bims-senagi Biomed News
on Senescence and aging
Issue of 2021–12–19
twenty-two papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
  2. High dietary protein and fat contents exacerbate hepatic senescence and SASP in mice.
  3. p53 in senescence - it's a marathon not a sprint.
  4. GH and Senescence: A New Understanding of Adult GH Action.
  5. The Quest to Define and Target Cellular Senescence in Cancer.
  6. A circular intronic RNA ciPVT1 delays endothelial cell senescence by regulating the miR-24-3p/CDK4/pRb axis.
  7. Senotherapeutic-like effect of Silybum marianum flower extract revealed on human skin cells.
  8. Growth differentiation factor 11 accelerates liver senescence through the inhibition of autophagy.
  9. Is it the time of seno-therapeutics application in cardiovascular pathological conditions related to ageing?
  10. Senescent tumor cells: an overlooked adversary in the battle against cancer.
  11. Inhibition of miR-21 Promotes Cellular Senescence in NT2-Derived Astrocytes.
  12. Autophagy in healthy aging and disease.
  13. Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.
  14. Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage.
  15. Sleep and Biological Aging: A Short Review.
  16. The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions.
  17. Exploring microenvironment strategies to delay mesenchymal stem cell senescence.
  18. Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?
  19. Anterior gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy‑induced senescence escape.
  20. Senolytic-mediated elimination of head and neck tumor cellsinduced into senescence by cisplatin.
  21. ATM modulates subventricular zone neural stem cell maintenance and senescence through Notch signaling pathway.
  22. Cathepsin S is a novel target for age-related dry eye.
  1. Aging Cell. 2021 Dec 13. e13528
    Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
    Cory M Dungan, Kevin A Murach, Christopher J Zdunek, Zuo Jian Tang, Georgia L VonLehmden, Camille R Brightwell, Zachary Hettinger, Davis A Englund, Zheng Liu, Christopher S Fry, Antonio Filareto, Michael Franti, Charlotte A Peterson.
      Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
    Keywords:  regeneration; satellite cells; senescence; senolytics; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13528
  2. FEBS J. 2021 Dec 15.
    High dietary protein and fat contents exacerbate hepatic senescence and SASP in mice.
    Jamil Nehme, Dengbao Yang, Abdullah Altulea, Marta Varela-Eirin, Lu Wang, Sumei Hu, Yingga Wu, Jacques Togo, Chaoqun Niu, John R Speakman, Marco Demaria.
      Dietary choices have a profound impact on the aging process. In addition to the total amount of energy intake, macronutrient composition influences both health and lifespan. However, the exact mechanisms by which dietary macronutrients influence onset and progression of age-associated features remain poorly understood. Cellular senescence is a state of stable growth arrest characterized by the secretion of numerous bioactive molecules with pro-inflammatory properties. Accumulation of senescent cells is considered one of the basic mechanisms of aging and an important contributor to chronic inflammation and tissue degeneration. Whether dietary macronutrients affect the accumulation and the phenotype of senescent cells with age is still unknown. Here, we show that feeding on diets with varying ratios of dietary macronutrients for 3 months has a significant effect on different senescence-associated markers in the mouse liver. High protein intake is associated with higher expression levels of the two classical senescence-associated growth arrest genes, p21 and p16. Furthermore, the expression of many pro-inflammatory secretory markers was increased in diets enriched in protein and further enhanced by increases in fat content. These results provide preliminary evidence that dietary macronutrients have a significant influence on senescence markers and merit further investigation.
    Keywords:  SASP; Senescence; inflammation; macronutrients composition
    DOI:  https://doi.org/10.1111/febs.16292
  3. FEBS J. 2021 Dec 17.
    p53 in senescence - it's a marathon not a sprint.
    Eleanor Sheekey, Masashi Narita.
      The tumour suppressor p53, a stress-responsive transcription factor, plays a central role in cellular senescence. The role of p53 in senescence-associated stable proliferative arrest has been extensively studied. However, increasing evidence indicates that p53 also modulates the ability of senescent cells to produce and secrete diverse bioactive factors (collectively called the senescence-associated secretory phenotype, SASP). Senescence has been linked with both physiological and pathological conditions, the latter including ageing, cancer and other age-related disorders, in part through the SASP. Cellular functions are generally dictated by the expression profile of lineage-specific genes. Indeed, expression of SASP factors and their regulators are often biased by cell type. In addition, emerging evidence suggests that p53 contributes to deregulation of more stringent lineage-specific genes during senescence. P53 itself is also tightly regulated at the protein level. In contrast to the rapid and transient activity of p53 upon stress ('acute-p53'), during senescence and other prolonged pathological conditions, p53 activities are sustained and fine-tuned through a combination of different inputs and outputs ('chronic-p53').
