bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒05‒08
twenty-one papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. J Gerontol A Biol Sci Med Sci. 2022 May 07. pii: glac097. [Epub ahead of print]
      Senescent cells express and secrete a variety of extracellular modulators that include cytokines, chemokines, proteases, growth factors and some enzymes associated with ECM remodeling, defined as the senescence-associated secretory phenotype (SASP). SASP reinforces senescent cell cycle arrest, stimulates and recruits immune cells for immune-mediated clearance of potentially tumorigenic cells, limits or induces fibrosis and promotes wound healing and tissue regeneration. On the other hand, SASP mediates chronic inflammation leading to destruction of tissue structure and function and stimulating the growth and survival of tumour cells. SASP is highly heterogeneous and the role of SASP depends on the context. The regulation of SASP occurs at multiple levels including chromatin remodelling, transcription, mRNA translation, intracellular trafficking and secretion. Several SASP modulators have already been identified setting the stage for future research on their clinical applications. In this review, we summarize in detail the potential signalling pathways that trigger and regulate SASP production during ageing and senescence.
    Keywords:  Epigenetic regulation; NcRNAs; SASP; Senescence; Transcription factor
  2. Eur J Pharmacol. 2022 May 02. pii: S0014-2999(22)00252-7. [Epub ahead of print] 174991
      During the last few decades, cancer has remained one of the deadliest diseases that endanger human health, emphasizing urgent drug discovery. Cellular senescence has gained a great deal of attention in recent years because of its link to the development of cancer therapy. Senescent cells are incapable of proliferating due to irreversibly inhibited the initiation of the cell cycle pathways. However, senescent cells aggregate in tissues and produce a pro-inflammatory secretome called senescence-associated secretory phenotype (SASP) that can cause serious harmful effects if not managed properly. There is mounting evidence that senescent cells lead to various phases of tumorigenesis in various anatomical sites, owing mostly to the paracrine activities of the SASP. Therefore, a new treatment field called senotherapeutics has been established. Senotherapeutics are newly developed anticancer agents that have been demonstrated to inhibit cancer effectively. In light of recent findings, several promising natural products have been identified as senescence inducers and senotherapeutics, including, miliusanes, epigallocatechin gallate, phloretin, silybin, resveratrol, genistein, sulforaphane, quercetin, allicin, fisetin, piperlongumine, berberine, triptolide, tocotrienols and curcumin analogs. Several of them have already been validated through preclinical trials and exert an enormous potential for clinical trials. This review article focuses on and summarises the latest advances on cellular senescence and its potential as a target for cancer treatment and highlights the well-known natural products as senotherapeutics for cancer treatment.
    Keywords:  Cancer; Cellular senescence; Natural products; Senolytic agents; Senotherapeutics
  3. Front Med (Lausanne). 2022 ;9 865230
      Background and Aims: The initiation of cellular senescence in response to protumorigenic stimuli counteracts malignant progression in (pre)malignant cells. Besides arresting proliferation, cells entering this terminal differentiation state adopt a characteristic senescence-associated secretory phenotype (SASP) which initiates alterations to their microenvironment and effects immunosurveillance of tumorous lesions. However, some effects mediated by senescent cells contribute to disease progression. Currently, the exploration of senescent cells' impact on the tumor microenvironment and the evaluation of senescence as possible target in colorectal cancer (CRC) therapy demand reliable detection of cellular senescence in vivo. Therefore, specific immunohistochemical biomarkers are required. Our aim is to analyze the clinical implications of senescence detection in colorectal carcinoma and to investigate the interactions of senescent tumor cells and their immune microenvironment in vitro and in vivo.Methods: Senescence was induced in CRC cell lines by low-dose-etoposide treatment and confirmed by Senescence-associated β-galactosidase (SA-β-GAL) staining and fluorescence activated cell sorting (FACS) analysis. Co-cultures of senescent cells and immune cells were established. Multiple cell viability assays, electron microscopy and live cell imaging were conducted. Immunohistochemical (IHC) markers of senescence and immune cell subtypes were studied in a cohort of CRC patients by analyzing a tissue micro array (TMA) and performing digital image analysis. Results were compared to disease-specific survival (DSS) and progression-free survival (PFS).
    Results: Varying expression of senescence markers in tumor cells was associated with in- or decreased survival of CRC patients. Proximity analysis of p21-positive senescent tumor cells and cytotoxic T cells revealed a significantly better prognosis for patients in which these cell types have the possibility to directly interact. In vitro, NK-92 cells (mimicking natural killer T cells) or TALL-104 cells (mimicking both cytotoxic T cells and natural killer T cells) led to dose-dependent specific cytotoxicity in >75 % of the senescent CRC cells but <20 % of the proliferating control CRC cells. This immune cell-mediated senolysis seems to be facilitated via direct cell-cell contact inducing apoptosis and granule exocytosis.
