ping Liu.

  Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-β signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence.

Keywords:  COVID-19; DNA damage response; TGF-β signalling; pulmonary fibrosis; replicative senescence; telomerase and telomeres

DOI:  https://doi.org/10.3390/cells11050877
J Cell Mol Med. 2022 Mar 12.

Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence.

Elena Frediani, Francesca Scavone, Anna Laurenzana, Anastasia Chillà, Katia Tortora, Ilaria Cimmino, Manuela Leri, Monica Bucciantini, Monica Mangoni, Gabriella Fibbi, Mario Del Rosso, Alessandra Mocali, Lisa Giovannelli, Francesca Margheri.

  Senescence occurs upon critical telomere shortening, or following DNA damage, oncogenic activation, hypoxia and oxidative stress, overall referred to stress-induced premature senescence (SIPS). In response to DNA damage, senescent cells release cytoplasmic chromatin fragments (CCFs), and express an altered secretome, the senescence-associated secretory phenotype (SASP), which contributes to generate a pro-inflammatory and pro-tumoral extracellular milieu. Polyphenols have gained significant attention owing to their anti-inflammatory and anti-tumour activities. Here, we studied the effect of oleuropein aglycone (OLE) and hydroxytyrosol (HT) on DNA damage, CCF appearance and SASP in a model of irradiation-induced senescence. Neonatal human dermal fibroblasts (NHDFs) were γ-irradiated and incubated with OLE, 5 µM and HT, 1 µM. Cell growth and senescence-associated (SA)-β-Gal-staining were used as senescence markers. DNA damage was evaluated by Comet assay, lamin B1 expression, release of CCFs, cyclic GMP-AMP Synthase (cGAS) activation. IL-6, IL-8, MCP-1 and RANTES were measured by ELISA assay. Our results showed that OLE and HT exerted a protective effect on 8 Gy irradiation-induced senescence, preserving lamin B1 expression and reducing cGAS/STING/NFκB-mediated SASP. The ability of OLE and HT to mitigate DNA damage, senescence status and the related SASP in normal cells can be exploited to improve the efficacy and safety of cancer radiotherapy.

Keywords:  DNA damage; SASP; human fibroblasts; polyphenols; radiation-induced senescence

DOI:  https://doi.org/10.1111/jcmm.17255
Oxid Med Cell Longev. 2022 ;2022 5503575

CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts.

Yu-Hsiu Chen, Xin Zhang, Kuei-Yueh Ko, Ming-Feng Hsueh, Virginia Byers Kraus.

Cellular senescence is characterized by cell cycle arrest and senescence-associated secretory phenotypes. Cellular senescence can be caused by various stress stimuli such as DNA damage, oxidative stress, and telomere attrition and is related to several chronic diseases, including atherosclerosis, Alzheimer's disease, and osteoarthritis. Chromobox homolog 4 (CBX4) has been shown to alleviate cellular senescence in human mesenchymal stem cells and is considered a possible target for senomorphic treatment. Here, we explored whether CBX4 expression is associated with replicative senescence in WI-38 fibroblasts, a classic human senescence model system. We also examined whether and how regulation of CBX4 modifies the senescence phenotype and functions as an antisenescence target in WI-38. During the serial culture of the WI-38 primary fibroblast cell line to a senescent state, we found increased expression of senescence markers, including senescence β-galactosidase (SA-βgal) activity, protein expression of p16, p21, and DPP4, and decreased proliferation marker EdU; moreover, CBX4 protein expression declined. With knockdown of CBX4, SA-βgal activity and p16 protein expression increased, and EdU decreased. With the activation of CBX4, SA-βgal activity, p16, and DPP4 protein decreased. In addition, CBX4 knockdown increased, while CBX4 activation decreased, gene expression of both CDKN2A (encoding the p16 protein) and DPP4. Genes related to DNA damage and cell cycle pathways were regulated by CBX4. These results demonstrate that CBX4 can regulate replicative senescence in a manner consistent with a senomorphic agent.

DOI: https://doi.org/10.1155/2022/5503575
Int J Mol Sci. 2022 Feb 25. pii: 2543. [Epub ahead of print]23(5):

Senescent CD4+CD28- T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis.

Luis González-Osuna, Alfredo Sierra-Cristancho, Emilio A Cafferata, Samanta Melgar-Rodríguez, Carolina Rojas, Paola Carvajal, Cristian Cortez, Rolando Vernal.

  Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4+ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28- Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4+CD28- T lymphocytes in periodontitis.

Keywords:  CD28; T-lymphocytes; Th17 lymphocytes; Tregs; alveolar bone loss; cell senescence; periodontitis

DOI:  https://doi.org/10.3390/ijms23052543
Int J Mol Sci. 2022 Feb 28. pii: 2701. [Epub ahead of print]23(5):

Age Related Osteoporosis: Targeting Cellular Senescence.

Ursula Föger-Samwald, Katharina Kerschan-Schindl, Maria Butylina, Peter Pietschmann.

  Age-related chronic diseases are an enormous burden to modern societies worldwide. Among these, osteoporosis, a condition that predisposes individuals to an increased risk of fractures, substantially contributes to increased mortality and health-care costs in elderly. It is now well accepted that advanced chronical age is one of the main risk factors for chronical diseases. Hence, targeting fundamental aging mechanisms such as senescence has become a promising option in the treatment of these diseases. Moreover, for osteoporosis, the main pathophysiological concepts arise from menopause causing estrogen deficiency, and from aging. Here, we focus on recent advances in the understanding of senescence-related mechanisms contributing to age-related bone loss. Furthermore, treatment options for senile osteoporosis targeting senescent cells are reviewed.

Keywords:  age-related osteoporosis; cellular senescence; osteoporosis therapy

DOI:  https://doi.org/10.3390/ijms23052701
Stem Cell Rev Rep. 2022 Mar 08.

Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence.

Wenxin Zhang, Jiayu Li, Yuchi Duan, Yanlin Li, Yanan Sun, Hui Sun, Xiao Yu, Xingyu Gao, Chang Zhang, Haiying Zhang, Yingai Shi, Xu He.