    Keywords:  DNA damage response; SASP; Senescence; p53; transcription
    DOI:  https://doi.org/10.1111/febs.16325
  4. J Endocr Soc. 2022 Jan 01. 6(1): bvab177
    GH and Senescence: A New Understanding of Adult GH Action.
    Vera Chesnokova, Shlomo Melmed.
      Replicative senescence occurs due to an inability to repair DNA damage and activation of p53/p21 and p16INK4 pathways. It is considered a preventive mechanism for arresting proliferation of DNA-damaged cells. Stably senescent cells are characterized by a senescence-associated secretory phenotype (SASP), which produces and secretes cytokines, chemokines, and/or matrix metalloproteinases depending on the cell type. SASP proteins may increase cell proliferation, facilitating conversion of premalignant to malignant tumor cells, triggering DNA damage, and altering the tissue microenvironment. Further, senescent cells accumulate with age, thereby aggravating age-related tissue damage. Here, we review a heretofore unappreciated role for growth hormone (GH) as a SASP component, acting in an autocrine and paracrine fashion. In senescent cells, GH is activated by DNA-damage-induced p53 and inhibits phosphorylation of DNA repair proteins ATM, Chk2, p53, and H2AX. Somatotroph adenomas containing abundant intracellular GH exhibit increased somatic copy number alterations, indicative of DNA damage, and are associated with induced p53/p21. As this pathway restrains proliferation of DNA-damaged cells, these mechanisms may underlie the senescent phenotype and benign nature of slowly proliferating pituitary somatotroph adenomas. In highly proliferative cells, such as colon epithelial cells, GH induced in response to DNA damage suppresses p53, thereby triggering senescent cell proliferation. As senescent cells harbor unrepaired DNA damage, GH may enable senescent cells to evade senescence and reenter the cell cycle, resulting in acquisition of harmful mutations. These mechanisms, at least in part, may underlie pro-aging effects of GH observed in animal models and in patients with chronically elevated GH levels.
    Keywords:  DNA damage; DNA repair; aging; growth hormone; senescence
    DOI:  https://doi.org/10.1210/jendso/bvab177
  5. Cancer Res. 2021 Dec 15. 81(24): 6087-6089
    The Quest to Define and Target Cellular Senescence in Cancer.
    Boshi Wang, Marco Demaria.
      Cellular senescence represents a double-edged sword in cancer and its therapy. On one side, senescence-associated growth arrest and immunomodulatory properties exert potent antimalignant functions. On the other side, senescence bypass and secretory phenotype are associated with tumor progression and relapse. Recent studies have demonstrated the enormous potential to combine pro- to antisenescence interventions as a new anticancer approach. However, the heterogeneity of senescence-associated features makes definition and targeting of therapy-induced senescent cells a challenging task. Here, we describe these challenges and discuss how to exploit senescence-associated features to improve treatment efficacy and tolerability.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2032
  6. Aging Cell. 2021 Dec 13. e13529
    A circular intronic RNA ciPVT1 delays endothelial cell senescence by regulating the miR-24-3p/CDK4/pRb axis.
    Xue Min, Meng-Yun Cai, Tong Shao, Zi-Yang Xu, Zhaofu Liao, Dong-Liang Liu, Meng-Yuan Zhou, Wei-Peng Wu, Yu-Lan Zhou, Miao-Hua Mo, Shun Xu, Xinguang Liu, Xing-Dong Xiong.
      Circular RNAs (circRNAs) have been established to be involved in numerous processes in the human genome, but their function in vascular aging remains largely unknown. In this study, we aimed to characterize and analyze the function of a circular intronic RNA, ciPVT1, in endothelial cell senescence. We observed significant downregulation of ciPVT1 in senescent endothelial cells. In proliferating endothelial cells, ciPVT1 knockdown induced a premature senescence-like phenotype, inhibited proliferation, and led to an impairment in angiogenesis. An in vivo angiogenic plug assay revealed that ciPVT1 silencing significantly inhibited endothelial tube formation and decreased hemoglobin content. Conversely, overexpression of ciPVT1 in old endothelial cells delayed senescence, promoted proliferation, and increased angiogenic activity. Mechanistic studies revealed that ciPVT1 can sponge miR-24-3p to upregulate the expression of CDK4, resulting in enhanced Rb phosphorylation. Moreover, enforced expression of ciPVT1 reversed the senescence induction effect of miR-24-3p in endothelial cells. In summary, the present study reveals a pivotal role for ciPVT1 in regulating endothelial cell senescence and may have important implications in the search of strategies to counteract the development of age-associated vascular pathologies.
