bims-senagi 2022-11-06 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–11–06
39 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model.
Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes.
Senotherapeutics for mesenchymal stem cell senescence and rejuvenation.
Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux.
The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside.
Unsupervised learning of aging principles from longitudinal data.
Low-dose tributyltin triggers human chondrocyte senescence and mouse articular cartilage aging.
Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells.
Metformin ameliorates 5-fluorouracil-induced intestinalinjury by inhibiting cellular senescence, inflammation, and oxidative stress.
Silencing P38 MAPK reduces cellular senescence in human fetal chorion throphoblast cells.
Age-related mechanisms in the context of rheumatic disease.
Angelica sinensis polysaccharides prevents hematopoietic regression in D-Galactose-Induced aging model via attenuation of oxidative stress in hematopoietic microenvironment.
Senescent fibroblasts support lung repair.
STAT1- and NFAT-independent amplification of purinoceptor function integrates cellular senescence with interleukin-6 production in preadipocytes.
Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice.
A senolysis-based theragnostic prodrug strategy towards chronic renal failure.
Elamipretide effects on the skeletal muscle phosphoproteome in aged female mice.
The telomerase connection of the brain and its implications for neurodegenerative diseases.
Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents.
Early onset of senescence and imbalanced epidermal homeostasis across the decades in photoexposed human skin: Fingerprints of inflammaging.
Caloric restriction reinforces the stem cell pool in the aged brain without affecting overall proliferation status.
The Naked Mole-Rat as a Model for Healthy Aging.
Ageing-resembling phenotype of long-term allogeneic hematopoietic cells recipients compared to their donors.
APOE ɛ4 allele and TOMM40-APOC1 variants jointly contribute to survival to older ages.
Identification of senescence-associated long non-coding RNAs to predict prognosis and immune microenvironment in patients with hepatocellular carcinoma.
Tra1 controls the transcriptional landscape of the aging cell.
Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.
Neutrophils in aging and aging-related pathologies.
A decellularized extracellular matrix derived from keratinocytes can suppress cellular senescence induced by replicative and oxidative stresses.
Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice.
The DNA damage induced immune response: Implications for cancer therapy.
Overexpression of adrenomedullin (ADM) alleviates the senescence of human dental pulp stem cells by regulating the miR-152/CCNA2 pathway.
The two faces of DNA oxidation in genomic and functional mosaicism during aging in human neurons.
Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.
Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice.
Covid-19-stress associated with worse sleep quality, particularly with increasing age.
Age-related SUMOylation of PLK1 is essential to meiosis progression in mouse oocytes.
Modalities of aging in organisms with different strategies of resource allocation.
TREM-1 exacerbates bleomycin-induced pulmonary fibrosis by aggravating alveolar epithelial cell senescence in mice.

Rejuvenation Res. 2022 Nov 02.

Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model.

Kento Takaya, Tatsuyuki Ishii, Toru Asou, Kazuo Kishi.

Chronic senescence, such as aging, contributes to age-related tissue dysfunction and disease development. The accumulation of senescent fibroblasts and the senescence-associated secretory phenotype are particularly implicated in this process. Removal of senescent cells has been reported to prevent tissue dysfunction and extend life span during aging. ABT-263 (navitoclax), which inhibits antiapoptotic proteins, is a leading antiaging drug; however, its role in human skin aging is unclear. This study aimed to determine the rejuvenating effects of ABT-263 on aging skin using a human skin graft mouse model. We assessed the viability of ABT-263-treated skin fibroblasts after inducing senescence. Aged human skin was transplanted under the back skin of nude mice and injected intraperitoneally with the drug or control. Analysis of the skin specimens revealed that ABT-263 induced selective elimination of senescent dermal fibroblasts. Senescent human skin treated with ABT-263 exhibited a decrease in the number of senescent cells and in the expression of aging-related secretory phenotype molecules, such as matrix metalloproteinases and interleukins and an increase in collagen density. Our results indicate that selective removal of senescent skin cells with ABT-263 can improve the aging phenotype of human skin without side effects. ABT-263 is, thus, a novel potential therapeutic agent for skin aging.

DOI: https://doi.org/10.1089/rej.2022.0048
Nature. 2022 Nov 02.

Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes.

Teh-Wei Wang, Yoshikazu Johmura, Narumi Suzuki, Satotaka Omori, Toshiro Migita, Kiyoshi Yamaguchi, Seira Hatakeyama, Satoshi Yamazaki, Eigo Shimizu, Seiya Imoto, Yoichi Furukawa, Akihiko Yoshimura, Makoto Nakanishi.

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases1. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.

DOI: https://doi.org/10.1038/s41586-022-05388-4
Drug Discov Today. 2022 Nov 01. pii: S1359-6446(22)00417-2. [Epub ahead of print] 103424

Senotherapeutics for mesenchymal stem cell senescence and rejuvenation.

Pooi-Fong Wong, Murugan Dharmani Devi, Thamil Selvee Ramasamy.

  Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.

Keywords:  cellular senescence; rejuvenation; senolytics; senomorphics; stem cell therapy

DOI:  https://doi.org/10.1016/j.drudis.2022.103424
J Adv Res. 2022 Nov;pii: S2090-1232(21)00262-9. [Epub ahead of print]41 205-218

Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux.

Shi Tai, Jiaxing Sun, Yuying Zhou, Zhaowei Zhu, Yuhu He, Mingxian Chen, Hui Yang, Yichao Xiao, Tao Tu, Liang Tang, Xuping Li, Jianping Zeng, Xilong Zheng, Shenghua Zhou.

   INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin's impact on VSMC senescence is largely undefined.
OBJECTIVES: To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues.
METHODS: Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings.
RESULTS: Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin's anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin.
CONCLUSIONS: Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.

Keywords:  Aging; Autophagic flux; Lysosome; Senescence; VSMC

DOI:  https://doi.org/10.1016/j.jare.2021.12.009
Front Aging. 2022 ;3 1005322

The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside.

María B Birkisdóttir, Ivar van Galen, Renata M C Brandt, Sander Barnhoorn, Nicole van Vliet, Claire van Dijk, Bhawani Nagarajah, Sandra Imholz, Conny T van Oostrom, Erwin Reiling, Ákos Gyenis, Pier G Mastroberardino, Dick Jaarsma, Harry van Steeg, Jan H J Hoeijmakers, Martijn E T Dollé, Wilbert P Vermeij.

  Despite efficient repair, DNA damage inevitably accumulates with time affecting proper cell function and viability, thereby driving systemic aging. Interventions that either prevent DNA damage or enhance DNA repair are thus likely to extend health- and lifespan across species. However, effective genome-protecting compounds are largely lacking. Here, we use Ercc1 Δ/- and Xpg -/- DNA repair-deficient mutants as two bona fide accelerated aging mouse models to test propitious anti-aging pharmaceutical interventions. Ercc1 Δ/- and Xpg -/- mice show shortened lifespan with accelerated aging across numerous organs and tissues. Previously, we demonstrated that a well-established anti-aging intervention, dietary restriction, reduced DNA damage, and dramatically improved healthspan, strongly extended lifespan, and delayed all aging pathology investigated. Here, we further utilize the short lifespan and early onset of signs of neurological degeneration in Ercc1 Δ/- and Xpg -/- mice to test compounds that influence nutrient sensing (metformin, acarbose, resveratrol), inflammation (aspirin, ibuprofen), mitochondrial processes (idebenone, sodium nitrate, dichloroacetate), glucose homeostasis (trehalose, GlcNAc) and nicotinamide adenine dinucleotide (NAD+) metabolism. While some of the compounds have shown anti-aging features in WT animals, most of them failed to significantly alter lifespan or features of neurodegeneration of our mice. The two NAD+ precursors; nicotinamide riboside (NR) and nicotinic acid (NA), did however induce benefits, consistent with the role of NAD+ in facilitating DNA damage repair. Together, our results illustrate the applicability of short-lived repair mutants for systematic screening of anti-aging interventions capable of reducing DNA damage accumulation.