  Stem cell senescence and exhaustion are closely related to organ failure and individual aging, which not only induces age-related diseases, but also hinders stem cell applications in regenerative medicine. Thus, it's imminent to find effective ways to delay and retrieve stem cell senescence. Metabolic abnormalities are one of the main characteristics of age-associated declines in stem cell function. Understanding the underlying mechanisms may reveal potential strategies for ameliorating age-associated phenotypes and treating age-related diseases. This review focuses on recent advances in the association between metabolism including glucose, lipid, glutamine and NAD+ metabolism and stem cell senescence, as well as the other properties like proliferation and differentiation. Layers of studies are summarized to demonstrate how metabolism varies in senescent stem cells and how metabolic reprogramming regulates stem cell senescence. Additionally, we mentioned some recent progress in therapeutic strategies to rejuvenate dysfunctional aged stem cells. Finally, a brief conclusion about the prospect of metabolic regulation as a potential strategy for rescuing stem cell senescence is displayed. Stem cell senescence is induced by the metabolic reprogramming. The metabolic alterations of glucose, lipid, glutamine and NAD+ can conversely facilitate or inhibit stem cell senescence. Glycolysis, OXPHOS and PPP are all attenuated. But gluconeogenesis alterations still remain unclear. In lipid metabolisms, both FAO and DNL are suppressed. As for the glutamine metabolism, stem cells' dependence on glutamine is enhanced. Last, NAD+ metabolism undergoes a down-regulated synthesis and up-regulated consumption. All these alterations can be potential targets for reversing stem cell senescence.

Keywords:  NAD+ metabolism; age-related diseases; glucose metabolism; glutamine metabolism; lipid metabolism; stem cell senescence

DOI:  https://doi.org/10.1007/s12015-022-10348-6
J Bone Miner Res. 2022 Mar 05.

Bone marrow adiposity in models of radiation- and aging-related bone loss is dependent on cellular senescence.

Abhishek Chandra, Anthony B Lagnado, Joshua N Farr, Megan Schleusner, David G Monroe, Dominik Saul, João F Passos, Sundeep Khosla, Robert J Pignolo.

  Oxidative stress-induced reactive oxygen species, DNA damage, apoptosis and cellular senescence have been associated with reduced osteoprogenitors in a reciprocal fashion to bone marrow adipocyte tissue (BMAT); however, a direct (causal) link between cellular senescence and BMAT is still elusive. Accumulation of senescent cells occur in naturally aged and in focally radiated bone tissue, but despite amelioration of age- and radiation-associated bone loss after senescent cell clearance, molecular events that precede BMAT accrual are largely unknown. Here we show by RNA-Sequencing data that BMAT-related genes were the most upregulated gene subset in radiated bones of C57BL/6 mice. Using focal radiation as a model to understand age-associated changes in bone, we performed a longitudinal assessment of cellular senescence and BMAT. Using qRT-PCR, RNA in situ hybridization of p21 transcripts and histological assessment of telomere dysfunction as a marker of senescence, we observed an increase in senescent cell burden of bone cells from day 1 post-radiation, without the presence of BMAT. BMAT was significantly elevated in radiated bones at day 7, confirming the qRT-PCR data in which most BMAT-related genes were elevated by day 7, and the trend continued until day 42 post-radiation. Similarly, elevation in BMAT-related genes was observed in bones of aged mice. The senolytic cocktail of Dasatinib (D) plus Quercetin (Q) - D+Q, which clears senescent cells, reduced BMAT in aged and radiated bones. MicroRNAs (miRs) linked with senescence marker p21 were downregulated in radiated- and aged- bones, while miR-27a, a miR that is associated with increased BMAT, was elevated both in radiated- and aged-bones. D+Q downregulated miR-27a in radiated bones at 42 days post-radiation. Overall, our study provides evidence that BMAT occurrence in oxidatively stressed bone environments, such as radiation and aging, is induced following a common pathway and is dependent on the presence of senescent cells. This article is protected by copyright. All rights reserved.

Keywords:  Aging; Bone Marrow Adiposity; Cellular Senescence; Radiation; p21

DOI:  https://doi.org/10.1002/jbmr.4537
Aging Cell. 2022 Mar 10. e13581

AAV-mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice.

J Roig-Soriano, C Griñán-Ferré, J F Espinosa-Parrilla, C R Abraham, A Bosch, M Pallàs, Miguel Chillón.

  Senescence represents a stage in life associated with elevated incidence of morbidity and increased risk of mortality due to the accumulation of molecular alterations and tissue dysfunction, promoting a decrease in the organism's protective systems. Thus, aging presents molecular and biological hallmarks, which include chronic inflammation, epigenetic alterations, neuronal dysfunction, and worsening of physical status. In this context, we explored the AAV9-mediated expression of the two main isoforms of the aging-protective factor Klotho (KL) as a strategy to prevent these general age-related features using the senescence-accelerated mouse prone 8 (SAMP8) model. Both secreted and transmembrane KL isoforms improved cognitive performance, physical state parameters, and different molecular variables associated with aging. Epigenetic landscape was recovered for the analyzed global markers DNA methylation (5-mC), hydroxymethylation (5-hmC), and restoration occurred in the acetylation levels of H3 and H4. Gene expression of pro- and anti-inflammatory mediators in central nervous system such as TNF-α and IL-10, respectively, had improved levels, which were comparable to the senescence-accelerated-mouse resistant 1 (SAMR1) healthy control. Additionally, this improvement in neuroinflammation was supported by changes in the histological markers Iba1, GFAP, and SA β-gal. Furthermore, bone tissue structural variables, especially altered during senescence, recovered in SAMP8 mice to SAMR1 control values after treatment with both KL isoforms. This work presents evidence of the beneficial pleiotropic role of Klotho as an anti-aging therapy as well as new specific functions of the KL isoforms for the epigenetic regulation and aged bone structure alteration in an aging mouse model.

Keywords:  AAV9; Klotho; SAMP8; anti-aging; epigenetics; neurodegeneration; osteoporosis; senescence

DOI:  https://doi.org/10.1111/acel.13581
Aging Cell. 2022 Mar 08. e13524

Biological mechanisms of aging predict age-related disease co-occurrence in patients.

Helen C Fraser, Valerie Kuan, Ronja Johnen, Magdalena Zwierzyna, Aroon D Hingorani, Andreas Beyer, Linda Partridge.

  Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co-occurrence of age-related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non-random associations between age-related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age-related diseases. Mechanisms of aging hence contribute both together and individually to age-related disease co-occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity.

Keywords:  age-related disease; aging; aging hallmarks; genetics; multimorbidity

DOI:  https://doi.org/10.1111/acel.13524
Int J Mol Sci. 2022 Feb 24. pii: 2476. [Epub ahead of print]23(5):

Altered p16Ink4a, IL-1β, and Lamin b1 Protein Expression Suggest Cellular Senescence in Deep Endometriotic Lesions.

Helena Malvezzi, Cristine Dobo, Renee Zon Filippi, Helen Mendes do Nascimento, Laura Palmieri da Silva E Sousa, Juliana Meola, Carla Azevedo Piccinato, Sérgio Podgaec.

  Endometriosis causes immunological and cellular alterations. Endometriosis lesions have lower levels of lamin b1 than the endometrium. Moreover, high levels of pro-inflammatory markers are observed in the peritoneal fluid, follicular fluid, and serum in endometriosis lesions. Thus, we hypothesized that the accumulation of senescent cells in endometriosis tissues would facilitate endometriosis maintenance in an inflammatory microenvironment. To study senescent cell markers and the senescence-associated secretory phenotype (SASP) in endometriosis lesions, we conducted a cross-sectional study with 27 patients undergoing video laparoscopy for endometriosis resection and 19 patients without endometriosis. Endometriosis lesions were collected from patients with endometriosis, while eutopic endometrium was collected from patients both with and without endometriosis. Tissues were evaluated for senescence markers (p16Ink4a, lamin b1, and IL-1β) and interleukin concentrations. The expression of p16Ink4a increased in lesions compared to that in eutopic endometrium from endometriosis patients in the secretory phase. In the proliferative phase, lesions exhibited lower lamin b1 expression but higher IL-4 expression than the eutopic endometrium. Further, IL-1β levels were higher in the lesions than in the eutopic endometrium in both the secretory and proliferative phases. We believe that our findings may provide targets for better therapeutic interventions to alleviate the symptoms of endometriosis.

Keywords:  deep endometriotic lesion; endometrium; inflammatory cytokines; senescence; senescence-associated secretory phenotype

DOI:  https://doi.org/10.3390/ijms23052476
Aging Cell. 2022 Mar 08. e13589

CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging.

Thais R Peclat, Katie L Thompson, Gina M Warner, Claudia C S Chini, Mariana G Tarragó, Delaram Z Mazdeh, Chunlian Zhang, Jose Zavala-Solorio, Ganesh Kolumam, Yao Liang Wong, Robert L Cohen, Eduardo N Chini.

  Nicotinamide adenine dinucleotide (NAD) levels decline during aging, contributing to physical and metabolic dysfunction. The NADase CD38 plays a key role in age-related NAD decline. Whether the inhibition of CD38 increases lifespan is not known. Here, we show that the CD38 inhibitor 78c increases lifespan and healthspan of naturally aged mice. In addition to a 10% increase in median survival, 78c improved exercise performance, endurance, and metabolic function in mice. The effects of 78c were different between sexes. Our study is the first to investigate the effect of CD38 inhibition in naturally aged animals.

Keywords:  CD38; NAD; aging; healthspan; longevity; mice; small molecule

DOI:  https://doi.org/10.1111/acel.13589
Sci Rep. 2022 Mar 09. 12(1): 3857

Role of senescent cells in the motile behavior of active, non-senescent cells in confluent populations.

Thamara Liz Gabuardi, Hyun Gyu Lee, Kyoung J Lee.

Characteristics of cell migration in a confluent population depend on the nature of cell-to-cell interactions as well as cell-intrinsic properties such as the directional persistence in crawling. In addition, biological tissues (or cell cultures) almost always carry anisotropies and they too can significantly affect cell motility. In the light of this viewpoint, the emergence of cellular senescences in a confluent population of active cells raises an interesting question. Cellular senescence is a process through which a cell enters a permanent growth-arrest state and generally exhibits a dramatic body expansion. Therefore, randomly emerging senescent cells transform an initially homogeneous cell population to a "binary mixture" of two distinct cell types. Here, using in vitro cultures of MDA-MB-231 cells we investigate how spatially localized cellular senescence affect the motility of active cells within a confluent population. Importantly, we estimate the intercellular surface energy of the interface between non-senescent and senescent MDA-MB-231 cells by combining the analysis on the motile behaviors of non-senescent cells encircling senescent cells and the result of extensive numerical simulations of a cellular Potts model. We find that the adhesion of normal cells to senescent cells is much weaker than that among normal cells and that the 'arclength' traveled by a normal cell along the boundary of a senescent cell, on average, is several times greater than the persistence length of normal cell in a densely packed homogeneous population. The directional persistent time of normal cell during its contact with a senescent cell also increases significantly. We speculate that the phenomenon could be a general feature associated with senescent cells as the enormous expansion of senescent cell's membrane would inevitably decrease the density of cell adhesion molecules.

DOI: https://doi.org/10.1038/s41598-022-07865-2
Aging Cell. 2022 Mar 09. e13580

Dynamic regulation of myofibroblast phenotype in cellular senescence.

Irene López-Antona, Constanza Contreras-Jurado, Laura Luque-Martín, Antonio Carpintero-Leyva, Paula González-Méndez, Ignacio Palmero.

  Cellular senescence is an antiproliferative response with a critical role in the control of cellular balance in diverse physiological and pathological settings. Here, we set to study the impact of senescence on the regulation of cell plasticity, focusing on the regulation of the myofibroblastic phenotype in primary fibroblasts. Myofibroblasts are contractile, highly fibrogenic cells with key roles in wound healing and fibrosis. Using cellular models of fibroblast senescence, we find a consistent loss of myofibroblastic markers and functional features upon senescence implementation. This phenotype can be transmitted in a paracrine manner, most likely through soluble secreted factors. A dynamic transcriptomic analysis during paracrine senescence confirmed the non-cell-autonomous transmission of this phenotype. Moreover, gene expression data combined with pharmacological and genetic manipulations of the major SASP signaling pathways suggest that the changes in myofibroblast phenotype are mainly mediated by the Notch/TGF-β axis, involving a dynamic switch in the TGF-β pathway. Our results reveal a novel link between senescence and myofibroblastic differentiation with potential implications in the physiological and pathological functions of myofibroblasts.

Keywords:  SASP; TGF-β; myofibroblast; plasticity; senescence

DOI:  https://doi.org/10.1111/acel.13580
Int J Mol Sci. 2022 Mar 06. pii: 2877. [Epub ahead of print]23(5):

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.

Anh-Nhung Le, Seong-Soon Park, Minh-Xuan Le, Unn Hwa Lee, Byung Kyun Ko, Hye Ryeong Lim, Ri Yu, Seong Hee Choi, Byung Ju Lee, Soo-Youn Ham, Chang Man Ha, Jeong Woo Park.

  Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-β-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.

Keywords:  DRG2; angiogenesis; endothelial cells; senescence; vascular dysfunction

DOI:  https://doi.org/10.3390/ijms23052877
Geroscience. 2022 Mar 06.

Brain cellular senescence in mouse models of Alzheimer's disease.

Angela O Dorigatti, Ruben Riordan, Zhen Yu, Grace Ross, Rong Wang, Nadjalisse Reynolds-Lallement, Kathy Magnusson, Veronica Galvan, Viviana I Perez.

  The accumulation of senescent cells contributes to aging pathologies, including neurodegenerative diseases, and its selective removal improves physiological and cognitive function in wild-type mice as well as in Alzheimer's disease (AD) models. AD models recapitulate some, but not all components of disease and do so at different rates. Whether brain cellular senescence is recapitulated in some or all AD models and whether the emergence of cellular senescence in AD mouse models occurs before or after the expected onset of AD-like cognitive deficits in these models are not yet known. The goal of this study was to identify mouse models of AD and AD-related dementias that develop measurable markers of cellular senescence in brain and thus may be useful to study the role of cellular senescence in these conditions. We measured the levels of cellular senescence markers in the brains of P301S(PS19), P301L, hTau, and 3xTg-AD mice that model amyloidopathy and/or tauopathy in AD and related dementias and in wild-type, age-matched control mice for each strain. Expression of cellular senescence markers in brains of transgenic P301L and 3xTg-AD mice was largely indistinguishable from that in WT control age-matched mice. In contrast, markers of cellular senescence were differentially increased in brains of transgenic hTau and P301S(PS19) mice as compared to WT control mice before the onset of AD-like cognitive deficits. Taken together, our data suggest that P301S(PS19) and hTau mice may be useful models for the study of brain cellular senescence in tauopathies including, but not limited to, AD.

Keywords:  Aging; Amyloidopathy; Inflammation; Tauopathies

DOI:  https://doi.org/10.1007/s11357-022-00531-5
J Eur Acad Dermatol Venereol. 2022 Mar 11.

Attenuation of intrinsic aging of the skin via elimination of senescent dermal fibroblasts with senolytic drugs.

H Kim, J Jang, M J Song, G Kim, C-H Park, D H Lee, S-H Lee, J H Chung.

   BACKGROUND: Skin aging is caused by numerous factors that result in structural and functional changes in cutaneous components. Research has shown that senescent cells are known to accumulate in skin aging, however, the role of senescent cells in skin aging has not been defined.
OBJECTIVES: To elucidate the role of senescent cell in skin aging, we evaluated the effect of known senolytic drugs on senescent dermal fibroblasts.
METHODS: Primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, UV irradiation, and H2O2 treatment. Cell viability was measured after treatment of ABT-263 and ABT-737 on HDFs. Young and aged hairless mice were intradermally injected with drugs or vehicle on the dorsal skin for 10 days. Skin specimens were obtained and reverse-transcription quantitative PCR, western blotting, and histological analysis were performed.
RESULTS: We found that ABT-263 and ABT-737 induced selective clearance of senescent dermal fibroblasts, regardless of the method of senescence induction. Aged mouse skin treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and proliferation of keratinocytes, as well as decreased senescence-associated secretory phenotypes, such as MMP-1 and IL-6.
CONCLUSIONS: Taken together, our results indicate that selective clearance of senescent skin cells can attenuate and improve skin aging phenotypes and that senolytic drugs may be of potential use as new therapeutic agents for treating aging of the skin.

Keywords:  dermal fibroblast; senescent cell; senolytic drug; skin aging

DOI:  https://doi.org/10.1111/jdv.18051
Bone Res. 2022 Mar 08. 10(1): 25

mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a.

Ajuan Chen, Jian Jin, Shasha Cheng, Zezheng Liu, Cheng Yang, Qingjing Chen, Wenquan Liang, Kai Li, Dawei Kang, Zhicong Ouyang, Chenfeng Yao, Xiaochun Bai, Qingchu Li, Dadi Jin, Bin Huang.

Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts, blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors. Due to these adverse effects, preosteoblast senescence is a crucial target for the treatment of age-related bone loss; however, the underlying mechanism remains unclear. We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model. Mechanistically, mTORC1 induced a change in the membrane potential from polarization to depolarization, thus promoting cell senescence by increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts. Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα, whereas its permeability to Na+ was found to be gated by protein kinase A (PKA)-induced phosphorylation. Prosenescent stresses increased the permeability of Scn1a to Na+ by suppressing PKA activity and induced depolarization in preosteoblasts. Together, our findings identify a novel pathway involving mTORC1, Scn1a expression and gating, plasma membrane depolarization, increased Ca2+ influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence. Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.

DOI: https://doi.org/10.1038/s41413-022-00204-1
Aging Cell. 2022 Mar 09. e13583

Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.

Andrea Irazoki, Marta Martinez-Vicente, Pilar Aparicio, Cecilia Aris, Esmaeil Alibakhshi, Maria Rubio-Valera, Juan Castellanos, Luis Lores, Manuel Palacín, Anna Gumà, Antonio Zorzano, David Sebastián.

  Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

Keywords:  aging; inflammation; lysosome; mitochondria; mitophagy; muscle

DOI:  https://doi.org/10.1111/acel.13583
Neurologia (Engl Ed). 2022 Mar 05. pii: S2173-5808(22)00017-7. [Epub ahead of print]

Immunosenescence: the role of age in multiple sclerosis.

A Ostolaza Ibáñez, J Corroza Laviñeta, T Ayuso Blanco.