    Keywords:  CDK4; ciPVT1; endothelial cell senescence; miR-24-3p; pRb
    DOI:  https://doi.org/10.1111/acel.13529
  7. PLoS One. 2021 ;16(12): e0260545
    Senotherapeutic-like effect of Silybum marianum flower extract revealed on human skin cells.
    Jieun Woo, Seoungwoo Shin, Eunae Cho, Dehun Ryu, David Garandeau, Hanane Chajra, Mathilde Fréchet, Deokhoon Park, Eunsun Jung.
      Cellular senescence causes irreversible growth arrest of cells. Prolonged accumulation of senescent cells in tissues leads to increased detrimental effects due to senescence associated secretory phenotype (SASP). Recent findings suggest that elimination of senescent cells has a beneficial effect on organismal aging and lifespan. In this study, using a validated replicative senescent human dermal fibroblasts (HDFs) model, we showed that elimination of senescent cells is possible through the activation of an apoptotic mechanism. We have shown in this replicative senescence model, that cell senescence is associated with DNA damage and cell cycle arrest (p21, p53 markers). We have shown that Silybum marianum flower extract (SMFE) is a safe and selective senolytic agent targeting only senescent cells. The elimination of the cells is induced through the activation of apoptotic pathway confirmed by annexin V/propidium iodide and caspase-3/PARP staining. Moreover, SMFE suppresses the expression of SASP factors such as IL-6 and MMP-1 in senescent HDFs. In a co-culture model of senescent and young fibroblasts, we demonstrated that senescent cells impaired the proliferative capacities of young cells. Interestingly, when the co-culture is treated with SMFE, the cell proliferation rate of young cells is increased due to the decrease of the senescent burden. Moreover, we demonstrated in vitro that senescent fibroblasts trigger senescent process in normal keratinocytes through a paracrine effect. Indeed, the conditioned medium of senescent HDFs treated with SMFE reduced the level of senescence-associated beta-galactosidase (SA-β-Gal), p16INK4A and SASP factors in keratinocytes compared with CM of senescent HDFs. These results indicate that SMFE can prevent premature aging due to senescence and even reprograms aged skin. Indeed, thanks to its senolytic and senomorphic properties SMFE is a candidate for anti-senescence strategies.
    DOI:  https://doi.org/10.1371/journal.pone.0260545
  8. Aging Cell. 2021 Dec 14. e13532
    Growth differentiation factor 11 accelerates liver senescence through the inhibition of autophagy.
    Jian Sun, Ying Li, Xiao Yang, Wei Dong, Jiankun Yang, Qi Hu, Cuntai Zhang, Haoshu Fang, Anding Liu.
      The "rejuvenating" effect of growth differentiation factor 11 (GDF11) is called into question recently, and its role, as well as plausible signaling mechanisms in liver senescence, is unclear. To overexpress or knockdown GDF11, aged male mice are injected with a single dose of adeno-associated viruses-GDF11 or adenovirus-small hairpin RNA-GDF11, respectively. GDF11 overexpression significantly accelerates liver senescence in aged mice, whereas GDF11 knockdown has opposite effects. Concomitantly, autophagic flux is impaired in livers from GDF11 overexpression mice. Conversely, GDF11 knockdown increases autophagic flux. Moreover, rapamycin successfully restores the impaired autophagic flux and alleviates liver senescence in GDF11 overexpression mice, while the GDF11 knockdown-mediated benefits are abolished by the autophagy inhibitor bafilomycin A1. GDF11 leads to a drop in lysosomal biogenesis resulting in defective autophagic flux at autophagosome clearance step. Mechanistically, GDF11 significantly activates mammalian target of rapamycin complex 1 (mTORC1) and subsequently represses transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. Inhibition of mTORC1 or TFEB overexpression rescues the GDF11-impaired autophagic flux and cellular senescence. Hepatocyte-specific deletion of GDF11 does not alter serum GDF11 levels and liver senescence. Collectively, suppression of autophagic activity via mTORC1/TFEB signaling may be a critical molecular mechanism by which GDF11 exacerbates liver senescence. Rather than a "rejuvenating" agent, GDF11 may have a detrimental effect on liver senescence.
    Keywords:  autophagy; hepatocyte; liver; senescence
    DOI:  https://doi.org/10.1111/acel.13532
  9. Curr Res Pharmacol Drug Discov. 2021 ;2 100027
    Is it the time of seno-therapeutics application in cardiovascular pathological conditions related to ageing?
    Carmela Rita Balistreri, Rosalinda Madonna, Peter Ferdinandy.
      It rates that in 2030, the cardiovascular diseases (CVD) will result in 40% of all deaths and rank as the leading cause. Thus, the research of appropriate therapies able to delay or retard their onset and progression is growing. Of particular interest is a new branch of the medical science, called anti-ageing medicine since CVD are the result of cardiovascular ageing. Senescent cells (SC) accumulate in cardiovascular system contributing to the onset of typical age-related cardiovascular conditions (i.e., atherosclerosis, medial aorta degeneration, vascular remodeling, stiffness). Such conditions progress in cardiovascular pathologies (i.e., heart failure, coronary artery disease, myocardial infarction, and aneurysms) by evocating the production of a proinflammatory and profibrotic senescence-associated secretory phenotype (SASP). Consequently, therapies able to specifically eliminate SC are in developing. The senotherapeutics represents an emerging anti-SC treatment, and comprises three therapeutic approaches: (a) molecules to selectively kill SC, defined senolytics; (b) compounds able in reducing evocated SC SASP, acting hence as SASP suppressors, or capable to change the senescent phenotype, called senomorphics; (c) inhibition of increase of the number of SC in the tissues. Here, it describes them and the emerging data about current investigations on their potential clinical application in CVD, stressing benefits and limitations, and suggesting potential solutions for applying them in near future as effective anti-CVD treatments.
    Keywords:  Anti-ageing medicine; CVD; Senolytics; Senomorphics; Senotherapeutics
    DOI:  https://doi.org/10.1016/j.crphar.2021.100027
  10. Exp Mol Med. 2021 Dec 16.
    Senescent tumor cells: an overlooked adversary in the battle against cancer.
    Soon Sang Park, Yong Won Choi, Jang-Hee Kim, Hong Seok Kim, Tae Jun Park.
      Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions.
    DOI:  https://doi.org/10.1038/s12276-021-00717-5
  11. Biochemistry (Mosc). 2021 Nov;86(11): 1434-1445
    Inhibition of miR-21 Promotes Cellular Senescence in NT2-Derived Astrocytes.
    Vanda Balint, Danijela Stanisavljevic Ninkovic, Natasa Anastasov, Stefan Lazic, Natasa Kovacevic-Grujicic, Milena Stevanovic, Andrijana Lazic.
      Astrocytes are the main homeostatic cells in the central nervous system (CNS) that provide mechanical, metabolic, and trophic support to neurons. Disruption of their physiological role or acquisition of senescence-associated phenotype can contribute to the CNS dysfunction and pathology. However, molecular mechanisms underlying the complex physiology of astrocytes are explored insufficiently. Recent studies have shown that miRNAs are involved in the regulation of astrocyte function through different mechanisms. Although miR-21 has been reported as an astrocytic miRNA with an important role in astrogliosis, no link between this miRNA and cellular senescence of astrocytes has been identified. To address the role of miR-21 in astrocytes, with special focus on cellular senescence, we used NT2/A (astrocytes derived from NT2/D1 cells). Downregulation of miR-21 expression in both immature and mature NT2/A by the antisense technology induced the arrest of cell growth and premature cellular senescence, as indicated by senescence hallmarks such as increased expression of cell cycle inhibitors p21 and p53 and augmented senescence-associated β-galactosidase activity. Additionally, in silico analysis predicted many of the genes, previously shown to be upregulated in astrocytes with the irradiation-induced senescence, as miR-21 targets. Taken together, our results point to miR-21 as a potential regulator of astrocyte senescence. To the best of our knowledge, these are the first data showing the link between miR-21 and cellular senescence of astrocytes. Since senescent astrocytes are associated with different CNS pathologies, development of novel therapeutic strategies based on miRNA manipulation could prevent senescence and may improve the physiological outcome.
    Keywords:  NT2/D1; astrocytes; miR-21; senescence
    DOI:  https://doi.org/10.1134/S0006297921110079
  12. Nat Aging. 2021 Aug;1(8): 634-650
    Autophagy in healthy aging and disease.