Keywords:  DNA damage repair; NAD; aging; anti-aging interventions; dietary restriction mimetics; pharmacological screening; progeria

DOI:  https://doi.org/10.3389/fragi.2022.1005322
Nat Commun. 2022 Nov 01. 13(1): 6529

Unsupervised learning of aging principles from longitudinal data.

Konstantin Avchaciov, Marina P Antoch, Ekaterina L Andrianova, Andrei E Tarkhov, Leonid I Menshikov, Olga Burmistrova, Andrei V Gudkov, Peter O Fedichev.

Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements. Assuming that aging results from a dynamic instability of the organism state, we designed a deep artificial neural network, including auto-encoder and auto-regression (AR) components. The AR model tied the dynamics of physiological state with the stochastic evolution of a single variable, the "dynamic frailty indicator" (dFI). In a subset of blood tests from the Mouse Phenome Database, dFI increased exponentially and predicted the remaining lifespan. The observation of the limiting dFI was consistent with the late-life mortality deceleration. dFI changed along with hallmarks of aging, including frailty index, molecular markers of inflammation, senescent cell accumulation, and responded to life-shortening (high-fat diet) and life-extending (rapamycin) treatments.

DOI: https://doi.org/10.1038/s41467-022-34051-9
Arch Toxicol. 2022 Nov 01.

Low-dose tributyltin triggers human chondrocyte senescence and mouse articular cartilage aging.

Yao-Pang Chung, Te-I Weng, Ding-Cheng Chan, Rong-Sen Yang, Shing-Hwa Liu.

  Tributyltin (TBT) is known as an endocrine-disrupting chemical. This study investigated the effects and possible mechanisms of TBT exposure on inducing human articular chondrocyte senescence in vitro at the human-relevant concentrations of 0.01-0.5 μM and mouse articular cartilage aging in vivo at the doses of 5 and 25 μg/kg/day, which were 5 times lower than the established no observed adverse effect level (NOAEL) and equal to NOAEL, respectively. TBT significantly increased the senescence-associated β-galactosidase activity and the protein expression levels of senescence markers p16, p53, and p21 in chondrocytes. TBT induced the protein phosphorylation of both p38 and JNK mitogen-activated protein kinases in which the JNK signaling was a main pathway to be involved in TBT-induced chondrocyte senescence. The phosphorylation of both ataxia-telangiectasia mutated (ATM) and histone protein H2AX (termed γH2AX) was also significantly increased in TBT-treated chondrocytes. ATM inhibitor significantly inhibited the protein expression levels of γH2AX, phosphorylated p38, phosphorylated JNK, p16, p53, and p21. TBT significantly stimulated the mRNA expression of senescence-associated secretory phenotype (SASP)-related factors, including IL-1β, TGF-β, TNF-α, ICAM-1, CCL2, and MMP13, and the protein expression of GATA4 and phosphorylated NF-κB-p65 in chondrocytes. Furthermore, TBT by oral gavage for 4 weeks in mice significantly enhanced the articular cartilage aging and abrasion. The protein expression of phosphorylated p38, phosphorylated JNK, GATA4, and phosphorylated NF-κB-p65, and the mRNA expression of SASP-related factors were enhanced in the mouse cartilages. These results suggest that TBT exposure can trigger human chondrocyte senescence in vitro and accelerating mouse articular cartilage aging in vivo.

Keywords:  Aging; Human chondrocytes; Mouse articular cartilage; Senescence; Tributyltin

DOI:  https://doi.org/10.1007/s00204-022-03407-x
Biol Pharm Bull. 2022 ;45(11): 1636-1643

Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells.

Akimasa Sanagawa, Yuji Hotta, Rara Sezaki, Natsumi Tomita, Tomoya Kataoka, Yoko Furukawa-Hibi, Kazunori Kimura.

  In the field of cosmetic research, there is a growing interest in alternatives to animal experiments, such as in vitro models using cultured cells. The trend is spreading to the field of food and drugs. Although various types of cells are used as in vitro models, the effect of cellular senescence on the expression and function of transporters in these models is unclear. In the present study, we examined the effect of replicative senescence (by passage culture) on the expression and function of transporters in renal proximal tubular epithelial cells (RPTECs). The increase in senescence-associated-β-galactosidase (SA-β-gal)-positive cells, cell cycle arrest markers, and senescence-associated secretory phenotype (SASP) markers was associated with an increase in passage numbers of RPTECs. Gene expression of various transporters in RPTEC was also altered. The mRNA level of organic cation transporter 2 decreased most rapidly with passage numbers among the transporters. The uptake of fluorescent cationic substrates in SA-β-gal-positive RPTECs was less than that in SA-β-gal-negative RPTECs. However, these changes in the expression of transporters seem to be significantly different from those observed in rodents and human kidneys in many aspects. As cellular senescence is observed in various situations, especially in RPTECs, it may be necessary to exclude it from toxicological and pharmacokinetic evaluations using in vitro models as much as possible. Additionally, when discussing cellular senescence, it is important to note the differences between aging in cells and aging and senescence in individuals.

Keywords:  cellular senescence; renal proximal tubular epithelial cell; senescence-associated-β-galactosidase; transporter

DOI:  https://doi.org/10.1248/bpb.b22-00322
Int Immunopharmacol. 2022 Oct 27. pii: S1567-5769(22)00826-8. [Epub ahead of print]113(Pt A): 109342

Metformin ameliorates 5-fluorouracil-induced intestinalinjury by inhibiting cellular senescence, inflammation, and oxidative stress.

Jing Xia, Jun Chen, Manoj Kumar Vashisth, Yuchen Ge, Qianlong Dai, Siyue He, Yi-Ling Shi, Xiao-Bo Wang.

  5-Fluorouracil (5-Fu), which inhibits metabolism, isanessentialpartof the first-line treatment of colorectal cancer but causes severe side effects, including nausea, vomiting, anorexia, and gastrointestinal injury with severe diarrhea, and requires dose reduction or treatment deferral, resulting in a poor prognosis. Metformin has anti-inflammatory effects, but its role in the mechanism of treatment in intestinal injury caused by 5-Fu remains unclear. In our present research, we assessed the impact of metformin on damagetotheintestinefrom5-Fuby inhibiting cellular senescence, intestinalcanal inflammation, and oxidative stress by using HUVECs, HIECs, and male BALB/c mice. It has been found that intestinal damage caused by 5-Fu is associated with the accumulation of senescent cells. Metformin relieved intestinaldamage by suppressing the activity of senescence-β-galactosidase (SA-β-gal) and the development of the senescence-associated secretory phenotype (SASP). Furthermore, we observed that the anti-aging effect was closely correlated with mTOR suppression in cell and mouse models. In conclusion, this is the first time that metformin has been able to reduce intestinaldamage related to chemotherapy by inhibiting cellular senescence and oxidative stress.

Keywords:  5-Fluorouracil; Inflammation; Intestinalinjury; Metformin; Oxidative stress; Senescence

DOI:  https://doi.org/10.1016/j.intimp.2022.109342
Am J Reprod Immunol. 2022 Nov 05.

Silencing P38 MAPK reduces cellular senescence in human fetal chorion throphoblast cells.

Brett Goldman, Enkhtuya Radnaa, Talar Kechichian, Ramkumar Menon.