    Conclusion: Counteracting tumorigenesis, cellular senescence is of significant relevance in CRC. We show the dual role of senescence bearing both beneficial and malignancy-promoting potential in vivo. Absence as well as exceeding expression of senescence markers are associated with bad prognosis in CRC. The antitumorigenic potential of senescence induction is determined by tumor micromilieu and immune cell-mediated elimination of senescent cells.
    Keywords:  cellular senescence; colorectal cancer; prognostic biomarker; senescence-associated secretory phenotype (SASP); senolysis
  4. Front Cardiovasc Med. 2022 ;9 854726
      Vascular calcification is an irreversible pathological process associated with a loss of vascular wall function. This process occurs as a result of aging and age-related diseases, such as cardiovascular and chronic kidney diseases, and leads to comorbidities. During these age-related diseases, the endothelium accumulates senescent cells, which stimulate calcification in vascular smooth muscle cells. Currently, vascular calcification is a silent pathology, and there are no early diagnostic tools. Therefore, by the time vascular calcification is diagnosed, it is usually untreatable. Some mediators, such as oxidative stress, inflammation, and extracellular vesicles, are inducers and promoters of vascular calcification. They play a crucial role during vascular generation and the progression of vascular calcification. Extracellular vesicles, mainly derived from injured endothelial cells that have acquired a senescent phenotype, contribute to calcification in a manner mostly dependent on two factors: (1) the number of extracellular vesicles released, and (2) their cargo. In this review, we present state-of-the-art knowledge on the composition and functions of extracellular vesicles involved in the generation and progression of vascular calcification.
    Keywords:  aging; aging-related diseases; extracellular vesicles; inflammation; medial arterial calcification; senescence; smooth vessel cells; vascular calcification
  5. Ageing Res Rev. 2022 Apr 28. pii: S1568-1637(22)00078-2. [Epub ahead of print] 101636
      Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.
    Keywords:  Neurogenesis; aging; dentate gyrus; hippocampus; memory; neurodegeneration
  6. Front Genet. 2022 ;13 869950
      N6-methyladenosine (m6A) is the most common and conserved internal eukaryotic mRNA modification. m6A modification is a dynamic and reversible post-transcriptional regulatory modification, initiated by methylase and removed by RNA demethylase. m6A-binding proteins recognise the m6A modification to regulate gene expression. Recent studies have shown that altered m6A levels and abnormal regulator expression are crucial in the ageing process and the occurrence of age-related diseases. In this review, we summarise some key findings in the field of m6A modification in the ageing process and age-related diseases, including cell senescence, autophagy, inflammation, oxidative stress, DNA damage, tumours, neurodegenerative diseases, diabetes, and cardiovascular diseases (CVDs). We focused on the biological function and potential molecular mechanisms of m6A RNA methylation in ageing and age-related disease progression. We believe that m6A modification may provide a new target for anti-ageing therapies.
    Keywords:  N6-methyladenosine; RNA methylation; aging; aging-related disease; epigenetics
  7. Cell Death Discov. 2022 May 06. 8(1): 254
      Age-related osteoporosis is characterized by the accumulation of senescent osteoblastic cells in bone microenvironment and significantly reduced osteogenic differentiation. Clearing of the senescent cells is helpful to improve bone formation in aged mice. Bone morphogenetic protein 9 (BMP9), a multifunctional protein produced and secreted by liver, was reported to improve osteoporosis caused by estrogen withdrawal. However, the mechanism of BMP9 has not been fully elucidated, and its effect on senile osteoporosis has not been reported. This study reveals that BMP9 significantly increases bone mass and improves bone biomechanical properties in aged mice. Furthermore, BMP9 reduces expression of senescent genes in bone microenvironment, accompanied by decreased senescence-associated secretory phenotypes (SASPs) such as Ccl5, Mmp9, Hmgb1, Nfkb1, and Vcam1. In vitro, Bmp9 treatment inhibits osteoblast senescence through activating Smad1, which suppresses the transcriptional activity of Stat1, thereby inhibits P21 expression and SASPs production. Furthermore, inhibiting the Smad1 signal in vivo can reverse the inhibitory effect of BMP9 on Stat1 and downstream senescent genes, which eliminates the protection of BMP9 on age-related osteoporosis. These findings highlight the critical role of BMP9 on reducing age-related bone loss by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis.