    Yahyah Aman, Tomas Schmauck-Medina, Malene Hansen, Richard I Morimoto, Anna Katharina Simon, Ivana Bjedov, Konstantinos Palikaras, Anne Simonsen, Terje Johansen, Nektarios Tavernarakis, David C Rubinsztein, Linda Partridge, Guido Kroemer, John Labbadia, Evandro F Fang.
      Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.
    DOI:  https://doi.org/10.1038/s43587-021-00098-4
  13. Cell Death Differ. 2021 Dec 16.
    Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.
    Irene Fernández-Duran, Andrea Quintanilla, Núria Tarrats, Jodie Birch, Priya Hari, Fraser R Millar, Anthony B Lagnado, Vanessa Smer-Barreto, Morwenna Muir, Valerie G Brunton, João F Passos, Juan Carlos Acosta.
      Cytoplasmic recognition of microbial lipopolysaccharides (LPS) in human cells is elicited by the caspase-4 and caspase-5 noncanonical inflammasomes, which induce a form of inflammatory cell death termed pyroptosis. Here we show that LPS-mediated activation of caspase-4 also induces a stress response promoting cellular senescence, which is dependent on the caspase-4 substrate gasdermin-D and the tumor suppressor p53. Furthermore, we found that the caspase-4 noncanonical inflammasome is induced and assembled in response to oncogenic RAS signaling during oncogene-induced senescence (OIS). Moreover, targeting caspase-4 expression in OIS showed its critical role in the senescence-associated secretory phenotype and the cell cycle arrest induced in cellular senescence. Finally, we observed that caspase-4 induction occurs in vivo in mouse models of tumor suppression and ageing. Altogether, we are showing that cellular senescence is induced by cytoplasmic LPS recognition by the noncanonical inflammasome and that this pathway is conserved in the cellular response to oncogenic stress.
    DOI:  https://doi.org/10.1038/s41418-021-00917-6
  14. Cell Rep. 2021 Dec 14. pii: S2211-1247(21)01554-0. [Epub ahead of print]37(11): 110068
    Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage.
    Vera Chesnokova, Svetlana Zonis, Athanasia Apostolou, Hannah Q Estrada, Simon Knott, Kolja Wawrowsky, Kathrin Michelsen, Anat Ben-Shlomo, Robert Barrett, Vera Gorbunova, Katia Karalis, Shlomo Melmed.
      Microenvironmental factors modulating age-related DNA damage are unclear. Non-pituitary growth hormone (npGH) is induced in human colon, non-transformed human colon cells, and fibroblasts, and in 3-dimensional intestinal organoids with age-associated DNA damage. Autocrine/paracrine npGH suppresses p53 and attenuates DNA damage response (DDR) by inducing TRIM29 and reducing ATM phosphorylation, leading to reduced DNA repair and DNA damage accumulation. Organoids cultured up to 4 months exhibit aging markers, p16, and SA-β-galactosidase and decreased telomere length, as well as DNA damage accumulation, with increased npGH, suppressed p53, and attenuated DDR. Suppressing GH in aged organoids increases p53 and decreases DNA damage. WT mice exhibit age-dependent colon DNA damage accumulation, while in aged mice devoid of colon GH signaling, DNA damage remains low, with elevated p53. As age-associated npGH induction enables a pro-proliferative microenvironment, abrogating npGH signaling could be targeted as anti-aging therapy by impeding DNA damage and age-related pathologies.
    Keywords:  3-dimensional human intestinal organoids; DNA damage response; DNA repair; growth hormone; growth hormone receptor knockout mice; human colon epithelium
    DOI:  https://doi.org/10.1016/j.celrep.2021.110068
  15. Curr Opin Endocr Metab Res. 2021 Jun;18 159-164
    Sleep and Biological Aging: A Short Review.
    Judith E Carroll, Aric A Prather.
      Obtaining healthy quantity and quality of sleep is a key to optimal mental and physical health, and cumulative evidence points to a role of sleep loss and sleep disturbances as a contributor to early disease onset and shortened survival. We propose that the molecular underpinnings that drive this risk are key drivers of the biological aging process, including altering metabolism, promoting damage, failure in repair and restoration machinery, leaving lasting impacts on cellular health, telomere loss, cellular senescence, and ultimately system failure. Our premise is that biological aging machinery is altered by sleep, and in the current short review we highlight the existing literature that links sleep with aging biology thought to drive age-related disease and shorten lifespan.
