bims-senagi 2022-09-11 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022‒09‒11
thirty-two papers selected by
Maria Grazia Vizioli
Mayo Clinic

The lysosomal proteome of senescent cells contributes to the senescence secretome.
Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.
Is "cellular senescence" a misnomer?
Targeting senescence as an anti-cancer therapy.
Downregulation of senescence-associated secretory phenotype by knockdown of secreted frizzled-related protein 4 contributes to the prevention of skin aging.
Immunosenescence in atherosclerosis: A role for chronic viral infections.
Factors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging.
Nutritional Niches of Cancer Therapy-Induced Senescent Cells.
Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer.
Identification of aging-associated immunotypes and immune stability as indicators of post-vaccination immune activation.
Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease.
Age-dependent effects of gut microbiota metabolites on brain resident macrophages.
The Role of Extracellular Vesicles in Senescence.
Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH.
A Novel 6,8,9-Trisubstituted Purine Analogue Drives Breast Cancer Luminal A Subtype MCF-7 to Apoptosis and Senescence through Hsp70 Inhibition.
Cellular senescence: a promising therapeutic target in colorectal cancer.
Conserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline of social associative memories.
LONP1 downregulation with ageing contributes to osteoarthritis via mitochondrial dysfunction.
Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity.
The landscape of aging.
Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance.
Aging conundrum: A perspective for ovarian aging.
TXNIP exacerbates the senescence and ageing-related dysfunction of β-cells by inducing cell cycle arrest through p38-p16/p21-CDK-Rb pathway.
Effect of cellular aging on memory T-cell homeostasis.
Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise.
Age-related decrease in periostin expression may be associated with attenuated fracture healing in old mice.
Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver.
Pharmaceutical interventions to slow human aging. Are we ready for cocktails?
Investigating population-level immunosenescence: From bench to bedside.
How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells.
The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells.
Impact of age and sex on hyperoxia-induced cardiovascular pathophysiology.

Aging Cell. 2022 Sep 10. e13707

The lysosomal proteome of senescent cells contributes to the senescence secretome.

Miguel Rovira, Rebecca Sereda, David Pladevall-Morera, Valentina Ramponi, Ines Marin, Mate Maus, Julio Madrigal-Matute, Antonio Díaz, Fernando García, Javier Muñoz, Ana María Cuervo, Manuel Serrano.

  Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age-related diseases. Senescent cells present a remarkable increase in lysosomal mass and elevated autophagic activity. Here, we report that two main autophagic pathways macroautophagy (MA) and chaperone-mediated autophagy (CMA) are constitutively upregulated in senescent cells. Proteomic analyses of the subpopulations of lysosomes preferentially engaged in each of these types of autophagy revealed profound quantitative and qualitative changes in senescent cells, affecting both lysosomal resident proteins and cargo proteins delivered to lysosomes for degradation. These studies have led us to identify resident lysosomal proteins that are highly augmented in senescent cells and can be used as novel markers of senescence, such as arylsulfatase ARSA. The abundant secretome of senescent cells, known as SASP, is considered their main pathological mediator; however, little is known about the mechanisms of SASP secretion. Some secretory cells, including melanocytes, use the small GTPase RAB27A to perform lysosomal secretion. We found that this process is exacerbated in the case of senescent melanoma cells, as revealed by the exposure of lysosomal membrane integral proteins LAMP1 and LAMP2 in their plasma membrane. Interestingly, a subset of SASP components, including cytokines CCL2, CCL3, CXCL12, cathepsin CTSD, or the protease inhibitor SERPINE1, are secreted in a RAB27A-dependent manner in senescent melanoma cells. Finally, proteins previously identified as plasma biomarkers of aging are highly enriched in the lysosomes of senescent cells, including CTSD. We conclude that the lysosomal proteome of senescent cells is profoundly reconfigured, and that some senescent cells can be highly active in lysosomal exocytosis.

Keywords:  SASP; aging; autophagy; cellular senescence; exocytosis; lysosome

DOI:  https://doi.org/10.1111/acel.13707
Aging (Albany NY). 2022 Sep 08. 14(undefined):

Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.

Lei Liu, Xianlin Yue, Zewei Sun, William S Hambright, Qi Feng, Yan Cui, Johnny Huard, Paul D Robbins, Zhihui Wang, Xiaodong Mu.

  The aging of the immune system, or immunosenescence, was recently verified to have a causal role in driving the aging of solid organs, while the senolytic elimination of senescent immune cells was found to effectively delay systemic aging. Our recent study also showed that immune cells in severely dystrophic muscles develop senescence-like phenotypes, including the increased expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Here we further investigated whether the specific clearance of senescent immune cells in dystrophic muscle may effectively improve the function of muscle stem cells and the phenotypes of dystrophic muscle. We observed increased percentage of senescent cells in macrophages from mdx/utro(-/-) mice (a murine model for muscular dystrophy disease, dystrophin-/-; utrophin-/-), while the treatment of mdx/utro(-/-) macrophages with senolytic drug fisetin resulted in reduced number of senescent cells. We administrated fisetin to mdx/utro(-/-) mice for 4 weeks, and observed obviously reduced number of senescent immune cells, restored number of muscle cells, and improve muscle phenotypes. In conclusion, our results reveal that senescent immune cells, such as macrophages, are greatly involved in the development of muscle dystrophy by impacting the function of muscle stem cells, and the senolytic ablation of these senescent cells with fisetin can be an effective therapeutic strategy for improving function of muscle stem cells and phenotypes of dystrophic muscles.

Keywords:  cellular senescence; immunosenescence; muscular dystrophy; senolytics; stem cells

DOI:  https://doi.org/10.18632/aging.204275
Geroscience. 2022 Sep 07.

Is "cellular senescence" a misnomer?

David Gems, Carina C Kern.

  One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as "senescent." Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation-a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype).

Keywords:  Aging; Cellular senescence; Fibroblast; Osteoarthritis; Remodeling activation; Remodeling-associated secretory phenotype (RASP)

DOI:  https://doi.org/10.1007/s11357-022-00652-x
Mol Oncol. 2022 Sep 05.

Targeting senescence as an anti-cancer therapy.

Laura Bousset, Jesús Gil.

  Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one -two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.

Keywords:  Cellular senescence; chemotherapy; oncogene-induced senescence (OIS); radiotherapy; senolytics; therapy-induced senescence (TIS)

DOI:  https://doi.org/10.1002/1878-0261.13312
Aging (Albany NY). 2022 Sep 07. 14(undefined):

Downregulation of senescence-associated secretory phenotype by knockdown of secreted frizzled-related protein 4 contributes to the prevention of skin aging.

Kento Takaya, Toru Asou, Kazuo Kishi.

  There is growing evidence that the appearance and texture of the skin that is altered during the aging process are considerably enhanced by the accumulation of senescent dermal fibroblasts. These senescent cells magnify aging via an inflammatory, histolytic, and senescence-associated secretory phenotype (SASP). Secreted frizzled-related protein 4 (SFRP4) was previously determined to be expressed in dermal fibroblasts of aging skin, and its increased expression has been shown to promote cellular senescence. However, its role in the SASP remains unknown. We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers. These findings suggest a potential candidate for the development of new skin rejuvenation therapies that suppress SASP.

Keywords:  SASP; SFRP4; fibroblast; skin

DOI:  https://doi.org/10.18632/aging.204273
Front Immunol. 2022 ;13 945016

Immunosenescence in atherosclerosis: A role for chronic viral infections.

Atefe Ghamar Talepoor, Mehrnoosh Doroudchi.

  Immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, ROS generation and DNA damage which are associated with atherogenesis. Accumulating evidence shows that several DNA and RNA viruses are stimulators of immunosenescence and atherosclerosis in an interrelated network. DNA viruses such as CMV, EBV and HBV upregulate p16, p21 and p53 senescence-associated molecules; induce inflammaging, metabolic reprogramming of infected cells, replicative senescence and telomere shortening. RNA viruses such as HCV and HIV induce ROS generation, DNA damage, induction of senescence-associated secretory phenotype (SASP), metabolic reprogramming of infected cells, G1 cell cycle arrest, telomere shortening, as well as epigenetic modifications of DNA and histones. The newly emerged SARS-CoV-2 virus is also a potent inducer of cytokine storm and SASP. The spike protein of SARS-CoV-2 promotes senescence phenotype in endothelial cells by augmenting p16, p21, senescence-associated β-galactosidase (SA-β-Gal) and adhesion molecules expression. The impact of SARS-CoV-2 mega-inflammation on atherogenesis, however, remains to be investigated. In this review we focus on the common processes in immunosenescence and atherogenesis caused by chronic viral infections and discuss the current knowledge on this topic.

Keywords:  atherosclerosis; cell senescence; immunosenescence; inflammaging; viral infections

DOI:  https://doi.org/10.3389/fimmu.2022.945016
Int J Mol Sci. 2022 Sep 04. pii: 10135. [Epub ahead of print]23(17):

Factors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging.

Hyun Jung Hwang, Nayeon Kim, Allison B Herman, Myriam Gorospe, Jae-Seon Lee.

  Aging causes a progressive decline in the structure and function of organs. With advancing age, an accumulation of senescent endothelial cells (ECs) contributes to the risk of developing vascular dysfunction and cardiovascular diseases, including hypertension, diabetes, atherosclerosis, and neurodegeneration. Senescent ECs undergo phenotypic changes that alter the pattern of expressed proteins, as well as their morphologies and functions, and have been linked to vascular impairments, such as aortic stiffness, enhanced inflammation, and dysregulated vascular tone. Numerous molecules and pathways, including sirtuins, Klotho, RAAS, IGFBP, NRF2, and mTOR, have been implicated in promoting EC senescence. This review summarizes the molecular players and signaling pathways driving EC senescence and identifies targets with possible therapeutic value in age-related vascular diseases.

Keywords:  age-related vascular disease; cellular senescence; endothelial cell; molecular player; putative target; signaling pathway

DOI:  https://doi.org/10.3390/ijms231710135
Nutrients. 2022 Sep 02. pii: 3636. [Epub ahead of print]14(17):

Nutritional Niches of Cancer Therapy-Induced Senescent Cells.

Àngela Llop-Hernández, Sara Verdura, Elisabet Cuyàs, Javier A Menendez.

  Therapy-induced senescence (TIS) is a state of stable proliferative arrest of both normal and neoplastic cells that is triggered by exposure to anticancer treatments. TIS cells acquire a senescence-associated secretory phenotype (SASP), which is pro-inflammatory and actively promotes tumor relapse and adverse side-effects in patients. Here, we hypothesized that TIS cells adapt their scavenging and catabolic ability to overcome the nutritional constraints in their microenvironmental niches. We used a panel of mechanistically-diverse TIS triggers (i.e., bleomycin, doxorubicin, alisertib, and palbociclib) and Biolog Phenotype MicroArrays to identify (among 190 different carbon and nitrogen sources) candidate metabolites that support the survival of TIS cells in limiting nutrient conditions. We provide evidence of distinguishable TIS-associated nutrient consumption profiles involving a core set of shared (e.g., glutamine) and unique (e.g., glucose-1-phosphate, inosine, and uridine) nutritional sources after diverse senescence-inducing interventions. We also observed a trend for an inverse correlation between the intensity of the pro-inflammatory SASP provoked by different TIS agents and diversity of compensatory nutritional niches utilizable by senescent cells. These findings support the detailed exploration of the nutritional niche as a new metabolic dimension to understand and target TIS in cancer.

Keywords:  cancer; glutamine; metabolism; miR146a; nutrition; senescence

DOI:  https://doi.org/10.3390/nu14173636
Front Oncol. 2022 ;12 975644

Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer.

Francesco Melia, Palita Udomjarumanee, Dmitry Zinovkin, Nahid Arghiani, Md Zahidul Islam Pranjol.

  Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence.

Keywords:  colon cancer; diabetes; endothelial cells; fibroblast; senescence; tumour microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.975644
Aging Cell. 2022 Sep 08. e13703

Identification of aging-associated immunotypes and immune stability as indicators of post-vaccination immune activation.

Alper Cevirgel, Sudarshan A Shetty, Martijn Vos, Nening M Nanlohy, Lisa Beckers, Elske Bijvank, Nynke Rots, Josine van Beek, Anne-Marie Buisman, Debbie van Baarle.

Immunosenescence describes immune dysfunction observed in older individuals. To identify individuals at-risk for immune dysfunction, it is crucial to understand the diverse immune phenotypes and their intrinsic functional capabilities. We investigated immune cell subsets and variation in the aging population. We observed that inter-individual immune variation was associated with age and cytomegalovirus seropositivity. Based on the similarities of immune subset composition among individuals, we identified nine immunotypes that displayed different aging-associated immune signatures, which explained inter-individual variation better than age. Additionally, we correlated the immune subset composition of individuals over approximately a year as a measure of stability of immune parameters. Immune stability was significantly lower in immunotypes that contained aging-associated immune subsets and correlated with a circulating CD38 + CD4+ T follicular helper cell increase 7 days after influenza vaccination. In conclusion, immune stability is a feature of immunotypes and could be a potential indicator of post-vaccination cellular kinetics.

DOI: https://doi.org/10.1111/acel.13703
Front Immunol. 2022 ;13 935114

Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease.

Zento Yamada, Junko Nishio, Kaori Motomura, Satoshi Mizutani, Soichi Yamada, Tetuo Mikami, Toshihiro Nanki.

  Fibrosing interstitial lung disease (ILD) develops due to the impaired reparative processes following lung tissue damage. Cellular senescence has been reported to contribute to the progression of fibrosis. However, the mechanisms by which these senescent cells initiate and/or drive the progression of lung tissue fibrosis are not yet fully understood. We demonstrated that p21WAF1/CIP1- and p16INK4A-pathway-dependent senescence in type 2 alveolar epithelial cells (AEC2) were both involved in the initiation and progression of lung fibrosis in murine bleomycin (BLM)-induced ILD. p21WAF1/CIP1-senescent AEC2 emerged rapidly, as early as 1 day after the intratracheal instillation of BLM. Their number subsequently increased and persisted until the later fibrosis phase. Very few p16INK4A-senescent AEC2 emerged upon the instillation of BLM, and their increase was slower and milder than that of p21WAF1/CIP1+ AEC2. AEC2 enriched with senescent cells sorted from BLM-ILD lungs expressed senescence-associated secretory phenotype (SASP)-related genes, including Il6, Serpin1, Tnfa, Ccl2, Tgfb, and Pdgfa, at the initiation and chronic phases of fibrosis, exhibiting distinct expression patterns of magnitude that were dependent on the disease phase. Ly6C+ inflammatory monocytes increased in the lungs immediately after the instillation of BLM and interstitial macrophages increased from day 3. The expression of Acta2 and Col1a1 was upregulated as early as day 1, indicating the activation of fibroblasts. We speculated that IL-6, plasminogen activator inhibitor-1 (PAI-1), and TGF-β contributed to the accumulation of senescent cells during the progression of fibrosis in an autocrine and paracrine manner. In addition, CCL2, produced in large amounts by senescent AEC2, may have induced the infiltration of Ly6C+ inflammatory monocytes in the early phase, and TGF-β and PDGFa from senescent AEC2 may contribute to the activation of fibroblasts in the very early phases. Our study indicated that senescent AEC2 plays a role in the pathogenesis of fibrosing ILD throughout the course of the disease and provides insights into its pathogenesis, which may lead to the development of new therapeutic methods targeting senescent cells or SASP molecules.

Keywords:  IL-6; interstitial lung disease; interstitial macrophages; p16; p21; senescence-associated secretary phenotype; type 2 alveolar epithelial cell

DOI:  https://doi.org/10.3389/fimmu.2022.935114
Front Cell Neurosci. 2022 ;16 944526

Age-dependent effects of gut microbiota metabolites on brain resident macrophages.

Dilara Hasavci, Thomas Blank.

  In recent years, development of age-related diseases, such as Alzheimer's and Parkinson's disease, as well as other brain disorders, including anxiety, depression, and schizophrenia have been shown to be associated with changes in the gut microbiome. Several factors can induce an alteration in the bacterial composition of the host's gastrointestinal tract. Besides dietary changes and frequent use of antibiotics, the microbiome is also profoundly affected by aging. Levels of microbiota-derived metabolites are elevated in older individuals with age-associated diseases and cognitive defects compared to younger, healthy age groups. The identified metabolites with higher concentration in aged hosts, which include choline and trimethylamine, are known risk factors for age-related diseases. While the underlying mechanisms and pathways remain elusive for the most part, it has been shown, that these metabolites are able to trigger the innate immunity in the central nervous system by influencing development and activation status of brain-resident macrophages. The macrophages residing in the brain comprise parenchymal microglia and non-parenchymal macrophages located in the perivascular spaces, meninges, and the choroid plexus. In this review, we highlight the impact of age on the composition of the microbiome and microbiota-derived metabolites and their influence on age-associated diseases caused by dysfunctional brain-resident macrophages.