   PROBLEM: Amniochorion senescence generates mechanistic signals to initiate parturition. Activation of p38 mitogen-activated kinase (MAPK) in fetal amnion cells is a key mediator of senescence as well as epithelial-mesenchymal transition (EMT) of amnion cells. However, the impact of p38 MAPK in chorion trophoblast cells (CTCs) is unclear. We tested if eliminating p38 will reduce oxidative stress (OS) induced cell fates like cellular senescence, EMT, and inflammation induced by these processes in CTCs.
METHODS: p38MAPK in CTCs was silenced using CRISPR/Cas9. OS was evoked by cigarette smoke extract (CSE) exposure. EMT was evoked by transforming growth factor (TGF)-β treatment. Cell cycle, senescence, EMT, and inflammation were analyzed.
RESULTS: CSE-induced changes in the cell cycle were not seen in p38KO CTCs compared to WT cells. OS induced by CSE evoked senescence and senescence-associated secretory phenotype (SASP as indicated by IL-6 and IL-8 increase) in WT but not in p38MAPK KO CTCs. No changes were noted in HLA-G expression regardless of the status of p38MAPK. Neither CSE nor TGF-β evoked EMT in either WT or p38 KO CTCs.
CONCLUSION: Senescence and senescence-associated inflammation in human fetal CTCs are mediated by p38MAPK. Compared to amnion epithelial cells, CTCs are resistant to EMT. This refractoriness may help them to maintain the barrier functions at the choriodecidual interface. This article is protected by copyright. All rights reserved.

Keywords:  EMT; Fetal membrane; aging; chorion trophoblast cells; inflammation; oxidative stress; parturition; senescence

DOI:  https://doi.org/10.1111/aji.13648
Nat Rev Rheumatol. 2022 Nov 03.

Age-related mechanisms in the context of rheumatic disease.

Ghada Alsaleh, Felix C Richter, Anna K Simon.

Ageing is characterized by a progressive loss of cellular function that leads to a decline in tissue homeostasis, increased vulnerability and adverse health outcomes. Important advances in ageing research have now identified a set of nine candidate hallmarks that are generally considered to contribute to the ageing process and that together determine the ageing phenotype, which is the clinical manifestation of age-related dysfunction in chronic diseases. Although most rheumatic diseases are not yet considered to be age related, available evidence increasingly emphasizes the prevalence of ageing hallmarks in these chronic diseases. On the basis of the current evidence relating to the molecular and cellular ageing pathways involved in rheumatic diseases, we propose that these diseases share a number of features that are observed in ageing, and that they can therefore be considered to be diseases of premature or accelerated ageing. Although more data are needed to clarify whether accelerated ageing drives the development of rheumatic diseases or whether it results from the chronic inflammatory environment, central components of age-related pathways are currently being targeted in clinical trials and may provide a new avenue of therapeutic intervention for patients with rheumatic diseases.

DOI: https://doi.org/10.1038/s41584-022-00863-8
Mol Biol Rep. 2022 Oct 31.

Angelica sinensis polysaccharides prevents hematopoietic regression in D-Galactose-Induced aging model via attenuation of oxidative stress in hematopoietic microenvironment.

Pengwei Jing, Xiaoying Song, Lirong Xiong, Biyao Wang, Yaping Wang, Lu Wang.

   BACKGROUND: Extrinsic molecular mechanisms that regulate hematopoietic stem/progenitor cell (HSPC) aging are still poorly understood, and a potential protective medication needs to be explored.
MATERIALS AND METHODS: The senescent parameters of hematopoietic cells and bone marrow stromal cells (BMSCs) including cell cycle analysis, senescence-associated SA-β-gal staining and signals, hematopoietic factors and cellular junction were analyzed in femur and tibia of rats. Furthermore, Sca-1+ HSPCs and BMSCs co-culture system was established to evaluate the direct effects of BMSC feeder layer to HSPCs. Oxidative DNA damage indicators in Sca-1+ HSCs and senescence-associated secretory phenotype (SASP) of BMSCs, gap junction intercellular communication between BMSCs, osteogenesis/adipogenisis differentiation balance of BMSCs were detected.
RESULTS: In the D-gal pre-administrated rats, ASP treatment rescued senescence of hematopoietic cells and BMSCs, reserved CFU-GEMM; also, ASP treatment attenuated stromal oxidative load, ameliorated SCF, CXCL12, and GM-CSF production, increased Connexin-43 (Cx43) expression. BMSCs and Sca-1+ HSPCs co-cultivation demonstrated that ASP treatment prevented oxidative DNA damage response in co-cultured Sca-1+ HSPCs induced by D-gal pre-administration of feeder layer and the underlying mechanism may be related to ASP ameliorating feeder layer dysfunction due to D-gal induced senescence via inhibiting secretion of IL-1, IL-6, TNF-α, and RANTES, enhancing Cx43-mediated intercellular communication, improving Runx2 expression whereas decreasing PPARγ expression in BMSCs.
CONCLUSION: The antioxidant property of ASP may provide a stroma-mediated potential therapeutic strategy for HSPC aging.

Keywords:  Angelica sinensis polysaccharide; Bone marrow stroma; Hematopoietic stem/progenitor cell; Oxidative stress; Stress-induced premature senescence

DOI:  https://doi.org/10.1007/s11033-022-07898-w
Nat Rev Mol Cell Biol. 2022 Nov 03.

Senescent fibroblasts support lung repair.

Paulina Strzyz.

DOI: https://doi.org/10.1038/s41580-022-00559-7
Br J Pharmacol. 2022 Nov 02.

STAT1- and NFAT-independent amplification of purinoceptor function integrates cellular senescence with interleukin-6 production in preadipocytes.

Yasser Majeed, Aisha Y Madani, Ahmed I Altamimi, Raphael Courjaret, Muneera Vakayil, Samuel J Fountain, Khaled Machaca, Nayef A Mazloum.

   BACKGROUND AND PURPOSE: Senescent preadipocytes promote adipose tissue dysfunction by secreting pro-inflammatory factors but little is known about the mechanisms regulating their production. We investigated if upregulated purinoceptor function sensitized senescent preadipocytes to cognate agonists and how such sensitization regulated inflammation.
EXPERIMENTAL APPROACH: Etoposide was used to trigger senescence in 3T3-L1 preadipocytes. CRISPR/Cas9 technology or pharmacology allowed studies of transcription factor function. Fura-2 imaging was used for calcium measurements. Interleukin-6 levels were quantified using quantitative PCR and ELISA. Specific agonists and antagonists supported studies of purinoceptor coupling to interleukin-6 production. Experiments in MS1 VEGF angiosarcoma cells and adipose tissue samples from obese mice complemented preadipocyte experiments.
KEY RESULTS: 1. DNA damage-induced senescence robustly upregulated purinoceptor expression levels in preadipocytes and MS1 VEGF angiosarcoma cells. 2. ATP-evoked Ca2+ release was potentiated in senescent preadipocytes and ATP exposure enhanced interleukin-6 production, an effect mimicked by ADP but not UTP in a calcium-independent manner. 3. Senescence-associated upregulation and activation of the adenosine A3 receptor also enhanced interleukin-6 production. 4. Nucleotide hydrolysis was not essential because exposure to ATPγS also enhanced interleukin-6 secretion. 5. Pharmacological experiments suggested coupling of P2X ion channels and P2Y12 -P2Y13 receptors to downstream interleukin-6 production. 6. Interleukin-6 signaling exacerbated inflammation during senescence and compromised adipogenesis.
CONCLUSIONS AND IMPLICATIONS: We report a previously uncharacterized link between cellular senescence and purinergic signaling in preadipocytes and endothelial cancer cells, raising the possibility that upregulated purinoceptors play key modulatory roles in senescence-associated conditions like obesity and cancer. There is potential for exploitation of specific purinoceptor antagonists as therapeutics in inflammatory disorders.