  8. Elife. 2022 May 04. pii: e75492. [Epub ahead of print]11
      Cancer survivors suffer from progressive frailty, multimorbidity and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sub-lethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow up was for one year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production via NOX4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.
    Keywords:  cancer biology; cell biology; mouse
  9. EMBO Rep. 2022 May 02. e54217
      Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan. While newer research has shown that DNA breaks and mutations may facilitate neuron diversity during development and neuronal function throughout life, a wealth of evidence indicates deficient DNA damage repair underlies many neurological disorders, especially age-associated neurodegenerative diseases. Recently, efforts to clarify the molecular link between DNA damage and neurodegeneration have improved our understanding of how the genomic location of DNA damage and defunct repair proteins impact neuron health. Additionally, work establishing a role for senescence in the aging and diseased brain reveals DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.
    Keywords:  DNA damage; DNA damage repair; inflammation; neurodegeneration; neuron
  10. Adv Exp Med Biol. 2022 ;1360 109-116
      Gadd45a, Gadd45b, and Gadd45g have been implicated in cell cycle arrest, DNA repair, apoptosis, innate immunity, genomic stability, and more recently in senescence. Evidence has accumulated that Gadd45a deficiency results in escape of mouse embryo fibroblasts from senescence, whereas Gadd45b deficiency promotes premature senescence and skin aging. Moreover, recently Gadd45b deficiency was found to promote senescence and attenuate liver fibrosis, whereas Gadd45a was observed to exert a protective effect against hepatic fibrosis. These findings indicate that the Gadd45 stress response proteins play important roles in modulating cellular responses to senescence. Thus, exploring how Gadd45 proteins modulate cellular senescence has the potential to provide new and innovative tools to treat cancer as well as liver disease.
    Keywords:  CCl4; Carbon tetrachloride; Collagen; Fibrosis; Gadd45; Gadd45a; Gadd45b; Gadd45g; Hepatic fibrosis; Liver; Senescence
  11. Nat Rev Genet. 2022 May 02.
      Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.
  12. Science. 2022 May 05. e
      Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.
  13. Front Cell Dev Biol. 2022 ;10 891763
      The Ror-family proteins, Ror1 and Ror2, act as receptors or co-receptors for Wnt5a and its related Wnt proteins to activate non-canonical Wnt signaling. Ror1 and/or Ror2-mediated signaling plays essential roles in regulating cell polarity, migration, proliferation and differentiation during developmental morphogenesis, tissue-/organo-genesis and regeneration of adult tissues following injury. Ror1 and Ror2 are expressed abundantly in developing tissues in an overlapping, yet distinct manner, and their expression in adult tissues is restricted to specific cell types such as tissue stem/progenitor cells. Expression levels of Ror1 and/or Ror2 in the adult tissues are increased following injury, thereby promoting regeneration or repair of these injured tissues. On the other hand, disruption of Wnt5a-Ror2 signaling is implicated in senescence of tissue stem/progenitor cells that is related to the impaired regeneration capacity of aged tissues. In fact, Ror1 and Ror2 are implicated in age-related diseases, including tissue fibrosis, atherosclerosis (or arteriosclerosis), neurodegenerative diseases, and cancers. In these diseases, enhanced and/or sustained (chronic) expression of Ror1 and/or Ror2 is observed, and they might contribute to the progression of these diseases through Wnt5a-dependent and -independent manners. In this article, we overview recent advances in our understanding of the roles of Ror1 and Ror2-mediated signaling in the development, tissue regeneration and age-related diseases, and discuss their potential to be therapeutic targets for chronic inflammatory diseases and cancers.
    Keywords:  cancers; cell polarity; cellular senescence; inflammation; migration; non-canonical wnt signaling; proliferation; stem/progenitor cells
  14. Semin Immunopathol. 2022 May 03.
      The neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) both have a myriad of risk factors including genetics, environmental exposures, and lifestyle. However, aging is the strongest risk factor for both diseases. Aging also profoundly influences the immune system, with immunosenescence perhaps the most prominent outcome. Through genetics, mouse models, and pathology, there is a growing appreciation of the role the immune system plays in neurodegenerative diseases. In this review, we explore the intersection of aging and the immune system in AD and PD.
    Keywords:  Alzheimer’s disease; Immunosenescence; Microglia; Parkinson’s disease; T cells
  15. Aging Pathobiol Ther. 2022 ;4(1): 23-24
      The geropathology concept assumes all age-related lesions are relevant, which allows the ability to grade each lesion in an organ with a severity score resulting in a quantitative value. Because aging pet cats have similar age-related diseases as older humans, knowledge of histopathology occurring during aging would be invaluable to determine how age-related lesions progress with increasing age and the connection with comorbidities. The ability to use the severity of specific organ geropathology to predict biological aging would provide new approaches to study pathways of aging and their role in the development of age-related diseases in animal models.