Keywords:  aging; bacteria; brain; gut microbiota; macrophages; metabolites; microglia; senescence

DOI:  https://doi.org/10.3389/fncel.2022.944526
Mol Cells. 2022 Sep 30. 45(9): 603-609

The Role of Extracellular Vesicles in Senescence.

Chaehwan Oh, Dahyeon Koh, Hyeong Bin Jeon, Kyoung Mi Kim.

  Cells can communicate in a variety of ways, such as by contacting each other or by secreting certain factors. Recently, extracellular vesicles (EVs) have been proposed to be mediators of cell communication. EVs are small vesicles with a lipid bilayer membrane that are secreted by cells and contain DNA, RNAs, lipids, and proteins. These EVs are secreted from various cell types and can migrate and be internalized by recipient cells that are the same or different than those that secrete them. EVs harboring various components are involved in regulating gene expression in recipient cells. These EVs may also play important roles in the senescence of cells and the accumulation of senescent cells in the body. Studies on the function of EVs in senescent cells and the mechanisms through which nonsenescent and senescent cells communicate through EVs are being actively conducted. Here, we summarize studies suggesting that EVs secreted from senescent cells can promote the senescence of other cells and that EVs secreted from nonsenescent cells can rejuvenate senescent cells. In addition, we discuss the functional components (proteins, RNAs, and other molecules) enclosed in EVs that enter recipient cells.

Keywords:  cellular senescence; circular RNA; exosome; extracellular vesicle; long noncoding RNA; microRNA

DOI:  https://doi.org/10.14348/molcells.2022.0056
Front Endocrinol (Lausanne). 2022 ;13 957616

Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH.

Laurianne Bonnet, Ida Alexandersson, Ritesh K Baboota, Tobias Kroon, Jan Oscarsson, Ulf Smith, Jeremie Boucher.

  Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines HepG2 and IHH with the senescence-inducing drugs nutlin-3a, doxorubicin and etoposide. The senescence-associated markers p16, p21, p53 and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis. Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of IR, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.

Keywords:  NAFLD; NASH; hepatocytes; insulin signaling; metabolism; senescence

DOI:  https://doi.org/10.3389/fendo.2022.957616
Anticancer Agents Med Chem. 2022 Sep 05.

A Novel 6,8,9-Trisubstituted Purine Analogue Drives Breast Cancer Luminal A Subtype MCF-7 to Apoptosis and Senescence through Hsp70 Inhibition.

Pinar Kul, Meral Tuncbilek, Mustafa Ergul, Ezgi Nurdan Yenilmez Tunoglu, Yusuf Tutar.

  BACKGROUND: Cancer cells restrain apoptotic and senescence pathways through Heat Shock Protein 70 (Hsp 70) at the intracellular level. These cells aid stimulus-independent growth and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells.OBJECTIVE: Misfolding of substrate proteins specially signaling substrate proteins may not function properly therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival.
METHOD: Targeting Hsps is a promising cancer therapy and in this study 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and Results: Hsp70 helps cancer cells to bypass the cellular senescence program, however binding of N6-(4-isopropylaniline) analogue 7 depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway.
CONCLUSION: Taken together, the purine-based inhibitor-compound 7 effectively inhibit MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy.

Keywords:  Hsp70 inhibition; Purine analogues; apoptosis; cytotoxic activity; drug design; senescence

DOI:  https://doi.org/10.2174/1871520622666220905122346
Future Oncol. 2022 Sep 07.

Cellular senescence: a promising therapeutic target in colorectal cancer.

Yue Wu, Min Xie, Jia-Huan Sun, Cong-Cong Li, Ge-Hong Dong, Qin-Sheng Zhang, Pei-Lin Cui.

  Colorectal cancer is one of the most malignant cancers worldwide, and efforts have been made to elucidate the mechanism of colorectal carcinogenesis. Cellular senescence is a physiological process in cell life, but it is also found in cancer initiation and progression. Lines of evidence show that senescence may influence the development and progression of colorectal carcinogenesis. Here, the authors review the characteristics of senescence and the recent findings of a relationship between senescence and colorectal cancer.

Keywords:  cellular senescence; colorectal cancer; senescence-associated secretory phenotype; therapy-induced senescence

DOI:  https://doi.org/10.2217/fon-2021-0661
Aging Cell. 2022 Sep 08. e13687

Conserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline of social associative memories.

Katy Pilarzyk, Latarsha Porcher, William R Capell, Steven D Burbano, Jeff Davis, Janet L Fisher, Nicole Gorny, Siena Petrolle, Michy P Kelly.

  In humans, associative memories are more susceptible to age-related cognitive decline (ARCD) than are recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD. Here, we found that both aging and traumatic brain injury-associated dementia increased the expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus. Further, age-related increases in hippocampal PDE11A4 mRNA and protein were conserved in mice, as was the increased vulnerability of associative versus recognition memories to ARCD. Interestingly, mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) ectopically accumulated in the membrane fraction and filamentous structures we term "ghost axons." These age-related increases in expression were driven by reduced exoribonuclease-mediated degradation of PDE11A mRNA and increased PDE11A4-pS117/pS124, the latter of which also drove the punctate accumulation of PDE11A4. In contrast, PDE11A4-pS162 caused dispersal. Importantly, preventing age-related increases in PDE11 expression via genetic deletion protected mice from ARCD of short-term and remote long-term associative memory (aLTM) in the social transmission of food preference assay, albeit at the expense of recent aLTM. Further, mimicking age-related overexpression of PDE11A4 in CA1 of old KO mice caused aging-like impairments in CREB function and remote social-but not non-social-LTMs. RNA sequencing and phosphoproteomic analyses of VHIPP identified cGMP-PKG-as opposed to cAMP-PKA-as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin, and retrograde endocannabinoid signaling as mechanisms by which PDE11A deletion protects against ARCD. Together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aged brain and contribute to ARCD of social memories.

Keywords:  Alzheimer's disease; COS-1; HEK293T; HT-22; STFP; TBI; age-related cognitive impairment; hippocampus; learning; memory; phosphodiesterase; proteopathy

DOI:  https://doi.org/10.1111/acel.13687
Free Radic Biol Med. 2022 Sep 02. pii: S0891-5849(22)00566-4. [Epub ahead of print]

LONP1 downregulation with ageing contributes to osteoarthritis via mitochondrial dysfunction.

Yuzhe He, Qianhai Ding, Wenliang Chen, Changjian Lin, Lujie Ge, Chenting Ying, Kai Xu, Zhipeng Wu, Langhai Xu, Jisheng Ran, Weiping Chen, Lidong Wu.

  Osteoarthritis (OA) is an age-related disorder and an important cause of disability that is characterized by a senescence-associated secretory phenotype and matrix degradation leading to a gradual loss of articular cartilage integrity. Mitochondria, as widespread organelles, are involved in regulation of complex biological processes such as energy synthesis and cell metabolism, which also have bidirectional communication with the nucleus to help maintain cellular homeostasis and regulate adaptation to a broad range of stressors. In light of the evidence that OA is strongly associated with mitochondrial dysfunction. In addition, mitochondria are considered to be the culprits of cell senescence, and mitochondrial function changes during ageing are considered to have a controlling role in cell fate. Mitochondrial dysfunction is also observed in age-related OA, however, the internal mechanism by which mitochondrial function changes with ageing to lead to the development of OA has not been elucidated. In this study, we found that the expression of Lon protease 1 (LONP1), a mitochondrial protease, was decreased in human OA cartilage and in ageing rat chondrocytes. Furthermore, LONP1 knockdown accelerated the progression and severity of osteoarthritis, which was associated with aspects of mitochondrial dysfunction including oxidative stress, metabolic changes and mitophagy, leading to downstream MAPK pathway activation. Antioxidant therapy with resveratrol suppressed oxidative stress and MAPK pathway activation induced by LONP1 knockdown to mitigate OA progression. Therefore, our findings demonstrate that LONP1 is a central regulator of mitochondrial function in chondrocytes and reveal that downregulation of LONP1 with ageing contributes to osteoarthritis.

Keywords:  Ageing; LONP1; Mitochondria; Osteoarthritis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.08.038
Nat Commun. 2022 Sep 03. 13(1): 5187

Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity.

Kyung Mok Kim, Anna Mura-Meszaros, Marie Tollot, Murali Shyam Krishnan, Marco Gründl, Laura Neubert, Marco Groth, Alejo Rodriguez-Fraticelli, Arthur Flohr Svendsen, Stefano Campaner, Nico Andreas, Thomas Kamradt, Steve Hoffmann, Fernando D Camargo, Florian H Heidel, Leonid V Bystrykh, Gerald de Haan, Björn von Eyss.

Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)-the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate "young-like" HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.

DOI: https://doi.org/10.1038/s41467-022-32970-1
Sci China Life Sci. 2022 Sep 02.

The landscape of aging.

Yusheng Cai, Wei Song, Jiaming Li, Ying Jing, Chuqian Liang, Liyuan Zhang, Xia Zhang, Wenhui Zhang, Beibei Liu, Yongpan An, Jingyi Li, Baixue Tang, Siyu Pei, Xueying Wu, Yuxuan Liu, Cheng-Le Zhuang, Yilin Ying, Xuefeng Dou, Yu Chen, Fu-Hui Xiao, Dingfeng Li, Ruici Yang, Ya Zhao, Yang Wang, Lihui Wang, Yujing Li, Shuai Ma, Si Wang, Xiaoyuan Song, Jie Ren, Liang Zhang, Jun Wang, Weiqi Zhang, Zhengwei Xie, Jing Qu, Jianwei Wang, Yichuan Xiao, Ye Tian, Gelin Wang, Ping Hu, Jing Ye, Yu Sun, Zhiyong Mao, Qing-Peng Kong, Qiang Liu, Weiguo Zou, Xiao-Li Tian, Zhi-Xiong Xiao, Yong Liu, Jun-Ping Liu, Moshi Song, Jing-Dong J Han, Guang-Hui Liu.

  Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

Keywords:  aging; intervention; mechanism

DOI:  https://doi.org/10.1007/s11427-022-2161-3
Pathol Oncol Res. 2022 ;28 1610401

Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance.

Li Liang, Yijie Chai, Fei Chai, Haijing Liu, Ningning Ma, Hong Zhang, Shuang Zhang, Lin Nong, Ting Li, Bo Zhang.

  The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated senescence-associated secretory phenotype (SASP) pathway has recently been identified in the suppression and promotion of cancers. However, its practical role in carcinogenesis remains to be comprehensively elucidated. Here, we describe an investigation analysing SASP activity and its correlations with DNA damage response (DDR), genomic mutations, and cell proliferation in gastric carcinogenesis among 30 cases with available endoscopic submucosal dissection (ESD) specimens of early neoplastic lesions (including low-grade dysplasia [LGD], high-grade dysplasia [HGD], and intramucosal carcinoma). The positive cells of senescence-associated β-galactosidase staining and cGAS, STING, interferon-regulatory factor 3 (IRF3), and signal transducer and activator of transcription 6 (STAT6) expression levels using immunostaining were elevated in HGD and in cancers. Similarly, increased expression of the Fanconi anemia group D2 (FANCD2) protein, tumour suppressor p53 binding protein 1 (TP53BP1), and replication protein A (RPA2) (i.e., primary DDR factors) was detected in HGD and in cancers; these increased expression levels were closely correlated with high expression of Ki67 and minichromosome maintenance complex component 7 (MCM7) proteins. Moreover, genomic mutations in TP53 gene were detected in 56.67% of the evaluated cases (17/30) using next-generation sequencing, and positive staining was verified in HGD and in cancers. Statistical analysis revealed that cell proliferation closely correlated with the expression of DDR factors, of which TP53BP1 was positively associated with SASP factors and IRF3 was positively correlated with cell proliferation. In addition, an analysis evaluating clinical features demonstrated that STAT6-positive cases showed a longer progression-free survival time than STAT6-negative cases. Our evaluation, conducted using a limited number of specimens, suggests SASP may be prevalent in early gastric neoplastic lesions and could be activated by accelerated cell proliferation-induced DDR. The clinical significance of SASP still needs to be determined.

Keywords:  DNA damage response; endoscopic submucosal dissection; gastric cancer; immunohistochemistry; p53; senescence-associated secretory phenotype

DOI:  https://doi.org/10.3389/pore.2022.1610401
Front Endocrinol (Lausanne). 2022 ;13 952471

Aging conundrum: A perspective for ovarian aging.

Jiachen Wu, Yang Liu, Yinhua Song, Lingjuan Wang, Jihui Ai, Kezhen Li.

  Progressive loss of physiological integrity and accumulation of degenerative changes leading to functional impairment and increased susceptibility to diseases are the main features of aging. The ovary, the key organ that maintains female reproductive and endocrine function, enters aging earlier and faster than other organs and has attracted extensive attention from society. Ovarian aging is mainly characterized by the progressive decline in the number and quality of oocytes, the regulatory mechanisms of which have yet to be systematically elucidated. This review discusses the hallmarks of aging to further highlight the main characteristics of ovarian aging and attempt to explore its clinical symptoms and underlying mechanisms. Finally, the intervention strategies related to aging are elaborated, especially the potential role of stem cells and cryopreservation of embryos, oocytes, or ovarian tissue in the delay of ovarian aging.

Keywords:  aging; interventions; oocyte; ovarian aging; ovary

DOI:  https://doi.org/10.3389/fendo.2022.952471
Antioxid Redox Signal. 2022 Sep 07.

TXNIP exacerbates the senescence and ageing-related dysfunction of β-cells by inducing cell cycle arrest through p38-p16/p21-CDK-Rb pathway.

Yang Li, Wenzhen Deng, Jinlin Wu, Qirui He, Gangyi Yang, Xie Luo, Yanjun Jia, Yaqian Duan, Liping Zhou, Dongfang Liu.

AIMS: Thioredoxin-interacting protein (TXNIP) is a crucial molecular promoter of oxidative stress and has been identified to be associated with cellular senescence. It is an important mediator of β-cell insulin secretion and has effects on β-cell mass. However, its role in β-cell senescence is unclear. The present study was designed to investigate the effects and mechanisms of TXNIP on the senescence and ageing- and diet- related dysfunction of β-cells.METHODS: Human pancreatic paraffin tissues and serum samples from different ages were collected to detect TXNIP expression. TXNIP-/- and C57BL/6J mice were fed either a normal chow diet (NCD) or a high-fat diet (HFD) until 5, 11, 14, or 20 months. The recapitulation experiment was conducted with TXNIP protein injection. MIN6 cells were transfected with LV-TXNIP and LV-siTXNIP. The biochemical indexes, ageing-related markers, cell cycle proteins and pathways were examined in vivo and in vitro.
RESULTS: TXNIP expression showed an age-related increase in β-cells and serum samples from humans. TXNIP significantly impaired glucose metabolism and insulin secretion in an age-dependent manner. TXNIP aggravated age-related and obesity-induced structural failures, oxidative stress, decreased proliferation, and increased apoptosis in β-cells and induced the cell cycle arrest. TXNIP interacted with p38 mitogen-activated protein kinase (p38MAPK) and modulated the p16/p21-CDK-Rb axis to accelerate β-cell senescence.
INNOVATION AND CONCLUSIONS: The present study demonstrated that TXNIP may exacerbate pancreatic β-cell senescence and age-related dysfunction by inducing cell cycle arrest through the p38-p16/p21-CDK-Rb pathway, in natural and pathological states.

DOI: https://doi.org/10.1089/ars.2021.0224
Front Immunol. 2022 ;13 947242

Effect of cellular aging on memory T-cell homeostasis.

Arpit C Swain, José A M Borghans, Rob J de Boer.

  The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this 'homeostatic' regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, 'global' competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional 'cognate' competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the 'gold-standard'. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for 'cognate' competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the 'gold-standard' level of TCR diversity in the memory T-cell pool.

Keywords:  Memory attrition; T cell; cellular aging; competitive exclusion; homeostatic regulation; mathematical modelling

DOI:  https://doi.org/10.3389/fimmu.2022.947242
Int J Mol Sci. 2022 Sep 01. pii: 9957. [Epub ahead of print]23(17):

Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise.

Adriana De Sousa Lages, Valentim Lopes, João Horta, João Espregueira-Mendes, Renato Andrade, Alexandre Rebelo-Marques.

  Globally, better health care access and social conditions ensured a significant increase in the life expectancy of the population. There is, however, a clear increase in the incidence of age-related diseases which, besides affecting the social and economic sustainability of countries and regions around the globe, leads to a decrease in the individual's quality of life. There is an urgent need for interventions that can reverse, or at least prevent and delay, the age-associated pathological deterioration. Within this line, this narrative review aims to assess updated evidence that explores the potential therapeutic targets that can mimic or complement the recognized anti-aging effects of physical exercise. We considered pertinent to review the anti-aging effects of the following drugs and supplements: Rapamycin and Rapamycin analogues (Rapalogs); Metformin; 2-deoxy-D-glucose; Somatostatin analogues; Pegvisomant; Trametinib; Spermidine; Fisetin; Quercetin; Navitoclax; TA-65; Resveratrol; Melatonin; Curcumin; Rhodiola rosea and Caffeine. The current scientific evidence on the anti-aging effect of these drugs and supplements is still scarce and no recommendation of their generalized use can be made at this stage. Further studies are warranted to determine which therapies display a geroprotective effect and are capable of emulating the benefits of physical exercise.

Keywords:  AMPK; aging; anti-aging; drug; health span; longevity; mTOR; senescence; supplement; therapeutics

DOI:  https://doi.org/10.3390/ijms23179957
J Orthop Res. 2022 Sep 04.

Age-related decrease in periostin expression may be associated with attenuated fracture healing in old mice.

Daniel Clark, Jeffrey Doelling, Diane Hu, Theodore Miclau, Mary Nakamura, Ralph Marcucio.

  Older adults suffer more bone fractures with higher rates of healing complications and increased risk of morbidity and mortality. An improved understanding of the cellular and molecular mechanism of fracture healing and how such processes are perturbed with increasing age may allow for better treatment options to manage fractures in older adults. Macrophages are attractive therapeutics due to their role in several phases of fracture healing. After injury, bone marrow-derived macrophages are recruited to the injury and propagate the inflammatory response, contribute to resolution of inflammation, and promote bone regeneration. A tissue resident population of macrophages named osteal macrophages are present in the periosteum and are directly associated with osteoblasts and these cells contribute to bone formation. Here, we utilized bulk RNA sequencing to analyze the transcriptional activity of osteal macrophages from old and young mice present in primary calvarial cultures. Macrophages demonstrated a diverse transcriptional profile, expressing genes involved in immune function as well as wound healing and regeneration. Periostin was significantly downregulated in macrophages from old mice compared to young. Periostin is an extracellular matrix protein with important functions that promote osteoblast activity during bone regeneration. An age-related decrease of periostin expression was verified in the fracture callus of old mice compared to young. Young periostin knockout mice demonstrated attenuated fracture healing outcomes that reflected what is observed in old mice. This work supports an important role of periostin in fracture healing, and therapeutically targeting the age-related decrease in periostin may improve healing outcomes in older populations. This article is protected by copyright. All rights reserved.

Keywords:  RNA sequencing; fracture healing; macrophage; periostin

DOI:  https://doi.org/10.1002/jor.25439
Mol Syst Biol. 2022 Sep;18(9): e11002

Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver.

Mihaela Bozukova, Chrysa Nikopoulou, Niklas Kleinenkuhnen, Dora Grbavac, Katrin Goetsch, Peter Tessarz.

  Regulation of gene expression is linked to the organization of the genome. With age, chromatin alterations occur on all levels of genome organization, accompanied by changes in the gene expression profile. However, little is known about the changes in the level of transcriptional regulation. Here, we used a multi-omics approach and integrated ATAC-, RNA- and NET-seq to identify age-related changes in the chromatin landscape of murine liver and to investigate how these are linked to transcriptional regulation. We provide the first systematic inventory of the connection between aging, chromatin accessibility, and transcriptional regulation in a whole tissue. Aging in murine liver is characterized by an increase in chromatin accessibility at promoter regions, but not in an increase in transcriptional output. Instead, aging is accompanied by a decrease in promoter-proximal pausing of RNA polymerase II (Pol II), while initiation of transcription is not decreased as assessed by RNA polymerase mapping using CUT&RUN. Based on the data reported, we propose that these age-related changes in transcriptional regulation are due to a reduced stability of the pausing complex.

Keywords:  aging; chromatin architecture; nascent transcription; promoter-proximal pausing

DOI:  https://doi.org/10.15252/msb.202211002
Aging Pathobiol Ther. 2022 ;4(2): 51-52

Pharmaceutical interventions to slow human aging. Are we ready for cocktails?

Manuela Rosenfeld, Warren Ladiges.

  Slowing human aging with pharmaceuticals is now recognized as a feasible strategy. However, the design of clinical trials is still focused on single drug approaches. The process of aging has multiple pathways, which no current drug has been shown to effectively target. Therefore, it is of interest to study combinations, or cocktails, of drugs. A recently published article reported that a drug cocktail of rapamycin, acarbose and phenylbutyrate slowed aging in middle-aged mice treated for three months. The impact of this report is discussed, with the implications for determining endpoints in humans for testing drug cocktails as well as testing other drug combinations.

Keywords:  Healthy aging; acarbose; aging mice; drug cocktail; phenylbutyrate; rapamycin

DOI:  https://doi.org/10.31491/apt.2022.06.086
Front Immunol. 2022 ;13 949928

Investigating population-level immunosenescence: From bench to bedside.

Lucas Leite Cunha, Victor Alexandre Dos Santos Valsecchi, Laura Sterian Ward.

  The immune response is remodeled with aging in a process called immunosenescence. Some immunologists conceive immunosenescence as an adaptation of immunity to the aged immune-environment rather than a merely collapsed reactivity of immune cells against microbes and tumor cells. Others believe on an uninterrupted activation of the innate immune system with aging, leading to a low grade, sterile and chronic proinflammatory state called inflammaging. For instance, it is possible that chronic infection by cytomegalovirus leads to persistent production of viral load. This phenomenon offers periodic stimuli to the immune system that ultimately contribute to the remodeling of the immune response. If investigating immunosenescence at the cellular level is already a difficult task, considering the population level is much more complex. However, by studying immunosenescence at the population level, we can extract valuable results with viable applications. While studies with animal models allow scientists to deepen their understanding of the mechanisms of immunosenescence, studying large populations can bring practical innovations to medicine and the health system. Many researchers and funders have dedicated themselves to producing methods for the evaluation of immunosenescence on a large scale, aiming to elucidate new mechanisms by which diseases are established in the elderly. The description of how the immune response is remodeled with aging emerges as a new tool to identify the subset of subjects in which unhealthy aging is a matter of time, to help better individualize clinical management and select patients who may benefit. of early interventions. This review focuses on functional assays as valuable methods for measuring the remodeling of the immune response with aging and discuss their clinical impact. We also recall fundamental concepts for understanding the aging process of the immune response. In addition, we highlight future prospects for immunosenescence research.

Keywords:  adaptive immunity; immunosenescence; inflammaging; innate immunity; population

DOI:  https://doi.org/10.3389/fimmu.2022.949928
Int J Mol Sci. 2022 Aug 31. pii: 9880. [Epub ahead of print]23(17):

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells.

Anna Aiello, Mattia Emanuela Ligotti, Maider Garnica, Giulia Accardi, Anna Calabrò, Fanny Pojero, Hugo Arasanz, Ana Bocanegra, Ester Blanco, Luisa Chocarro, Miriam Echaide, Leticia Fernandez-Rubio, Pablo Ramos, Sergio Piñeiro-Hermida, Grazyna Kochan, Nahid Zareian, Farzin Farzaneh, David Escors, Calogero Caruso, Giuseppina Candore.

  Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.

Keywords:  adjuvants; aging; dendritic cells; immunosenescence; immunostimulation; innate immunity; trained immunity; vaccines

DOI:  https://doi.org/10.3390/ijms23179880
Front Cell Dev Biol. 2022 ;10 946678

The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells.

Pablo Morgado-Cáceres, Gianella Liabeuf, Ximena Calle, Lautaro Briones, Jaime A Riquelme, Roberto Bravo-Sagua, Valentina Parra.

  The complex physiology of eukaryotic cells requires that a variety of subcellular organelles perform unique tasks, even though they form highly dynamic communication networks. In the case of the endoplasmic reticulum (ER) and mitochondria, their functional coupling relies on the physical interaction between their membranes, mediated by domains known as mitochondria-ER contacts (MERCs). MERCs act as shuttles for calcium and lipid transfer between organelles, and for the nucleation of other subcellular processes. Of note, mounting evidence shows that they are heterogeneous structures, which display divergent behaviors depending on the cell type. Furthermore, MERCs are plastic structures that remodel according to intra- and extracellular cues, thereby adjusting the function of both organelles to the cellular needs. In consonance with this notion, the malfunction of MERCs reportedly contributes to the development of several age-related disorders. Here, we integrate current literature to describe how MERCs change, starting from undifferentiated cells, and their transit through specialization, malignant transformation (i.e., dedifferentiation), and aging/senescence. Along this journey, we will review the function of MERCs and their relevance for pivotal cell types, such as stem and cancer cells, cardiac, skeletal, and smooth myocytes, neurons, leukocytes, and hepatocytes, which intervene in the progression of chronic diseases related to age.

Keywords:  aging; cellular diffentiation; chronic diseases; endoplasmic reticulum; mitochondria

DOI:  https://doi.org/10.3389/fcell.2022.946678
Mech Ageing Dev. 2022 Sep 05. pii: S0047-6374(22)00109-9. [Epub ahead of print] 111727

Impact of age and sex on hyperoxia-induced cardiovascular pathophysiology.

Riddhi Vichare, Faizan Saleem, Hussein Mansour, Katarina Bojkovic, Feng Cheng, Manas Biswal, Siva Kumar Panguluri.

  Hyperoxia is characterized by pronounced inflammatory responses, pulmonary cell apoptosis, and adverse cardiac remodeling due to an excess supply of oxygen. Hyperoxic episodes are frequent in mechanically ventilated patients and are associated with in-hospital mortality. This study extends the analysis of prior published research by our group as it investigates the influence of age in male and female rodents exposed to hyperoxic conditions. Age is an independent cardiovascular risk factor, often compounded by variables like obesity, diabetes, and a decline in sex hormones and their receptors. This study simulates clinical hyperoxia by subjecting rodents to > 90% of oxygen for 72hours and compares the changes in cardiac structural and functional parameters with those exposed to normal air. While in both sexes conduction abnormalities with ageing were discernible, aged females owing to their inherent higher baseline QTc, were at a higher risk of developing arrhythmias as compared to age-matched males. Quantitative real-time RT-PCR and western blot analysis reflected altered expression of cardiac potassium channels, resulting in conduction abnormalities in aged female rodents. Unaffected by age and sex, hyperoxia-treated mice had altered body composition, as evidenced by a considerable reduction in body weight. Interestingly, compensatory hypertrophy observed as a protective mechanism in young males was absent in aged males, whereas protection of hearts from hyperoxia-induced cardiac hypertrophy was absent in aged female mice, both of which may be at least in part due to a reduction in sex steroid receptors and the systemic steroid levels. Finally, statistical analysis revealed that hyperoxia had the greatest impact on most of the cardiac parameters, followed by age and then sex. This data established an imperative finding that can change the provision of care for aged individuals admitted to ICU by elucidating the impact of intrinsic aging on hyperoxia-induced cardiac remodeling.

Keywords:  Arrhythmia; Cardiac hypertrophy; ECG; Echocardiogram; Hyperoxia; ICU; Ion channel; Sex hormone

DOI:  https://doi.org/10.1016/j.mad.2022.111727