   INTRODUCTION: The number of elderly people with multiple sclerosis (MS) has increased in line with population ageing. As the immune system presents profound changes over an individual's lifetime, it is important to understand the differences between these patients and younger patients.
DEVELOPMENT: Immunosenescence, defined as age-related alterations naturally occurring in the immune system, particularly influences tolerance, response, and adverse effects of disease-modifying treatments for MS. Thymic involution is the most noteworthy characteristic of this phenomenon. This process leads to a reduction in the number of virgin T cells. Other effects include an inverted CD4+/CD8+ cell ratio, severe alterations in NK cell functioning, and reduced tissue repair capacity in the brain.
CONCLUSIONS: The number of older people with MS is increasing due to population ageing, advances in disease-modifying treatments, and improved health and social care of these patients. Ageing of the immune system increases the risk of infections, tumours, and autoimmune diseases in elderly individuals. Furthermore, neurodegeneration is accelerated in patients with MS due to the nervous system's loss of remyelination capacity. Understanding of the changes affecting the immune system in the elderly population is essential to improving the care provided to this ever-growing patient group.

Keywords:  Ageing; Envejecimiento; Esclerosis múltiple; Esclerosis múltiple de comienzo tardío; Immunosenescence; Inmunosenescencia; Late-onset multiple sclerosis; Multiple sclerosis

DOI:  https://doi.org/10.1016/j.nrleng.2020.05.023
Int J Mol Sci. 2022 Mar 07. pii: 2879. [Epub ahead of print]23(5):

Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis.

Yiqi Wan, Zhirui Liu, Andong Wu, Abdul Haseeb Khan, Ying Zhu, Shuangjin Ding, Xueer Li, Ya Zhao, Ximo Dai, Jin Zhou, Jiankun Liu, Yuanyuan Li, Xueting Gong, Man Liu, Xiao-Li Tian.

  Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated AQR as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including C. elegans (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.

Keywords:  AQR; PLAU; diabetes; endothelial senescence; inflammation

DOI:  https://doi.org/10.3390/ijms23052879
J Biomed Sci. 2022 Mar 07. 29(1): 17

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts.

Young Hyun Jung, Chang Woo Chae, Gee Euhn Choi, Him Cha Shin, Jae Ryong Lim, Han Seung Chang, Joonmo Park, Ji Hyeon Cho, Mo Ran Park, Hyun Jik Lee, Ho Jae Han.

   BACKGROUND: Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved.
METHODS: DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration.
RESULTS: Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1-IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation.
CONCLUSIONS: C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.

Keywords:  Androgen receptor; Cyanidin 3-O-arabinoside; DHT; Mitochondrial calcium; Senescence

DOI:  https://doi.org/10.1186/s12929-022-00800-7
Cells. 2022 Mar 02. pii: 858. [Epub ahead of print]11(5):

Maintenance of Chronological Aging Features in Culture of Normal Human Dermal Fibroblasts from Old Donors.

Julie Rorteau, Fabien P Chevalier, Sébastien Bonnet, Théo Barthélemy, Amandine Lopez-Gaydon, Lisa S Martin, Nicolas Bechetoille, Jérôme Lamartine.

  Chronological aging is defined as a time-dependent decline of tissue homeostasis which severely impacts skin. Understanding the mechanisms of skin aging is an active research area limited by the lack of relevant in vitro models. Being a component of aging, replicative or stress-induced senescence is repeatedly used to mimic skin aging in vitro, thus presenting only a partial view of the complexity of aging. Herein, we aimed to clarify whether primary normal human dermal fibroblasts retained age-related characteristics when cultured in 2D monolayer, and could be used as a relevant model for aging research. We compared three groups of fibroblasts isolated from different aged donors. We observed strongly decreased population doubling capacities, a reduced clonogenic ability, an impairment in extracellular matrix production together with modifications of respiratory metabolism with an increase in age. These disruptions were particularly marked when comparing fibroblasts isolated from old individuals (over 70 years old) to those isolated from young individuals (18-37 years old), while cells from middle-aged donors exhibited an intermediate profile. These alterations of cell features can be related to the signs of dermis aging, thus showing that cultured primary cells indeed retain some characteristics of the original tissue from which they were extracted.

Keywords:  aging; clonogenicity; extracellular matrix; fibroblast; mitochondria; population doubling; skin

DOI:  https://doi.org/10.3390/cells11050858
Hum Exp Toxicol. 2022 Jan-Dec;41:41 9603271221076107

Fluorometholone inhibits high glucose-induced cellular senescence in human retinal endothelial cells.

Xuemei Zhou, Lifeng Wang, Zhongwei Zhang, Jing Liu, Qun Qu, Yuanyuan Zu, Dejing Shi.

  Diabetic retinopathy (DR) is a common diabetic complication that severely impacts the life quality of diabetic patients. Recently, cellular senescence in human retinal endothelial cells (HRECs) induced by high glucose has been linked to the pathogenesis of DR. Fluorometholone (FML) is a glucocorticoid drug applied in the treatment of inflammatory and allergic disorders of the eye. The objective of the present study is to investigate the protective function of FML on high glucose-induced cellular senescence in HRECs. The in vitro injury model was established by stimulating HRECs with 30 mm glucose. After evaluating the cytotoxicity of FML in HRECs, 0.05% and 0.1% FML were used as the optimal concentration in the entire experiment. It was found that the excessive released inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) in HRECs induced by high glucose were significantly suppressed by FML, accompanied by the inhibitory effects on the expression levels of vascular endothelial growth factor (VEGF) and tissue factor (TF). Declined telomerase activity and enhanced senescence-associated β-galactosidase (SA-β-gal) activity were found in high glucose-challenged HRECs, which were dramatically alleviated by FML, accompanied by the inactivation of the p53/p21 and retinoblastoma (Rb) signaling. Interestingly, FML ameliorated high glucose-induced dephosphorylation of Akt. Lastly, the protective effects of FML against high glucose-induced cellular senescence in HRECs were abolished by the co-treatment of the PI3K/Akt signaling inhibitor LY294002, suggesting the involvement of this pathway. Taken together, these data revealed that FML-inhibited high glucose-induced cellular senescence mediated by Akt in HERCs, suggesting a novel molecular mechanism of FML.

Keywords:  Akt; cell senescence; diabetic retinopathy; fluorometholone; p53

DOI:  https://doi.org/10.1177/09603271221076107
Cells. 2022 Mar 02. pii: 862. [Epub ahead of print]11(5):

Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.

Jovian Lin Jing, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber, Mohammad Alfatah.

  Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.

Keywords:  AMPK; Saccharomyces cerevisiae; cellular lifespan extension; chronological aging; iron; mitochondria

DOI:  https://doi.org/10.3390/cells11050862
Front Aging. 2022 ;pii: 805126. [Epub ahead of print]2

The Complicated Nature of Somatic mtDNA Mutations in Aging.

Monica Sanchez-Contreras, Scott R Kennedy.

  Mitochondria are the main source of energy used to maintain cellular homeostasis. This aspect of mitochondrial biology underlies their putative role in age-associated tissue dysfunction. Proper functioning of the electron transport chain (ETC), which is partially encoded by the extra-nuclear mitochondrial genome (mtDNA), is key to maintaining this energy production. The acquisition of de novo somatic mutations that interrupt the function of the ETC have long been associated with aging and common diseases of the elderly. Yet, despite over 30 years of study, the exact role(s) mtDNA mutations play in driving aging and its associated pathologies remains under considerable debate. Furthermore, even fundamental aspects of age-related mtDNA mutagenesis, such as when mutations arise during aging, where and how often they occur across tissues, and the specific mechanisms that give rise to them, remain poorly understood. In this review, we address the current understanding of the somatic mtDNA mutations, with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging technologies that offer potential ways forward in increasing our understanding of somatic mtDNA mutagenesis in the aging process.

Keywords:  aging; mitochondria; mtDNA; mutagenesis; sequencing; somatic mutations

DOI:  https://doi.org/10.3389/fragi.2021.805126
Mol Cell Oncol. 2022 ;9(1): 2030158

Escape from senescence: revisiting cancer therapeutic strategies.

Christos P Zampetidis, Argyris Papantonis, Vassilis G Gorgoulis.

Although senescence has been considered as an irreversible cell arrest state, accumulating evidence challenge this view. Consequently, senescence appears as an imperfect barrier to impede cancer progression, constituting a step prior to disease relapse. Therefore, cancer treatment strategies may benefit if revisited to include senolytic agents.

DOI: https://doi.org/10.1080/23723556.2022.2030158
Genome Res. 2022 Mar 11. pii: gr.275672.121. [Epub ahead of print]

Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart.

Isabela Gerdes Gyuricza, Joel M Chick, Gregory R Keele, Andrew G Deighan, Steven C Munger, Ron C Korstanje, Steven P Gygi, Gary A Churchill.

Investigation of the molecular mechanisms of aging in the human heart is challenging due to confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12 and 18 months to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal activation of pathways related to exocytosis and cellular transport with age, while processes involved in protein folding decrease with age. Additional changes are apparent only in the protein data including reduced fatty acid oxidation and increased autophagy. For proteins that form complexes, we see a decline in correlation between their component subunits with age, suggesting age-related loss of stoichiometry. The most affected complexes are themselves involved in protein homeostasis, which potentially contributes to a cycle of progressive breakdown in protein quality control with age. Our findings highlight the important role of post-transcriptional regulation in aging. In addition, we identify genetic loci that modulate age-related changes in protein homeostasis, suggesting that genetic variation can alter the molecular aging process.

DOI: https://doi.org/10.1101/gr.275672.121
Curr Stem Cell Rep. 2021 Jun;7(2): 72-84

Metabolic Regulation of Stem Cells in Aging.

Andrea Keller, Tyus Temple, Behnam Sayanjali, Maria M Mihaylova.

   Purpose of Review: From invertebrates to vertebrates, the ability to sense nutrient availability is critical for survival. Complex organisms have evolved numerous signaling pathways to sense nutrients and dietary fluctuations, which influence many cellular processes. Although both overabundance and extreme depletion of nutrients can lead to deleterious effects, dietary restriction without malnutrition can increase lifespan and promote overall health in many model organisms. In this review, we focus on age-dependent changes in stem cell metabolism and dietary interventions used to modulate stem cell function in aging.
Recent Findings: Over the last half-century, seminal studies have illustrated that dietary restriction confers beneficial effects on longevity in many model organisms. Many researchers have now turned to dissecting the molecular mechanisms by which these diets affect aging at the cellular level. One subpopulation of cells of particular interest are adult stem cells, the most regenerative cells of the body. It is generally accepted that the regenerative capacity of stem cells declines with age, and while the metabolic requirements of each vary across tissues, the ability of dietary interventions to influence stem cell function is striking.
Summary: In this review, we will focus primarily on how metabolism plays a role in adult stem cell homeostasis with respect to aging, with particular emphasis on intestinal stem cells while also touching on hematopoietic, skeletal muscle, and neural stem cells. We will also discuss key metabolic signaling pathways influenced by both dietary restriction and the aging process, and will examine their role in improving tissue homeostasis and lifespan. Understanding the mechanisms behind the metabolic needs of stem cells will help bridge the divide between a basic science interpretation of stem cell function and a whole-organism view of nutrition, thereby providing insight into potential dietary or therapeutic interventions.

Keywords:  Aging; Metabolism; stem cells

DOI:  https://doi.org/10.1007/s40778-021-00186-6
Cells. 2022 Feb 22. pii: 767. [Epub ahead of print]11(5):

Pseudotime Analysis Reveals Exponential Trends in DNA Methylation Aging with Mortality Associated Timescales.

Kalsuda Lapborisuth, Colin Farrell, Matteo Pellegrini.

  The epigenetic trajectory of DNA methylation profiles has a nonlinear relationship with time, reflecting rapid changes in DNA methylation early in life that progressively slow with age. In this study, we use pseudotime analysis to determine the functional form of these trajectories. Unlike epigenetic clocks that constrain the functional form of methylation changes with time, pseudotime analysis orders samples along a path, based on similarities in a latent dimension, to provide an unbiased trajectory. We show that pseudotime analysis can be applied to DNA methylation in human blood and brain tissue and find that it is highly correlated with the epigenetic states described by the Epigenetic Pacemaker. Moreover, we show that the pseudotime trajectory can be modeled with respect to time, using a sum of two exponentials, with coefficients that are close to the timescales of human age-associated mortality. Thus, for the first time, we can identify age-associated molecular changes that appear to track the exponential dynamics of mortality risk.

Keywords:  DNA methylation; epigenetic aging; pseudotime analysis; trajectory inference

DOI:  https://doi.org/10.3390/cells11050767
Phytomedicine. 2022 Mar 01. pii: S0944-7113(22)00095-2. [Epub ahead of print]99 154017

Activating PGC-1α-mediated signaling cascades in the aorta contributes to the amelioration of vascular senescence and atherosclerosis by 2,3,4',5-tetrahydroxystilbene-2-O-β-d-glycoside.

Chun Yan Wang, Jie Wang, Ji Cao, Jin Xu, Ruo Man Wu, Xiao Le Xu.

   BACKGROUND: 2,3,4',5-tetrahydroxystilbene-2-O-β-d-glycoside (TSG), the main active polyphenolic component of Polygonum multiflorum, possesses many pharmacological activities. Its anti-aging effect influences a variety of tissues with diverse mechanisms. However, the effectiveness and exact mechanisms of TSG against vascular senescence in atherosclerosis remain unclear. The present study is aimed to investigate the effects of TSG against vascular senescence in atherosclerosis both in vivo and in vitro, and the possible underlying mechanisms focusing on aortic peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-mediated signaling cascades which have never been studied.
METHODS: In vivo, 12-mo-old male LDLr-/- mice were randomly separated into control, high-fat diet (HFD), and TSG -treatment groups. At the end of the 12 weeks, the blood samples and aorta tissues of mice were collected for further analysis. In vitro, to mimic the condition of endothelial senescence in hyperlipidemic mice, human aortic endothelial cells (HAECs) were incubated with oxidized low-density lipoprotein (ox-LDL) to induce senescence.
RESULTS: TSG administration improved lipid profiles, ameliorated HFD-exacerbated vascular senescence and atherosclerosis. The protective effect of TSG via inhibiting telomere malfunction, oxidative stress, and mitochondrial damage was found both in vivo and in vitro. Notably, TSG administration increased aortic PGC-1α mRNA and protein expression along with the regulation of its targeted genes TERT, NRF1, TFAM, Mn-SOD, and catalase. Further, by using PGC-1α siRNA in ox-LDL-treated HAECs, it is proved that TSG reduced endothelial senescence, telomere malfunction, oxidative stress, and mitochondrial damage at least partly through activating the PGC-1α pathway.
CONCLUSIONS: These results provide new evidence for TSG in the treatment of atherosclerosis and the activation of aortic PGC-1α is involved in its beneficial effects.

Keywords:  2,3,4′,5-tetrahydroxystilbene-2-O-β-d-glycoside; Atherosclerosis; PGC-1α; Vascular senescence

DOI:  https://doi.org/10.1016/j.phymed.2022.154017
Aging Cell. 2022 Mar 09. e13577

Partial reprogramming strategy for intervertebral disc rejuvenation by activating energy switch.

Feng Cheng, Chenggui Wang, Yufei Ji, Biao Yang, Jiawei Shu, Kesi Shi, Lulu Wang, Shaoke Wang, Yuang Zhang, Xianpeng Huang, Xiaopeng Zhou, Kaishun Xia, Chengzhen Liang, Qixin Chen, Fangcai Li.

  Rejuvenation of nucleus pulposus cells (NPCs) in degenerative discs can reverse intervertebral disc degeneration (IDD). Partial reprogramming is used to rejuvenate aging cells and ameliorate progression of aging tissue to avoiding formation of tumors by classical reprogramming. Understanding the effects and potential mechanisms of partial reprogramming in degenerative discs provides insights for development of new therapies for IDD treatment. The findings of the present study show that partial reprogramming through short-term cyclic expression of Oct-3/4, Sox2, Klf4, and c-Myc (OSKM) inhibits progression of IDD, and significantly reduces senescence related phenotypes in aging NPCs. Mechanistically, short-term induction of OSKM in aging NPCs activates energy metabolism as a "energy switch" by upregulating expression of Hexokinase 2 (HK2) ultimately promoting redistribution of cytoskeleton and restoring the aging state in aging NPCs. These findings indicate that partial reprogramming through short-term induction of OSKM has high therapeutic potential in the treatment of IDD.

Keywords:  cellular senescence; intervertebral disc degeneration; nucleus pulposus cells; reprogramming

DOI:  https://doi.org/10.1111/acel.13577
Aging Cell. 2022 Mar 10. e13585

Effects of dietary macronutrients on the hepatic transcriptome and serum metabolome in mice.

Yingga Wu, Cara L Green, Guanlin Wang, Dengbao Yang, Li Li, Baoguo Li, Lu Wang, Min Li, Jianbo Li, Yanchao Xu, Xueying Zhang, Chaoqun Niu, Sumei Hu, Jacques Togo, Mohsen Mazidi, Davina Derous, Alex Douglas, John R Speakman.

  Dietary macronutrient composition influences both hepatic function and aging. Previous work suggested that longevity and hepatic gene expression levels were highly responsive to dietary protein, but almost unaffected by other macronutrients. In contrast, we found expression of 4005, 4232, and 4292 genes in the livers of mice were significantly associated with changes in dietary protein (5%-30%), fat (20%-60%), and carbohydrate (10%-75%), respectively. More genes in aging-related pathways (notably mTOR, IGF-1, and NF-kappaB) had significant correlations with dietary fat intake than protein and carbohydrate intake, and the pattern of gene expression changes in relation to dietary fat intake was in the opposite direction to the effect of graded levels of caloric restriction consistent with dietary fat having a negative impact on aging. We found 732, 808, and 995 serum metabolites were significantly correlated with dietary protein (5%-30%), fat (8.3%-80%), and carbohydrate (10%-80%) contents, respectively. Metabolomics pathway analysis revealed sphingosine-1-phosphate signaling was the significantly affected pathway by dietary fat content which has also been identified as significant changed metabolic pathway in the previous caloric restriction study. Our results suggest dietary fat has major impact on aging-related gene and metabolic pathways compared with other macronutrients.

Keywords:  aging; carbohydrate; fat; metabolome; protein; transcriptome

DOI:  https://doi.org/10.1111/acel.13585
Elife. 2022 Mar 08. pii: e73524. [Epub ahead of print]11

Distinct and diverse chromatin-proteomes of ageing mouse organs reveal protein signatures that correlate with physiological functions.

Giorgio Oliviero, Sergey Kovalchuk, Adelina Rogowska-Wrzesinska, Veit Schwämmle, Ole N Jensen.

  Temporal molecular changes in ageing mammalian organs are of relevance to disease etiology because many age-related diseases are linked to changes in the transcriptional and epigenetic machinery that regulate gene expression. We performed quantitative proteome analysis of chromatin-enriched protein extracts to investigate the dynamics of the chromatin-proteomes of the mouse brain, heart, lung, kidney, liver, and spleen at 3, 5, 10, and 15 months of age. Each organ exhibited a distinct chromatin-proteome and sets of unique proteins. The brain and spleen chromatin-proteomes were the most extensive, diverse, and heterogenous among the six organs. The spleen chromatin proteome appeared static during the lifespan, presenting a young phenotype that reflects the permanent alertness state and important role of this organ in physiological defense and immunity. We identified a total of 5928 proteins, including 2472 nuclear or chromatin associated proteins across the six mouse organs. Up to 3125 proteins were quantified in each organ demonstrating distinct and organ-specific temporal protein expression timelines and regulation at the post-translational level. Bioinformatics meta-analysis of these chromatin proteomes revealed distinct physiological and ageing-related features for each organ. Our results demonstrate the efficiency of organelle specific proteomics for in vivo studies of a model organism and consolidate the hypothesis that chromatin-associated proteins are involved in distinct and specific physiological functions in ageing organs.

Keywords:  cell biology; developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.73524
Stem Cell Reports. 2022 Feb 21. pii: S2213-6711(22)00092-3. [Epub ahead of print]

Aging of intestinal stem cells.

Kodandaramireddy Nalapareddy, Yi Zheng, Hartmut Geiger.

  The intestine is one of the organs that relies on stem cell function for maintaining tissue homeostasis. Recent findings on intestinal aging show that intestinal architecture, such as villus length, crypt size, and cell composition changes in the aged crypts. The correspondent decline in the regenerative capacity of the intestine is mainly due to a decline in intestinal stem cell function upon aging, as the underlying mechanisms of aging intestinal stem cells are beginning to unravel. This review summarizes our current knowledge on stem cell-intrinsic mechanisms of aging of intestinal stem cells and their connection to extrinsic factors, such as niche cells and microbiota and will introduce recent approaches to attenuate or even revert the aging of intestinal stem cells.

Keywords:  Cdc42 activity; Wnt; aging; intestinal stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2022.02.003
Nat Commun. 2022 Mar 09. 13(1): 1225

Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.

Xiao-Ru Ma, Xudong Zhu, Yujie Xiao, Hui-Min Gu, Shuang-Shuang Zheng, Liang Li, Fan Wang, Zhao-Jun Dong, Di-Xian Wang, Yang Wu, Chenyu Yang, Wenhong Jiang, Ke Yao, Yue Yin, Yang Zhang, Chao Peng, Lixia Gao, Zhuoxian Meng, Zeping Hu, Chong Liu, Li Li, Hou-Zao Chen, Yousheng Shu, Zhenyu Ju, Jing-Wei Zhao.

The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

DOI: https://doi.org/10.1038/s41467-022-28844-1
Epigenetics Chromatin. 2022 Mar 07. 15(1): 9

Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns.

Tamar Shahal, Elad Segev, Thomas Konstantinovsky, Yonit Marcus, Gabi Shefer, Metsada Pasmanik-Chor, Assaf Buch, Yuval Ebenstein, Paul Zimmet, Naftali Stern.

   BACKGROUND: The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging.
RESULTS: Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the inter-personal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age.
CONCLUSIONS: Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.

Keywords:  Aging; DNA methylation; Diabetes mellitus; Epigenetic age; Epigenetic clock; Personalized aging card; Personalized medicine

DOI:  https://doi.org/10.1186/s13072-022-00441-y
Nutrients. 2022 Feb 23. pii: 949. [Epub ahead of print]14(5):

The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging.

Eva Untersmayr, Annette Brandt, Larissa Koidl, Ina Bergheim.

  The intestinal barrier, composed of the luminal microbiota, the mucus layer, and the physical barrier consisting of epithelial cells and immune cells, the latter residing underneath and within the epithelial cells, plays a special role in health and disease. While there is growing knowledge on the changes to the different layers associated with disease development, the barrier function also plays an important role during aging. Besides changes in the composition and function of cellular junctions, the entire gastrointestinal physiology contributes to essential age-related changes. This is also reflected by substantial differences in the microbial composition throughout the life span. Even though it remains difficult to define physiological age-related changes and to distinguish them from early signs of pathologies, studies in centenarians provide insights into the intestinal barrier features associated with longevity. The knowledge reviewed in this narrative review article might contribute to the definition of strategies to prevent the development of diseases in the elderly. Thus, targeted interventions to improve overall barrier function will be important disease prevention strategies for healthy aging in the future.

Keywords:  aging; inflammaging; mucosal barrier

DOI:  https://doi.org/10.3390/nu14050949
Front Cell Dev Biol. 2021 ;9 828657

DNA Damage and Activation of cGAS/STING Pathway Induce Tumor Microenvironment Remodeling.

Rong Shen, Disheng Liu, Xiaoning Wang, Zhao Guo, Haonan Sun, Yanfeng Song, Degui Wang.

  DNA damage occurs throughout tumorigenesis and development. The immunogenicity of DNA makes it an immune stimulatory molecule that initiates strong inflammatory responses. The cGAS/STING pathway has been investigated as a critical receptor in both exogenous and endogenous DNA sensing to activate the innate immune response. Growing lines of evidence have indicated that activation of the cGAS/STING pathway is critical in antitumor immunity. Recent studies have demonstrated the outstanding advancement of this pathway in tumor-combined immunotherapy; accordingly, increased studies focus on exploration of STING pathway agonists and analogues. However, current studies propose the potential use of the cGAS/STING pathway in tumor initiation and metastasis. Here, we review the molecular mechanisms and activation of the cGAS/STING pathway, and the relationship between DNA damage and this pathway, particularly highlighting the remodeling of immune contexture in tumor environment (TME) triggered by cascade inflammatory signals. A detailed understanding of TME reprogramming initiated by this pathway may pave the way for the development of new therapeutic strategies and rational clinical application.

Keywords:  DNA damage; TME; cGAS/STING; immune response; interferon; oncotherapy; remodeling

DOI:  https://doi.org/10.3389/fcell.2021.828657