Keywords:  Adora3; DNA damage; inflammation; interleukin-; purinergic signaling; senescence

DOI:  https://doi.org/10.1111/bph.15978
Biogerontology. 2022 Oct 31.

Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice.

Emily C Peters, Luke Safayan, Tyler J Marx, Emily Ngu, Anastasiia Vasileva, India Zappia, William H Powell, Frank A Duca, Jennifer H Stern.

  Chronic calorie restriction (CR) results in lengthened lifespan and reduced disease risk. Many previous studies have implemented 30-40% calorie restriction to investigate these benefits. The goal of our study was to investigate the effects of calorie restriction, beginning at 4 months of age, on metabolic and physical changes induced by aging. Male C57BL/6NCrl calorie restricted and ad libitum fed control mice were obtained from the National Institute on Aging (NIA) and studied at 10, 18, 26, and 28 months of age to better understand the metabolic changes that occur in response to CR in middle age and advanced age. Food intake was measured in ad libitum fed controls to assess the true degree of CR (15%) in these mice. We found that 15% CR decreased body mass and liver triglyceride content, improved oral glucose clearance, and increased all limb grip strength in 10- and 18-month-old mice. Glucose clearance in ad libitum fed 26- and 28-month-old mice is enhanced relative to younger mice but was not further improved by CR. CR decreased basal insulin concentrations in all age groups and improved insulin sensitivity and rotarod time to fall in 28-month-old mice. The results of our study demonstrate that even a modest reduction (15%) in caloric intake may improve metabolic and physical health. Thus, moderate calorie restriction may be a dietary intervention to promote healthy aging with improved likelihood for adherence in human populations.

Keywords:  Calorie restriction; Glucose homeostasis; Healthspan; Insulin sensitivity; Liver fat

DOI:  https://doi.org/10.1007/s10522-022-09996-5
Chem Sci. 2022 Oct 19. 13(40): 11738-11745

A senolysis-based theragnostic prodrug strategy towards chronic renal failure.

Yihe Song, Xinming Li, Donglei Shi, Tianyue Sun, Wenwen Liu, Xiaokang Li, Sicong Qiao, Xin Chen, Yuan Guo, Jian Li.

Selective elimination of senescent cells (senolysis) has become a promising therapeutic strategy for the management of chronic renal failure (CRF), but the senolytic molecular pathways towards CRF therapy are limited. Here, we present for the first time a senescence-associated β-galactosidase (SA-β-gal) activatable theragnostic prodrug strategy to pertinently and effectively treat CRF in mice with the aid of fluorescence-guided senolysis. The signs of premature senescence, including the overexpression of β-gal, have been found in kidneys of mice with CRF, making this enzyme particularly suitable as a trigger of prodrugs for CRF therapy. With this unique design, our pioneering prodrug TSPD achieved the activation of a fluorophore for tracking and the specific release of the parent drug, gemcitabine, in β-gal-enriched cells after activation with SA-β-gal. In mice with CRF, abdominal administration of TSPD was effective for improvement of the kidney functions, supporting the feasibility of the SA-β-gal-dependent senolysis therapy towards CRF.

DOI: https://doi.org/10.1039/d2sc03525a
Geroscience. 2022 Nov 02.

Elamipretide effects on the skeletal muscle phosphoproteome in aged female mice.

Matthew D Campbell, Miguel Martín-Pérez, Jarrett D Egertson, Matthew J Gaffrey, Lu Wang, Theo Bammler, Peter S Rabinovitch, Michael MacCoss, Wei-Jun Qian, Judit Villen, David Marcinek.

  The age-related decline in skeletal muscle mass and function is known as sarcopenia. Sarcopenia progresses based on complex processes involving protein dynamics, cell signaling, oxidative stress, and repair. We have previously found that 8-week treatment with elamipretide improves skeletal muscle function, reverses redox stress, and restores protein S-glutathionylation changes in aged female mice. This study tested whether 8-week treatment with elamipretide also affects global phosphorylation in skeletal muscle consistent with functional improvements and S-glutathionylation. Using female 6-7-month-old mice and 28-29-month-old mice, we found that phosphorylation changes did not relate to S-glutathionylation modifications, but that treatment with elamipretide did partially reverse age-related changes in protein phosphorylation in mouse skeletal muscle.

Keywords:  Aging; Mitochondria; Phosphorylation; Proteomics; S-Glutathionylation; Sarcopenia

DOI:  https://doi.org/10.1007/s11357-022-00679-0
Stem Cells. 2022 Nov 04. pii: sxac078. [Epub ahead of print]

The telomerase connection of the brain and its implications for neurodegenerative diseases.

Gabriele Saretzki.

  Telomerase, consisting of the protein subunit TERT and RNA component TERC, is best known for maintaining and extending human telomeres, the ends of linear chromosomes, in tissues, where it is active, such as stem cells, germline cells, lymphocytes and endothelial cells. This function is considered as canonical. However, various non-canonical functions for the protein part TERT have been discovered. There are multiple such roles which can interfere with several signalling pathways, cancer development and many other processes. One of these non-canonical functions includes shuttling of the TERT protein out of the nucleus upon increased oxidative stress into the cytoplasm and organelles such as mitochondria. Mitochondrial TERT is able to protect cells from oxidative stress, DNA damage and apoptosis although the exact mechanisms are incompletely understood. Recently, a protective role for TERT was described in brain neurons. Here TERT is able to counteract effects of toxic neurodegenerative proteins via changes in gene expression, activation of neurotrophic factors as well as activation of protein degrading pathways such as autophagy. Protein degradation processes are prominently involved in degrading toxic proteins in the brain like amyloid-β, pathological tau and α-synuclein that are responsible for various neurodegenerative diseases. These new findings can have implications for the development of novel treatment strategies for neurodegenerative diseases. The current review summarises our knowledge on the role of the telomerase protein TERT in brain function, in particular, under the aspect of age-related neurodegenerative diseases. It also describes various strategies to increase TERT levels in the brain.

Keywords:  TERT; Telomerase; brain; neurodegenerative diseases; telomerase activator

DOI:  https://doi.org/10.1093/stmcls/sxac078
J Endocrinol Invest. 2022 Nov 01.

Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents.

V R Muñoz, R C Gaspar, M C S Mancini, R D de Lima, R F L Vieira, B M Crisol, G C Antunes, J C S Trombeta, I L P Bonfante, F M Simabuco, A S R da Silva, C R Cavaglieri, E R Ropelle, D E Cintra, J R Pauli.

   PURPOSE: Aging is associated with changes in glucose homeostasis related to both decreased insulin secretion and/or impaired insulin action, contributing to the high prevalence of type 2 diabetes (T2D) in the elderly population. Additionally, studies are showing that chronically high levels of circulating insulin can also lead to insulin resistance. In contrast, physical exercise has been a strategy used to improve insulin sensitivity and metabolic health. However, the molecular alterations resulting from the effects of physical exercise in the liver on age-related hyperinsulinemia conditions are not yet fully established. This study aimed to investigate the effects of 7 days of aerobic exercise on hepatic metabolism in aged hyperinsulinemic rats (i.e., Wistar and F344) and in Slc2a4+/- mice (hyperglycemic and hyperinsulinemic mice).
RESULTS: Both aged models showed alterations in insulin and glucose tolerance, which were associated with essential changes in hepatic fat metabolism (lipogenesis, gluconeogenesis, and inflammation). In contrast, 7 days of physical exercise was efficient in improving whole-body glucose and insulin sensitivity, and hepatic metabolism. The Slc2a4+/- mice presented significant metabolic impairments (insulin resistance and hepatic fat accumulation) that were improved by short-term exercise training. In this scenario, high circulating insulin may be an important contributor to age-related insulin resistance and hepatic disarrangements in some specific conditions.
CONCLUSION: In conclusion, our data demonstrated that short-term aerobic exercise was able to control mechanisms related to hepatic fat accumulation and insulin sensitivity in aged rodents. These effects could contribute to late-life metabolic health and prevent the development/progression of age-related T2D.

Keywords:  Aging; Hyperinsulinemia; Liver; Physical exercise

DOI:  https://doi.org/10.1007/s40618-022-01947-8
Exp Dermatol. 2022 Nov;31(11): 1748-1760

Early onset of senescence and imbalanced epidermal homeostasis across the decades in photoexposed human skin: Fingerprints of inflammaging.

Bradley B Jarrold, Christina Yan Ru Tan, Chin Yee Ho, Ai Ling Soon, TuKiet T Lam, Xiaojing Yang, Calvin Nguyen, Wei Guo, Yap Ching Chew, Yvonne M DeAngelis, Lydia Costello, Paola De Los Santos Gomez, Stefan Przyborski, Sophie Bellanger, Oliver Dreesen, Alexa B Kimball, John E Oblong.

  Inflammaging is a theory of ageing which purports that low-level chronic inflammation leads to cellular dysfunction and premature ageing of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defence from the environment, particularly solar radiation. To better understand the impact of ageing and photoexposure on epidermal biology, we performed a system biology-based analysis of photoexposed face and arm, and photoprotected buttock sites, from women between the ages of 20s to 70s. Biopsies were analysed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-α were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic ageing were accelerated. Genes associated with differentiation and senescence showed increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increased in the 50's. Proteomics comparing 60's vs 20's confirmed elevated levels of differentiation and glycolytic-related proteins. Representative immunostaining for proteins of differentiation, senescence and oxygen sensing/hypoxia showed similar relationships. This system biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

Keywords:  differentiation; epidermal morphology; epidermis; epigenetics; glycolysis; hypoxia; inflammaging; inflammation; photoexposed; senescence

DOI:  https://doi.org/10.1111/exd.14654
Gene. 2022 Nov 01. pii: S0378-1119(22)00846-0. [Epub ahead of print] 147026

Caloric restriction reinforces the stem cell pool in the aged brain without affecting overall proliferation status.

Begun Erbaba, Duygu Macaroglu, Ilgim Ardic, Ayca Arslan-Ergul, Michelle M Adams.

  Overfeeding (OF) and obesity increase the risk for brain aging and neurodegenerative diseases due to increased oxidative stress and neuroinflammation, which likely contribute to cellular dysfunction. In contrast, caloric restriction (CR) is an intervention known for its effects on extending both life- and health-span. In the current study, the effects on the aging brain of two short-term feeding regimens, OF and CR, were investigated. We applied these diets for 12 weeks to both young and aged zebrafish. We performed protein and mRNA level analysis to examine diet-mediated effects on any potential age-related alterations in the brain. Markers implicated in the regulation of brain aging, cell cycle, proliferation, inflammation, and cytoskeleton were analyzed. The most prominent result observed was a downregulation in the expression levels of the stem cell marker, Sox2, in CR-fed animals as compared to OF-fed fish. Furthermore, our data highlighted significant age-related downregulations in Tp53, Myca, and L-plastin levels. The multivariate analyses of all datasets suggested that as opposed to OF, the adaptive mechanisms increasing lifespan via CR are likely exerting their effects by reinforcing the stem cell pool and downregulating inflammation. The data reveal important therapeutic targets with respect to the state of nutrient uptake for the slowing down of the detrimental effects of aging, resulting in a healthy and extended lifespan, as well as lowering the risk for neurodegenerative disease.

Keywords:  Aging; Brain; Caloric Restriction; Overfeeding; Sox2; Zebrafish

DOI:  https://doi.org/10.1016/j.gene.2022.147026
Annu Rev Anim Biosci. 2022 Nov 01.

The Naked Mole-Rat as a Model for Healthy Aging.

Kaori Oka, Masanori Yamakawa, Yoshimi Kawamura, Nobuyuki Kutsukake, Kyoko Miura.

Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-lived rodents with a maximum life span exceeding 37 years. They exhibit a delayed aging phenotype and resistance to age-related functional decline/diseases. Specifically, they do not display increased mortality with age, maintain several physiological functions until nearly the end of their lifetime, and rarely develop cancer and Alzheimer's disease. NMRs live in a hypoxic environment in underground colonies in East Africa and are highly tolerant of hypoxia. These unique characteristics of NMRs have attracted considerable interest from zoological and biomedical researchers. This review summarizes previous studies of the ecology, hypoxia tolerance, longevity/delayed aging, and cancer resistance of NMRs and discusses possible mechanisms contributing to their healthy aging. In addition, we discuss current issues and future perspectives to fully elucidate the mechanisms underlying delayed aging and resistance to age-related diseases in NMRs. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 11 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-animal-050322-074744
Immun Ageing. 2022 Nov 02. 19(1): 51

Ageing-resembling phenotype of long-term allogeneic hematopoietic cells recipients compared to their donors.

Michał Cezary Czarnogórski, Justyna Sakowska, Mateusz Maziewski, Maciej Zieliński, Agnieszka Piekarska, Igor Obuchowski, Mikołaj Młyński, Magdalena Dutka, Alicja Sadowska-Klasa, Ewa Zarzycka, Maria Bieniaszewska, Piotr Trzonkowski, Jacek M Witkowski, Andrzej Hellmann, Katarzyna Ruckemann-Dziurdzińska, Jan M Zaucha.

   BACKGROUND: Ageing is a complex phenomenon that leads to decreased proliferative activity, loss of function of the cells, and cellular senescence. Senescence of the immune system exacerbates individual's immune response, both humoral and cellular but increases the frequency of infections. We hypothesized that physiological ageing of adaptive immune system occurs in recipients of allogeneic hematopoietic cells transplant (allo-HCT) at faster rate when compared to their respective donors since the small number of donor cells undergo immense proliferative stress restoring recipients hematopoiesis. We compared molecular characterizations of ageing between recipients and donors of allo-HCT: telomeric length and immunophenotypic changes in main lymphocyte subsets - CD4+, CD8+, CD19+, CD56+.
RESULTS: Median telomeric length (TL) of CD8+ lymphocytes was significantly longer in donors compared to recipients (on average 2,1 kb and 1,7 kb respectively, p = 0,02). Similar trends were observed for CD4+ and CD19+ although the results did not reach statistical significance. We have also found trends in the immunophenotype between recipients and donors in the subpopulations of CD4+ (naïve and effector memory), CD8+ Eomes+ and B-lymphocytes (B1 and B2). Lower infection risk recipients had also a significantly greater percentage of NK cells (22,3%) than high-risk patients (9,3%) p = 0,04.
CONCLUSION: Our data do not support the initial hypothesis of accelerated aging in the long term all-HCT recipients with the exception of the recipients lymphocytes (mainly CD8+) which present some molecular features, characteristic for physiological ageing (telomeric shortening, immunophenotype) when compared to their respective donors. However, a history of lower infection numbers in HCT recipients seems to be associated with increased percentage of NK cells. The history of GVHD seems not to affect the rate of ageing. Therefore, it is safe to conclude that the observed subtle differences between recipients' and donors' cells result mainly from the proliferative stress in the early period after allo-HCT and the difference between hosts' and recipients' microenvironments.

Keywords:  Ageing; Immunosenescence; Telomeric shortening; allo-HCT

DOI:  https://doi.org/10.1186/s12979-022-00308-6
Aging Cell. 2022 Nov 03. e13730

APOE ɛ4 allele and TOMM40-APOC1 variants jointly contribute to survival to older ages.

Alexander M Kulminski, Ethan Jain-Washburn, Ian Philipp, Liang He, Yury Loika, Elena Loiko, Olivia Bagley, Svetlana Ukraintseva, Anatoliy Yashin, Konstantin Arbeev, Eric Stallard, Mary F Feitosa, Nicole Schupf, Kaare Christensen, Irina Culminskaya.

  Age-related diseases characteristic of post-reproductive life, aging, and life span are the examples of polygenic non-Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non-carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non-carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid- and immunity-related mechanisms, whereas the AD risk, can be driven by the AD-biomarker-related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care.

Keywords:  Alzheimer's disease; aging; apolipoprotein E polymorphism; haplotypes; linkage disequilibrium

DOI:  https://doi.org/10.1111/acel.13730
Front Genet. 2022 ;13 956094

Identification of senescence-associated long non-coding RNAs to predict prognosis and immune microenvironment in patients with hepatocellular carcinoma.

Chengzhi Gao, Guangming Zhou, Min Cheng, Lan Feng, Pengbo Cao, Gangqiao Zhou.

  Background: Cellular senescence plays a complicated and vital role in cancer development because of its divergent effects on tumorigenicity. However, the long non-coding RNAs (lncRNAs) associated with tumor senescence and their prognostic value in hepatocellular carcinoma (HCC) remain unexplored. Methods: The trans-cancer oncogene-induced senescence (OIS) signature was determined by gene set variation analysis (GSVA) in the cancer genome atlas (TCGA) dataset. The OIS-related lncRNAs were identified by correlation analyses. Cox regression analyses were used to screen lncRNAs associated with prognosis, and an optimal predictive model was created by regression analysis of the least absolute shrinkage and selection operator (LASSO). The performance of the model was evaluated by Kaplan-Meier survival analyses, nomograms, stratified survival analyses, and receiver operating characteristic curve (ROC) analyses. Gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) were carried out to explore the functional relevance and immune cell infiltration, respectively. Results: Firstly, we examined the pan-cancer OIS signature, and found several types of cancer with OIS strongly associated with the survival of patients, including HCC. Subsequently, based on the OIS signature, we identified 76 OIS-related lncRNAs with prognostic values in HCC. We then established an optimal prognostic model based on 11 (including NRAV, AC015908.3, MIR100HG, AL365203.2, AC009005.1, SNHG3, LINC01138, AC090192.2, AC008622.2, AL139423.1, and AC026356.1) of these lncRNAs by LASSO-Cox regression analysis. It was then confirmed that the risk score was an independent and potential risk indicator for overall survival (OS) (HR [95% CI] = 4.90 [2.74-8.70], p < 0.001), which outperforms those traditional clinicopathological factors. Furthermore, patients with higher risk scores also showed more advanced levels of a proinflammatory senescence-associated secretory phenotype (SASP), higher infiltration of regulatory T (Treg) cells and lower infiltration of naïve B cells, suggesting the regulatory effects of OIS on immune microenvironment. Additionally, we identified NRAV as a representative OIS-related lncRNA, which is over-expressed in HCC tumors mainly driven by DNA hypomethylation. Conclusion: Based on 11 OIS-related lncRNAs, we established a promising prognostic predictor for HCC patients, and highlighted the potential immune microenvironment-modulatory roles of OIS in HCC, providing a broad molecular perspective of tumor senescence.

Keywords:  NRAV; hepatocellular carcinoma; immune microenvironment; long noncoding RNA; oncogene-induced senescence; prognostic signature

DOI:  https://doi.org/10.3389/fgene.2022.956094
G3 (Bethesda). 2022 Oct 31. pii: jkac287. [Epub ahead of print]

Tra1 controls the transcriptional landscape of the aging cell.

Khaleda Afrin Bari, Matthew D Berg, Julie Genereaux, Christopher J Brandl, Patrick Lajoie.

  Gene expression undergoes considerable changes during the aging process. The mechanisms regulating the transcriptional response to cellular aging remain poorly understood. Here, we employ the budding yeast Saccharomyces cerevisiae to better understand how organisms adapt their transcriptome to promote longevity. Chronological lifespan (CLS) assays in yeast measure the survival of non-dividing cells at stationary phase over time, providing insights into the aging process of post-mitotic cells. Tra1 is an essential component of both the yeast SAGA/SLIK and NuA4 complexes, where it recruits these complexes to acetylate histones at targeted promoters. Importantly, Tra1 regulates the transcriptional response to multiple stresses. To evaluate the role of Tra1 in chronological aging, we took advantage of a previously characterized mutant allele that carries mutations in the TRA1 PI3K domain (tra1Q3). We found that loss of functions associated with tra1Q3 sensitized cells to growth media acidification and shortens lifespan. Transcriptional profiling reveals that genes differentially regulated by Tra1 during the aging process are enriched for components of the response to stress. Notably, expression of catalases (CTA1, CTT1) involved in hydrogen peroxide detoxification decreases in chronologically aged tra1Q3 cells. Consequently, they display increased sensitivity to oxidative stress. tra1Q3 cells are unable to grow on glycerol indicating a defect in mitochondria function. Aged tra1Q3 cells also display reduced expression of peroxisomal genes, exhibit decreased numbers of peroxisomes and cannot grow on media containing oleate. Thus, Tra1 emerges as an important regulator of longevity in yeast via multiple mechanisms.

Keywords:  SAGA complex; Tra1; chronological aging; peroxisomes; yeast

DOI:  https://doi.org/10.1093/g3journal/jkac287
Endocrinol Diabetes Metab. 2022 Nov 05. e384

Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.

Nels C Olson, Margaret F Doyle, Petra Buzkova, Sally A Huber, Ian H de Boer, Colleen M Sitlani, Russell P Tracy, Bruce M Psaty, Kenneth J Mukamal, Joseph A Delaney.

   INTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain.
METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA+ ), memory (CD45RO+ ), senescent (CD28- ), and T effector memory RA+ (TEMRA) (CD28- CD57+ CD45RA+ ) CD4+ and CD8+ T cells, and memory B cells (CD19+ CD27+ ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4+ and CD8+ subsets with incident DM risk.
RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4+ , CD8+ or CD19+ cell phenotypes with incident DM.
CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.

Keywords:  cellular senescence; diabetes mellitus; epidemiology; lymphocyte subsets

DOI:  https://doi.org/10.1002/edm2.384
Immunol Rev. 2022 Oct 31.

Neutrophils in aging and aging-related pathologies.

Kristof Van Avondt, Jan-Kolja Strecker, Claudia Tulotta, Jens Minnerup, Christian Schulz, Oliver Soehnlein.

  Over the past millennia, life expectancy has drastically increased. While a mere 25 years during Bronze and Iron ages, life expectancy in many European countries and in Japan is currently above 80 years. Such an increase in life expectancy is a result of improved diet, life style, and medical care. Yet, increased life span and aging also represent the most important non-modifiable risk factors for several pathologies including cardiovascular disease, neurodegenerative diseases, and cancer. In recent years, neutrophils have been implicated in all of these pathologies. Hence, this review provides an overview of how aging impacts neutrophil production and function and conversely how neutrophils drive aging-associated pathologies. Finally, we provide a perspective on how processes of neutrophil-driven pathologies in the context of aging can be targeted therapeutically.

Keywords:  aging; cancer; inflammation; myocardial infarction; neutrophil; stroke

DOI:  https://doi.org/10.1111/imr.13153
Biomater Sci. 2022 Nov 01.

A decellularized extracellular matrix derived from keratinocytes can suppress cellular senescence induced by replicative and oxidative stresses.

Takashi Hoshiba.

Cellular senescence is one of the barriers to maintain in vitro three-dimensional (3D) epidermal models for a long period of time. Therefore, a new culture substrate should be developed to suppress keratinocyte senescence to establish an epidermal model. In this study, reconstituted extracellular matrices (ECM) were prepared by culturing keratinocytes at different passages using the decellularization technique. The ECM prepared by decellularization (dECM) supports keratinocyte adhesion and growth. It has also been demonstrated that the dECM suppresses keratinocyte senescence by increasing the antioxidant activity. In particular, the dECM derived from younger passaged keratinocytes suppresses senescence more significantly than the dECM derived from highly passaged keratinocytes. Moreover, the dECM derived from younger passaged keratinocytes can suppress keratinocyte senescence during passage culture. Finally, the dECM derived from younger passaged keratinocytes increased AQP3 gene expression as an indicator of the functions of basal keratinocytes and the AQP3 expression ability to respond to all-trans retinoic acid. The dECM derived from younger passaged keratinocytes could be a useful culture substrate for developing an in vitro epidermal model.

DOI: https://doi.org/10.1039/d2bm00897a
Elife. 2022 Oct 31. pii: e81943. [Epub ahead of print]11

Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice.

Eva M Szego, Laura Malz, Nadine Bernhardt, Angela Rösen-Wolff, Björn H Falkenburger, Hella Luksch.

  Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and the STING pathway has been implicated in the pathogenesis of further neurodegenerative diseases. To test whether STING activation is sufficient to induce neurodegeneration, we analysed a mouse model that expresses the constitutively active STING variant N153S. In this model, we focused on dopaminergic neurons, which are particularly sensitive to stress and represent a circumscribed population that can be precisely quantified. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. These neuroinflammatory markers were already elevated in juvenile mice although at this age the number of dopaminergic neurons was still unaffected, thus preceding the degeneration of dopaminergic neurons. More neuroinflammatory markers were blunted in mice deficient for inflammasomes than in mice deficient for signalling by type I interferons. Neurodegeneration, however, was blunted in both mice. Collectively, these findings demonstrate that chronic activation of the STING pathway is sufficient to cause degeneration of dopaminergic neurons. Targeting the STING pathway could therefore be beneficial in Parkinson's disease and further neurodegenerative diseases.

Keywords:  medicine; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.81943
DNA Repair (Amst). 2022 Oct 03. pii: S1568-7864(22)00142-2. [Epub ahead of print]120 103409

The DNA damage induced immune response: Implications for cancer therapy.

Eliana M Barros, Stuart A McIntosh, Kienan I Savage.

  Genomic instability is a hallmark of tumourigenesis, influencing tumour development and progression. In particular, defects in the DNA damage response (DDR) have been extensively investigated and are known to shape therapeutic response. Since immune checkpoint blockade (ICB) therapy has been approved for treatment of tumours with defective mismatch repair the interplay between DDR pathway deficiency and the immune system has been of particular interest. The cGAS/STING signalling pathway has recently emerged as a key mediator of inflammation in response to DNA damage.This was identified through transcriptional profiling of BRCA1/2 deficient breast cancers and Fanconi Anaemia (FA) patient bone marrow, revealing a common transcriptional subgroup associated with BRCA1/2 and FA deficiency characterised by upregulation of innate immune signalling genes. Additionally, it is now apparent that the DNA damage arising from a multitude of DNA repair defects and DNA damage induced by some classical chemotherapies/radiation also has the ability to induce an innate immune response mediated by cGAS/STING activation. Here we review the role of intrinsic and extrinsic DNA damage in mediating immune activation and its context within tumourigenesis, as well as the potential therapeutic opportunities it represents for the treatment of cancer, such as combining DNA damaging agents with immunotherapies.

Keywords:  DNA-damage cGAS STING innate immune

DOI:  https://doi.org/10.1016/j.dnarep.2022.103409
Cell Cycle. 2022 Oct 30. 1-15

Overexpression of adrenomedullin (ADM) alleviates the senescence of human dental pulp stem cells by regulating the miR-152/CCNA2 pathway.

Wenxue Dou, Jiaye Xie, Jianan Chen, Jiajun Zhou, Zunyue Xu, Zheng Wang, Qiang Zhu.

  The limitation of human dental pulp stem cells (DPSCs), which have potential application value in regenerative medicine, is that they are prone to age in vitro. Studies have shown adrenomedullin (ADM) is believed to promote the proliferation of human DPSCs, but whether it can also affect aging remains to be investigated. A lentivirus vector was used to construct human DPSCs overexpressing ADM. Senescence tests were carried out on cells of the 7th and 15th passage. Transcriptome analysis was conducted to analyze microRNA expression regulation changes after human DPSCs overexpressed ADM. H2O2 induced the aging model of human DPSCs, and we examined the mechanism of recovery of aging through transfection experiments with miR-152 mimic, pCDH-CCNA2, and CCNA2 siRNA. Overexpression of ADM significantly upregulated the G2/M phase ratio of human DPSCs in natural passage culture (P = 0.001) and inhibited the expression of p53 (P = 0.014), P21 WAF1 (P = 0.015), and P16 INK4A (P = 0.001). Decreased ROS accumulation was observed in human DPSCs during long-term natural passage (P = 0.022). Transcriptome analysis showed that miR-152 was significantly upregulated during human DPSC senescence (P = 0.001) and could induce cell senescence by directly targeting CCNA2. Transfection with miR-152 mimic significantly reversed the inhibitory effect of ADM overexpression on p53 (P = 0.006), P21 WAF1 (P = 0.012), and P16 INK4A (P = 0.01) proteins in human DPSCs (H2O2-induced). In contrast, pCDH-CCNA2 weakened the effect of the miR-152 mimic, thus promoting cell proliferation and antiaging. ADM-overexpressing human DPSCs promote cell cycle progression and resist cellular senescence through CCNA2 expression promotion by inhibiting miR-152.

Keywords:  Dental pulp stem cells (DPSCs); adrenomedullin (ADM); miR-152/ccna2

DOI:  https://doi.org/10.1080/15384101.2022.2135621
Front Aging. 2022 ;3 991460

The two faces of DNA oxidation in genomic and functional mosaicism during aging in human neurons.

Michael A Lodato, Jennifer S Ziegenfuss.

  Maintaining genomic integrity in post-mitotic neurons in the human brain is paramount because these cells must survive for an individual's entire lifespan. Due to life-long synaptic plasticity and electrochemical transmission between cells, the brain engages in an exceptionally high level of mitochondrial metabolic activity. This activity results in the generation of reactive oxygen species with 8-oxo-7,8-dihydroguanine (8-oxoG) being one of the most prevalent oxidation products in the cell. 8-oxoG is important for the maintenance and transfer of genetic information into proper gene expression: a low basal level of 8-oxoG plays an important role in epigenetic modulation of neurodevelopment and synaptic plasticity, while a dysregulated increase in 8-oxoG damages the genome leading to somatic mutations and transcription errors. The slow yet persistent accumulation of DNA damage in the background of increasing cellular 8-oxoG is associated with normal aging as well as neurological disorders such as Alzheimer's disease and Parkinson's disease. This review explores the current understanding of how 8-oxoG plays a role in brain function and genomic instability, highlighting new methods being used to advance pathological hallmarks that differentiate normal healthy aging and neurodegenerative disease.

Keywords:  8-oxo-2’-deoxoguanosine; aging; epigenetics; mutation signature; neurodegeneration; oxidative damage; single-cell ‘omics; somatic mutation

DOI:  https://doi.org/10.3389/fragi.2022.991460
EMBO J. 2022 Oct 31. e111952

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Felipe Cabral-Miranda, Giovanni Tamburini, Gabriela Martinez, Alvaro O Ardiles, Danilo B Medinas, Yannis Gerakis, Mei-Li Diaz Hung, René Vidal, Matias Fuentealba, Tim Miedema, Claudia Duran-Aniotz, Javier Diaz, Cristobal Ibaceta-Gonzalez, Carleen M Sabusap, Francisca Bermedo-Garcia, Paula Mujica, Stuart Adamson, Kaitlyn Vitangcol, Hernan Huerta, Xu Zhang, Tomohiro Nakamura, Sergio Pablo Sardi, Stuart A Lipton, Brian K Kennedy, Juan Pablo Henriquez, J Cesar Cárdenas, Lars Plate, Adrian G Palacios, Claudio Hetz.

  Aging is a major risk factor for neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors associated with synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Keywords:  ER stress; UPR; XBP1s; aging brain; proteostasis

DOI:  https://doi.org/10.15252/embj.2022111952
Aging (Albany NY). 2022 Oct 24. 14(20): 8140-8149

Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice.

Mikhail V Blagosklonny.

  Making provocative headlines, three outstanding publications demonstrated that early-life treatment with rapamycin, including treatments during developmental growth, extends lifespan in animals, confirming predictions of hyperfunction theory, which views aging as a quasi-program (an unintended continuation of developmental growth) driven in part by mTOR. Despite their high theoretical importance, clinical applications of two of these studies in mice, Drosophila and Daphnia cannot be implemented in humans because that would require growth retardation started at birth. A third study demonstrated that a transient (around 20% of total lifespan in Drosophila) treatment with rapamycin early in Drosophila adult life is as effective as lifelong treatment, whereas a late-life treatment is not effective. However, previous studies in mice demonstrated that a transient late-life treatment is highly effective. Based on hyperfunction theory, this article attempts to reconcile conflicting results and suggests the optimal treatment strategy to extend human lifespan.

Keywords:  geroscience; gerostatics; healthspan; senescence; sirolimus

DOI:  https://doi.org/10.18632/aging.204354
J Gerontol B Psychol Sci Soc Sci. 2022 Oct 30. pii: gbac173. [Epub ahead of print]

Covid-19-stress associated with worse sleep quality, particularly with increasing age.

Kyoungeun Lee, Brialisse Sayre, Sophia Martin, Taylor A James, Audrey Duarte.

   OBJECTIVES: Based on SST, one might predict that older adults' well-being would be less negatively impacted by Covid-19-stress, as with other stressors, than younger people. However, whether sleep quality, which is negatively affected by aging, is similarly protected from the negative consequences of Covid-19-stress with age is unknown. Here, we examined the association between Covid-19-stress, above and beyond general-stress, and sleep quality and how it varies by age.
METHOD: From December 2020 to April 2021, 386 adults reported their Covid-19-stress, sleep quality, and resilience in an online study.
RESULTS: While older age was related to lower Covid-19-stress, Covid-19-stress was associated with worse sleep quality with greater age.
DISCUSSION: These results suggest that at least some aspects of one's well-being may be more susceptible to the negative consequences of stress with increasing age. Our results might be better understood via SAVI model, which posits that older adults have increased susceptibility to prolonged and unavoidable stress.

Keywords:  Covid-19 pandemic; Resilience; Sleep

DOI:  https://doi.org/10.1093/geronb/gbac173
J Cell Physiol. 2022 Nov 01.

Age-related SUMOylation of PLK1 is essential to meiosis progression in mouse oocytes.

Xiao-Long Mo, Feng Liu, Chun-Hua Xing, Meng-Meng Shan, Bo Yao, Qi-Qi Sun, Yuan-Jing Zou, Kun-Huan Zhang, Jun Tan, Shao-Chen Sun, Yan-Ping Ren.

  Polo like kinase 1 (PLK1) is a protein kinase involved in regulating the spindle assembly and cell cycle control in mammalian oocytes. SUMOylation, one way of post-translational modification, regulates oocyte meiosis by controlling several substrates. However, the relation between PLK1 and SUMOylation in oocytes is still unknown. In this study, we investigated that whether PLK1 was modified by SUMOylation in oocytes and its potential relationship with age-related meiotic abnormalities. We showed that PLK1 had colocalization and protein interaction with Small Ubiquitin-Like Modifier (SUMO)-1 and SUMO-2/3 in mouse oocytes, indicating that PLK1 could be modified by SUMO-1 and SUMO-2/3. Overexpression of PLK1 SUMOylation site mutants PLK1K178R and PLK1K191R caused the increase of the abnormal spindle rate of oocytes and the decline of the first polar body extrusion rate with the abnormal localization of PLK1, suggesting that the SUMOylation modification of PLK1 is essential for normal meiosis in oocytes. Compared with young mice, the expression of PLK1 protein increased and the expression of SUMO-1 and SUMO-2/3 protein decreased in the oocytes of aged mice, indicating that the SUMOylation of PLK1 might be related to the mouse aging. Therefore, our data suggested that PLK1 could be SUMOylated by SUMO-1 and SUMO-2/3 in mouse oocytes and SUMOylation of PLK1 regulated the meiosis progression of oocytes which was related with aging.

Keywords:  Polo-like kinase 1; SUMOylation; aging; meiosis; oocyte

DOI:  https://doi.org/10.1002/jcp.30910
Ageing Res Rev. 2022 Oct 29. pii: S1568-1637(22)00212-4. [Epub ahead of print]82 101770

Modalities of aging in organisms with different strategies of resource allocation.

Alexander Suvorov.

  Although the progress of aging research relies heavily on a theoretical framework, today there is no consensus on many critical questions in aging biology. I hypothesize that a systematic analysis of the intersection of different evolutionary mechanisms of aging with diverse resource allocation strategies in different organisms may reconcile aging hypotheses. The application of disposable soma, mutation accumulation, antagonistic pleiotropy, and life-history theory is considered across organisms with asexual reproduction, organisms with sexual reproduction and indeterminate growth in different conditions of extrinsic mortality, and organisms with determinate growth, with endotherms/homeotherms as a subgroup. This review demonstrates that different aging mechanisms are complementary to each other, and in organisms with different resource allocation strategies they form aging modalities ranging from immortality to suicidal programs. It also revamps the role of growth arrest in aging. Growth arrest evolved in many different groups of organisms as a result of resource reallocation from growth to reproduction (e.g., semelparous animals, holometabolic insects), or from growth to nutrient storage (endotherms/homeotherms). Growth arrest in different animal lineages has similar molecular mechanisms and similar consequences for longevity due to the conflict between growth-promoting and growth-suppressing programs and suppression of regenerative capacity.

Keywords:  Determinate growth; Endotherm; Homeotherm; Iteroparity; MTOR; Semelparity

DOI:  https://doi.org/10.1016/j.arr.2022.101770
Int Immunopharmacol. 2022 Oct 27. pii: S1567-5769(22)00823-2. [Epub ahead of print]113(Pt A): 109339

TREM-1 exacerbates bleomycin-induced pulmonary fibrosis by aggravating alveolar epithelial cell senescence in mice.

Jian-Bing Xiong, Jia-Xi Duan, Nan Jiang, Chen-Yu Zhang, Wen-Jing Zhong, Jin-Tong Yang, Yu-Biao Liu, Feng Su, Yong Zhou, Dai Li, Hui-Hui Yang, Cha-Xiang Guan.

  Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro, activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H2O2. In conclusion, our findings elucidate a pro-fibrotic effect of TREM-1 by inducing AECs senescence in PF, providing a potential strategy for fibrotic disease treatment.

Keywords:  Alveolar epithelial cells; Pulmonary fibrosis; Senescence; TREM-1

DOI:  https://doi.org/10.1016/j.intimp.2022.109339