    DOI:  https://doi.org/10.1016/j.coemr.2021.03.021
  16. Hum Reprod Update. 2021 Dec 16. pii: dmab038. [Epub ahead of print]
    The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions.
    Laura Secomandi, Michela Borghesan, Michael Velarde, Marco Demaria.
       BACKGROUND: Advanced maternal age is associated with decreased oocyte quantity and quality as well as uterine and placental dysfunctions. These changes lead to infertility, pregnancy complications and birth defects in the offspring. As the mean age of giving birth is increasing worldwide, prevention of age-associated infertility and pregnancy complications, along with the more frequent use of ART, become extremely important. Currently, significant research is being conducted to unravel the mechanisms underlying female reproductive aging. Among the potential mechanisms involved, recent evidence has suggested a contributing role for cellular senescence, a cellular state of irreversible growth arrest characterized by a hypersecretory and pro-inflammatory phenotype. Elucidating the role of senescence in female reproductive aging holds the potential for developing novel and less invasive therapeutic measures to prevent or even reverse female reproductive aging and increase offspring wellbeing.
    OBJECTIVE AND RATIONALE: The review will summarize the positive and negative implications of cellular senescence in the pathophysiology of the female reproductive organs during aging and critically explore the use of novel senotherapeutics aiming to reverse and/or eliminate their detrimental effects. The focus will be on major senescence mechanisms of the ovaries, the uterus, and the placenta, as well as the potential and risks of using senotherapies that have been discovered in recent years.
    SEARCH METHODS: Data for this review were identified by searches of MEDLINE, PubMed and Google Scholar. References from relevant articles using the search terms 'Cellular Senescence', 'Aging', 'Gestational age', 'Maternal Age', 'Anti-aging', 'Uterus', 'Pregnancy', 'Fertility', 'Infertility', 'Reproduction', 'Implant', 'Senolytic', 'Senostatic', 'Senotherapy' and 'Senotherapeutic' where selected. A total of 182 articles published in English between 2005 and 2020 were included, 27 of which focus on potential senotherapies for reproductive aging. Exclusion criteria were inclusion of the terms 'male' and 'plants'.
    OUTCOMES: Aging is a major determinant of reproductive wellbeing. Cellular senescence is a basic aging mechanism, which can be exploited for therapeutic interventions. Within the last decade, several new strategies for the development and repurposing of drugs targeting senescent cells have emerged, such as modulators of the anti-inflammatory response, oxidative stress, DNA damage, and mitochondria and protein dysfunctions. Several studies of female reproductive aging and senotherapies have been discussed that show promising results for future interventions.
    WIDER IMPLICATIONS: In most countries of the Organization for Economic Co-operation and Development, the average age at which women give birth is above 30 years. Currently, in countries such as the Netherlands, Australia, Spain, Finland, Germany and the UK, birth rates among 30- to 34-year-olds are now higher than in any other age groups. This review will provide new knowledge and scientific advancement on the senescence mechanisms during female reproductive aging, and benefit fundamental and clinical scientists and professionals in the areas of reproduction, cancer, immunobiology and fibrosis.
    Keywords:  ART; DNA damage; aging; atresia; cell signaling; cellular senescence; cytokines; ovarian aging; senolytic drugs; senotherapy
    DOI:  https://doi.org/10.1093/humupd/dmab038
  17. Stem Cells Dev. 2021 Dec 16.
    Exploring microenvironment strategies to delay mesenchymal stem cell senescence.
    Xunhui Guo, Jiayi Wang, Wei Zou, Wenjuan Wei, Xin Guan, Jing Liu.
      Mesenchymal stem cells (MSCs) have recently emerged as an important candidate for cell therapy and tissue regeneration. However, some limitations in translational research and therapies still exist, such as insufficient cell supply, inadequate differentiation potential, and decreased immune capacity, all of which result from replicative senescence during long-term in vitro culture. In vitro, stem cells lack a protective microenvironment owing to the absence of physical and biochemical cues compared with the in vivo niche, which provides dynamic physicochemical and biological cues. This difference results in accelerated aging after long-term in vitro culture. Therefore, it remains a great challenge to delay replicative senescence in culture. Constructing a microenvironment to delay replicative senescence of MSCs by maintaining their phenotypes, properties, and functions is a feasible strategy to solve this problem and has made measurable progress both in preclinical studies and clinical trials. Here, we review the current knowledge on the characteristics of senescent MSCs, explore the molecular mechanisms of MSCs senescence, describe the niche of MSCs, and discuss some current microenvironment strategies to delay MSCs replicative senescence that can broaden their range of therapeutic applications.
    DOI:  https://doi.org/10.1089/scd.2021.0254
  18. Front Aging Neurosci. 2021 ;13 760200
    Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?
    Xi Zhang, Nanxin Huang, Lan Xiao, Fei Wang, Tao Li.
      Aging affects almost all the aspects of brain functions, but the mechanisms remain largely undefined. Increasing number of literatures have manifested the important role of glial cells in regulating the aging process. Oligodendroglial lineage cell is a major type of glia in central nervous system (CNS), composed of mature oligodendrocytes (OLs), and oligodendroglia precursor cells (OPCs). OLs produce myelin sheaths that insulate axons and provide metabolic support to meet the energy demand. OPCs maintain the population throughout lifetime with the abilities to proliferate and differentiate into OLs. Increasing evidence has shown that oligodendroglial cells display active dynamics in adult and aging CNS, which is extensively involved in age-related brain function decline in the elderly. In this review, we summarized present knowledge about dynamic changes of oligodendroglial lineage cells during normal aging and discussed their potential roles in age-related functional decline. Especially, focused on declined myelinogenesis during aging and underlying mechanisms. Clarifying those oligodendroglial changes and their effects on neurofunctional decline may provide new insights in understanding aging associated brain function declines.
    Keywords:  OPC; aging; myelinogenesis; neurofunctional decline; oligodendrocyte
    DOI:  https://doi.org/10.3389/fnagi.2021.760200
  19. Int J Oncol. 2022 Jan;pii: 5. [Epub ahead of print]60(1):
    Anterior gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy‑induced senescence escape.
    Amine Maarouf, Alice Boissard, Cécile Henry, Géraldine Leman, Olivier Coqueret, Catherine Guette, Eric Lelièvre.
      Among the different chemotherapies available, genotoxic drugs are widely used. In response to these drugs, particularly doxorubicin, tumor cells can enter into senescence. Chemotherapy‑induced senescence (CIS) is a complex response. Long described as a definitive arrest of cell proliferation, the present authors and various groups have shown that this state may not be complete and could allow certain cells to reproliferate. The mechanism could be due to the activation of new signaling pathways. In the laboratory, the proteins involved in these pathways and triggering cell proliferation were studied. The present study determined a new role for anterior gradient protein 2 (AGR2) in vivo in patients and in vitro in a senescence escape model. AGR2's implication in breast cancer patients and proliferation of senescent cells was assessed based on a SWATH‑MS proteomic study of patients' samples and RNA interference technology on cell lines. First, AGR2 was identified and it was found that its concentration is higher in the serum of patients with breast cancer and that this high concentration is associated with metastasis occurrence. An inverse correlation between intratumoral AGR2 expression and the senescence marker p16 was also observed. This observation led to the study of the role of AGR2 in the CIS escape model. In this model, it was found that AGR2 is overexpressed in cells during senescence escape and that its loss considerably reduces this phenomenon. Furthermore, it was shown that the extracellular form of AGR2 stimulated the reproliferation of senescent cells. The power of proteomic analysis based on the SWATH‑MS approach allowed the present study to highlight the mammalian target of rapamycin (mTOR)/AKT signaling pathway in the senescence escape mechanism mediated by AGR2. Analysis of the two signaling pathways revealed that AGR2 modulated RICTOR and AKT phosphorylation. All these results showed that AGR2 expression in sera and tumors of breast cancer patients is a marker of tumor progression and metastasis occurrence. They also showed that its overexpression regulates CIS escape via activation of the mTOR/AKT signaling pathway.
    Keywords:  anterior gradient 2; chemotherapy; senescence
    DOI:  https://doi.org/10.3892/ijo.2021.5295
  20. Mol Pharmacol. 2021 Dec 14. pii: MOLPHARM-AR-2021-000354. [Epub ahead of print]
    Senolytic-mediated elimination of head and neck tumor cellsinduced into senescence by cisplatin.
    Fereshteh Ahmadinejad, Tasia Bos, Bin Hu, Erin Britt, Jennifer Koblinski, Andrew J Souers, Joel D Leverson, Anthony C Faber, David A Gewirtz, Hisashi Harada.
      Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local and distant metastasis and disease relapse are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in head and neck cancer models from which tumor cells can escape both in vitro and in vivo We further establish the effectiveness of the senolytic, ABT-263 (Navitoclax), in elimination of senescent tumor cells after cisplatin treatment. Additionally, we show that ABT-263 interferes with the interaction between BCL-XL and BAX, anti- and pro-apoptotic proteins, respectively, followed by BAX activation. Our in vivo studies also confirm senescence induction in tumor cells by cisplatin, and the promotion of apoptosis coupled with a significant decrease in tumor size after sequential treatment with ABT-263. These results support the premise that senolytic agents could be utilized to eliminate residual senescent tumor cells after chemotherapy and thereby potentially delay disease recurrence in head and neck cancer patients. Significance Statement Disease recurrence is the most common cause of death in head and neck cancer patients. BCL-XL inhibitors such as ABT-263 (Navitoclax) have the capacity to be used in combination with cisplatin in head and neck cancer patients to eliminate senescent cells and possibly prevent disease relapse.
    Keywords:  chemotherapy; mechanisms of cell killing/apoptosis
    DOI:  https://doi.org/10.1124/molpharm.121.000354
  21. Stem Cell Res. 2021 Dec 07. pii: S1873-5061(21)00465-7. [Epub ahead of print]58 102618
    ATM modulates subventricular zone neural stem cell maintenance and senescence through Notch signaling pathway.
    Chuanming Dong, Xianli Wang, Lixin Sun, Liang Zhu, Danjing Yang, Shane Gao, Wenjun Zhang, Bin Ling, Aibin Liang, Zhengliang Gao, Jun Xu.
      Ataxia telangiectasia mutated (ATM) plays an essential role in DNA damage response and the maintenance of genomic stability. However, the role of ATM in regulating the function of adult neural stem cells (NSCs) remains unclear. Here we report that ATM deficiency led to accumulated DNA damage and decreased DNA damage repair capacity in neural progenitor cells. Moreover, we observed ATM ablation lead to the short-term increase of proliferation of neural progenitor cells, resulting in the depletion of the NSC pool over time, and this loss of NSC quiescence resulted in accelerated cell senescence. We further apply RNA sequencing to unravel that ATM knockout significantly affected Notch signaling pathway, furthermore, notch activation inhibit the abnormal increased proliferation of ATM-/- NSCs. Taken together, these findings indicate that ATM can serve as a key regulator for the normal function of adult NSCs by maintaining their stemness and preventing cellular senescence primarily through Notch signaling pathway.
    Keywords:  ATM; Aging; Neural stem cell; Notch signaling pathway; Quiescence
    DOI:  https://doi.org/10.1016/j.scr.2021.102618
  22. Exp Eye Res. 2021 Dec 12. pii: S0014-4835(21)00461-9. [Epub ahead of print] 108895
    Cathepsin S is a novel target for age-related dry eye.
    Zhiyuan Yu, Jinmiao Li, Gowthaman Govindarajan, Sarah Hamm-Alvarez, Jahan Alam, De-Quan Li, Cintia S de Paiva.
      Cathepsin S (Ctss) is a protease that is proinflammatory on epithelial cells. The purpose of this study was to investigate the role of Ctss in age-related dry eye disease. Ctss-/- mice [in a C57BL/6 (B6) background] of different ages were compared to B6 mice. Ctss activity in tears and lacrimal gland (LG) lysates was measured. The corneal barrier function was investigated in naïve mice or after topical administration of Ctss eye drops 5X/day for two days. Eyes were collected, and conjunctival goblet cell density was measured in PAS-stained sections. Immunoreactivity of the tight junction proteins, ZO-1 and occludin, was investigated in primary human cultured corneal epithelial cells (HCEC) without or with Ctss, with or without a Ctss inhibitor. A significant increase in Ctss activity was observed in the tears and LG lysates in aged B6 compared to young mice. This was accompanied by higher Ctss transcripts and protein expression in LG and spleen. Compared to B6, 12 and 24-month-old Ctss-/- mice did not display age-related corneal barrier disruption and goblet cell loss. Treatment of HCEC with Ctss for 48 hours disrupted occludin and ZO-1 immunoreactivity compared to control cells. This was prevented by the Ctss inhibitor LY3000328 or Ctss-heat inactivation. Topical reconstitution of Ctss in Ctss-/- mice for two days disrupted corneal barrier function. Aging on the ocular surface is accompanied by increased expression and activity of the protease Ctss. Our results suggest that cathepsin S modulation might be a novel target for age-related dry eye disease.
    Keywords:  Aging; Cathepsin S; Corneal barrier; Dry eye; Goblet cells; Inflammaging; Tight junction proteins
    DOI:  https://doi.org/10.1016/j.exer.2021.108895
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