    Keywords:  Alzheimer’s disease; Geropathology; age-related diseases; age-related lesions; domestic cats; pathways of aging; standard lesion curve
  16. Nat Cell Biol. 2022 May 02.
      Innate DNA sensing via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) mechanism surveys microbial invasion and cellular damage and thus participates in various human infectious diseases, autoimmune diseases and cancers. However, how DNA sensing rapidly and adaptively shapes cellular physiology is incompletely known. Here we identify the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway, a previously unknown cGAS-STING mechanism, enabling an innate immunity control of cap-dependent messenger RNA translation. Upon cGAMP binding, STING at the ER binds and directly activates the ER-located kinase PERK via their intracellular domains, which precedes TBK1-IRF3 activation and is irrelevant to the unfolded protein response. The activated PERK phosphorylates eIF2α, forming an inflammatory- and survival-preferred translation program. Notably, this STING-PERK-eIF2α pathway is evolutionarily primitive and physiologically critical to cellular senescence and organ fibrosis. Pharmacologically or genetically targeting this non-canonical cGAS-STING pathway attenuated lung and kidney fibrosis. Collectively, the findings identify an alternative innate immune pathway and its critical role in organ fibrosis, report an innate immunity-directed translation program and suggest the therapeutic potential for targeting the STING-PERK pathway in treating fibrotic diseases.
  17. Elife. 2022 May 04. pii: e76808. [Epub ahead of print]11
      Many age-associated changes in the human hematopoietic system have been reproduced in murine models; however, such changes have not been as robustly explored in rats despite the fact these larger rodents are more physiologically similar to humans. We examined peripheral blood of male F344 rats ranging from three to twenty-seven months of age and found significant age-associated changes with distinct leukocyte population shifts. We report CD25+ CD4+ population frequency is a strong predictor of healthy aging, generate a model using blood parameters, and find rats with blood profiles that diverge from chronologic age indicate debility; thus, assessments of blood composition may be useful for non-lethal disease profiling or as a surrogate measure for efficacy of aging interventions. Importantly, blood parameters and DNA methylation alterations, defined distinct juncture points during aging, supporting a non-linear aging process. Our results suggest these inflection points are important considerations for aging interventions. Overall, we present rat blood aging metrics that can serve as a resource to evaluate health and the effects of interventions in a model system physiologically more reflective of humans.
    Keywords:  evolutionary biology; immunology; inflammation; rat
  18. Stem Cells. 2022 Mar 03. 40(1): 35-48
      DNA damage repair (DDR) is a safeguard for genome integrity maintenance. Increasing DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. Our goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1, and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming. GFP-Trap one-step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography-tandem mass spectrometry analysis, uncovered macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OS-GFP reporter cells enhanced specifically nonhomologous end joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1, was confirmed in human umbilical vein endothelial cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming. We propose the macroH2A1 splicing isoform macroH2A1.1 as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.
    Keywords:  DNA damage; cell reprogramming; induced pluripotent stem cells; macroH2A1.1
  19. J Adv Res. 2022 03;37 267-278
      Background: Elderly population has been progressively rising in the world, thus the demand for anti-aging heath products to assure longevity as well as to ameliorate age-related complications is also on the rise. Among various anti-aging health products, nicotinamide mononucleotide (NMN) has been gaining attentions of the consumers and the scientific community.Aim of review: This article intends to provide an overview on the current knowledge on promises and safety concerns of NMN as an anti-aging health product.
    Key scientific concepts of review: Nicotinamide adenine dinucleotide (NAD+) levels in the body deplete with aging and it is associated with downregulation of energy production in mitochondria, oxidative stress, DNA damage, cognitive impairment and inflammatory conditions. However, NMN, as the precursor of NAD+, can slow down this process by elevating NAD+ levels in the body. A number of in vivo studies have indicated affirmative results of therapeutic effects for various age-induced complications with NMN supplementation. One preclinical and one clinical study have been conducted to investigate the safety concerns of NMN administration while a few more human clinical trials are being conducted. As there is a large influx of NMN based anti-aging products on the market, proper clinical investigations are urgently needed to find out the effectiveness and safety of NMN supplementation.
    Keywords:  Age-induced diseases; Anti-aging; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide; Supplement
  20. J Clin Invest. 2022 May 02. pii: e158449. [Epub ahead of print]132(9):
      The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels.