bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒06‒26
34 papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Mech Ageing Dev. 2022 Jun 18. pii: S0047-6374(22)00071-9. [Epub ahead of print] 111689
      Ageing is a complex biological phenomenon representing the major risk factor for developing age-related diseases, such as cardiovascular pathologies, neurodegenerative diseases, and cancer. Geroscience, the new vision of gerontology, identifies cellular senescence as an interconnected biological process that characterises ageing and age-related diseases. Therefore, many strategies have been employed in the last years to reduce the harmful effects of senescence, and among these, the most intriguing ones use nutraceutical compounds. Here we show that a pre-treatment with Quercetin, a bioactive flavonoid present in many fruits and vegetables, increasing cellular antioxidant defence, can alleviate Doxorubicin (Doxo)-induced cellular senescence in human normal WI-38 fibroblasts. Furthermore, our work demonstrates that Quercetin pre-treatment, reducing the number of senescent cells and the production of the senescence-associated secretory phenotype (SASP) factors, can decrease the pro-tumour effects of conditioned medium from Doxo-induced senescent fibroblasts on osteosarcoma cells. Overall, our findings are consistent with the hypothesis that targeting senescent cells can be an emerging strategy for cancer treatment, especially in elderly patients, in which senescent cells are already abundant in several tissues and organs.
    Keywords:  Ageing; Cancer; Osteosarcoma; Quercetin; SASP; Senescence
  2. Cells. 2022 Jun 19. pii: 1966. [Epub ahead of print]11(12):
      It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.
    Keywords:  SASP; aging; development; endothelial cells; metabolic function; senescence; stem cells
  3. Biogerontology. 2022 Jun 21.
      Cellular senescence, which is characterized by permanent proliferation arrest, has become an important target for the amelioration of various human diseases. The activity of senescent cells is mainly related to the senescence-associated secretory phenotype (SASP). The SASP can cause chronic inflammation in local tissues and organs through autocrine and paracrine mechanisms, and a series of factors secreted by senescent cells can deteriorate the cellular microenvironment, promoting tumor formation and exacerbating aging-related diseases. Therefore, avoiding the promotion of cancer is an urgent problem. In recent years, increased attention has been given to the mechanistic study of microRNAs in senescence. As important posttranscriptional regulators, microRNAs possess unique tissue-specific expression in senescence. MicroRNAs can regulate the SASP by regulating proteins in the senescence signaling pathway, the reverse transcriptase activity of telomerase, the generation of reactive oxygen species and oxidative damage to mitochondria. Numerous studies have confirmed that removing senescent cells does not cause significant side effects, which also opens the door to the development of treatment modalities against senescent cells. Herein, this review discusses the double-edged sword of cellular senescence in tumors and aging-related diseases and emphasizes the roles of microRNAs in regulating the SASP, especially the potential of microRNAs to be used as therapeutic targets to inhibit senescence, giving rise to novel therapeutic approaches for the treatment of aging-associated diseases.
    Keywords:  Aging-associated diseases; Cancer; MicroRNA; SASP; Senescence
  4. Neuroscience. 2022 Jun 15. pii: S0306-4522(22)00289-5. [Epub ahead of print]
      Cellular senescence is an important contributor to aging and age-related diseases such as Alzheimer's disease (AD). Senescent cells are characterized by a durable cell proliferation arrest and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP), which participates in the progression of neurodegenerative disorders. Clearance of senescent glial cells in an AD mouse model prevented cognitive decline suggesting pharmacological agents targeting cellular senescence might provide novel therapeutic approaches for AD. Δ133p53α, a natural protein isoform of p53, was previously shown to be a negative regulator of cellular senescence in primary human astrocytes, with clinical implications from its diminished expression in brain tissues from AD patients. Here we show that treatment of proliferating human astrocytes in culture with amyloid-beta oligomers (Aβ), an endogenous pathogenic agent of AD, results in reduced expression of Δ133p53α, as well as induces the cells to become senescent and express proinflammatory SASP cytokines such as IL-6, IL-1β and TNFα. Our data suggest that Aβ-induced astrocyte cellular senescence is associated with accelerated DNA damage, and upregulation of full-length p53 and its senescence-inducing target gene p21WAF1. We also show that exogenously enhanced expression of Δ133p53α rescues human astrocytes from Aβ-induced cellular senescence and SASP through both protection from DNA damage and dominant-negative inhibition of full-length p53, leading to inhibition of Aβ-induced, astrocyte-mediated neurotoxicity. The results presented here demonstrate that Δ133p53α manipulation could modulate cellular senescence in the context of AD, possibly opening new therapeutic avenues.
    Keywords:  Alzheimer’s; DNA damage; SASP; p53; p53 isoforms
  5. Cells. 2022 Jun 20. pii: 1977. [Epub ahead of print]11(12):
      Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function.
    Keywords:  aging; lysosome; senescence
  6. Clin Exp Pharmacol Physiol. 2022 Jun 24.
      Pulmonary arterial hypertension (PAH) is a rare and chronic lung vasculature disease characterized by pulmonary vasculature remodeling, including abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional endothelial cells (ECs). Remodeling of the pulmonary vasculature occurs from maturity to senescence, and it has become apparent that cellular senescence plays a central role in the pathogenesis of various degenerative vascular diseases and pulmonary pathologies. Cellular senescence represents a state of stable proliferative arrest accompanied by the senescence-associated secretory phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment. Evidences show that in PAH patients, higher levels of cytokines, chemokines, and inflammatory mediators can be detected and correlate with clinical outcome. Moreover, senescent cells accrue with age in epithelial, endothelial, fibroblastic, and immunological compartments within human lungs, and evidence showed that ECs and PASMCs in lungs from patients with chronic obstructive pulmonary disease were characterized by a higher number of senescent cells. However, there is little evidence uncovering the molecular pulmonary vasculature senescence in PAH. Herein, we review the cellular senescence in pulmonary vascular remodeling, and emphasize its importance in PAH. We further introduce some signaling pathways which might be involved in vasculature senescence and PAH, with the intent to discuss the possibility of the PAH therapy via targeting cellular senescence and reduce PAH progression and mortality.
    Keywords:  cellular senescence; pulmonary arterial hypertension; pulmonary vasculature remodeling; senescence-associated secretory phenotype (SASP); senotherapy
  7. Front Endocrinol (Lausanne). 2022 ;13 915139
      Cell senescence is a crucial process in cell fate determination and is involved in an extensive array of aging-associated diseases. General perceptions and experimental evidence point out that the decline of physical function as well as aging-associated diseases are often initiated by cell senescence and organ ageing. Therefore, regulation of cell senescence process can be a promising way to handle aging-associated diseases such as osteoporosis. The circadian clock regulates a wide range of cellular and physiological activities, and many age-linked degenerative disorders are associated with the dysregulation of clock genes. BMAL1 is a core circadian transcription factor and governs downstream genes by binding to the E-box elements in their promoters. Compelling evidence has proposed the role of BMAL1 in cellular senescence and aging-associated diseases. In this review, we summarize the linkage between BMAL1 and factors of cell senescence including oxidative stress, metabolism, and the genotoxic stress response. Dysregulated and dampened BMAL1 may serve as a potential therapeutic target against aging- associated diseases.
    Keywords:  BMAL1; aging; cellular senescence; genotoxic stress; metabolism; oxidative stress
  8. Front Aging Neurosci. 2022 ;14 917797
      Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive. In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic (DA) neurons in PD.
    Keywords:  Parkinson’s disease; aging; cellular senescence; dopamine neurons; immune response; neuroinflammation
  9. Aging Cell. 2022 Jun 19. e13657
      With the aging of the global population, accumulating interest is focused on manipulating the fundamental aging-related signaling pathways to delay the physiological aging process and eventually slow or prevent the appearance or severity of multiple aging-related diseases. Recently, emerging evidence has shown that RNA modifications, which were historically considered infrastructural features of cellular RNAs, are dynamically regulated across most of the RNA species in cells and thereby critically involved in major biological processes, including cellular senescence and aging. In this review, we summarize the current knowledge about RNA modifications and provide a catalog of RNA modifications on different RNA species, including mRNAs, miRNAs, lncRNA, tRNAs, and rRNAs. Most importantly, we focus on the regulation and roles of these RNA modifications in aging-related diseases, including neurodegenerative diseases, cardiovascular diseases, cataracts, osteoporosis, and fertility decline. This would be an important step toward a better understanding of fundamental aging mechanisms and thereby facilitating the development of novel diagnostics and therapeutics for aging-related diseases.
    Keywords:  RNA modification; aging; aging-related disease; epitranscriptome
  10. Int J Mol Sci. 2022 Jun 10. pii: 6531. [Epub ahead of print]23(12):
      The accumulation of senescent cells in aging tissues is associated with age-related diseases and functional decline. Thus, senolysis, a therapy aimed at rejuvenation by removing senescent cells from the body, is being developed. However, this therapy requires the identification of membrane surface antigens that are specifically expressed on senescent cells for their selective elimination. We showed that atypical chemokine receptor 3 (ACKR3), a receptor of the CXC motif chemokine 12 (CXCL12) implicated in cancer, inflammation, and cardiovascular disorders, is selectively expressed on the surface of senescent human fibroblasts but not on proliferating cells. Importantly, the differential presence of ACKR3 enabled the isolation of senescent cells by flow cytometry using anti-ACKR3 antibodies. Furthermore, antibody-dependent cellular cytotoxicity assays revealed that cell surface ACKR3 preferentially sensitizes senescent but not dividing fibroblasts to cell injury by natural killer cells. Conclusively, the selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells. These results might contribute to the future development of novel senolysis approaches.
    Keywords:  antibody-dependent cellular cytotoxicity; atypical chemokine receptor 3; fibroblast; natural killer cell; senolysis
  11. Int J Oral Sci. 2022 Jun 20. 14(1): 29
      Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6-CREB-SOD2-dependent pathway in IgG4-RS.
  12. Inflamm Res. 2022 Jun 24.
      BACKGROUND: Excessive exposure of the skin to UV radiation (UVR) triggers a remodeling of the immune system and leads to the photoaging state which is reminiscent of chronological aging. Over 30 years ago, it was observed that UVR induced an immunosuppressive state which inhibited skin contact hypersensitivity.METHODS: Original and review articles encompassing inflammation and immunosuppression in the photoaging and chronological aging processes were examined from major databases including PubMed, Scopus, and Google Scholar.
    RESULTS: Currently it is known that UVR treatment can trigger a cellular senescence and inflammatory state in the skin. Chronic low-grade inflammation stimulates a counteracting immunosuppression involving an expansion of immunosuppressive cells, e.g., regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and regulatory dendritic cells (DCreg). This increased immunosuppressive activity not only suppresses the function of effector immune cells, a state called immunosenescence, but it also induces bystander degeneration of neighboring cells. Interestingly, the chronological aging process also involves an accumulation of pro-inflammatory senescent cells and signs of chronic low-grade inflammation, called inflammaging. There is also clear evidence that inflammaging is associated with an increase in anti-inflammatory and immunosuppressive activities which promote immunosenescence.
    CONCLUSION: It seems that photoaging and normal aging evoke similar processes driven by the remodeling of the immune system. However, it is likely that there are different molecular mechanisms inducing inflammation and immunosuppression in the accelerated photoaging and the chronological aging processes.
    Keywords:  Aging; Anti-inflammatory; Carcinogenesis; Lifespan; UVA; UVB
  13. Aging Cell. 2022 Jun 21. e13658
      The redox co-factor nicotinamide adenine dinucleotide (NAD) declines with age, and NAD deficits are specifically associated with dysfunctional energy metabolism in late-onset Alzheimer's disease (LOAD). Nicotinamide riboside (NR), a dietary NAD precursor, has been suggested to ameliorate the aging process or neurodegeneration. We assessed whether NR with or without caffeine, which increases nicotinamide mononucleotide transferase subtype 2 (NMNAT2), an essential enzyme in NAD production, modulates bioenergetic functions in LOAD. In LOAD patients-and young or old control individuals-derived dermal fibroblasts as well as in induced pluripotent stem cell-differentiated neural progenitors and astrocytes, NR and caffeine cell type-specifically increased the NAD pool, transiently enhanced mitochondrial respiration or glycolysis and altered the expression of genes in the NAD synthesis or consumption pathways. However, continued treatment led to reversed bioenergetic effects. Importantly, NR and caffeine did not alter the characteristics of a previously documented inherent LOAD-associated bioenergetic phenotype. Thus, although NR and caffeine can partially restore diminished NAD availability, increasing NAD alone may not be sufficient to boost or restore energy metabolism in brain aging or alter aberrant energy management in LOAD. Nicotinamide riboside might still be of value in combination with other agents in preventive or therapeutic intervention strategies to address the aging process or age-associated dementia.
    Keywords:  Alzheimer's disease; NAD; aging; bioenergetics; caffeine; induced pluripotent stem cells (iPSC); nicotinamide riboside
  14. Eur J Histochem. 2022 Jun 21. 66(3):
      Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a decline in cell division and an abnormal release of reactive oxygen species (ROS), and ferroptosis is represented by iron deposition associated with an excessive accumulation of ROS. ROS and cellular stress pathways are also drivers of NAFLD/NASH development. The etiology of NAFLD/NASH lies in poor diets enriched in fat and sugar. This food regimen leads to liver steatosis, resulting in progressive degeneration of the organ, with a late onset of irreversible fibrosis and cirrhosis. Few studies have investigated the possible connection between senescence and ferroptosis in NAFLD/NASH progression, despite the two events sharing some molecular players. We hypothesized a possible link between senescence and ferroptosis in a NAFLD background. To thoroughly investigate this in the context of "Western-style" diet (WSD) abuse, we used an amylin-modified liver NASH mouse model. The main NASH hallmarks have been confirmed in this model, as well as an increase in apoptosis, and Ki67 and p53 expression in the liver. Senescent beta-galactosidase-positive cells were elevated, as well as the expression of the related secretory molecules Il-6 and MMP-1. Features of DNA damage and iron-overload were found in the livers of NASH mice. Gpx4 (glutathione peroxidase 4) expression, counteracting ferroptotic cell death, was increased. Notably, an increased number of senescent cells showing overexpression of gpx4 was also found. Our data seem to suggest that senescent cells acquire a gpx4-mediated mechanism of ferroptosis resistance and thus remain in the liver, fostering the deterioration of liver fitness.
  15. Genes Cells. 2022 Jun 20.
      The 6th conference of the international cell senescence association (ICSA) on the theme of "A New Era of Senescence Research: The Challenge of Controlling Aging and Cancer" was held on December 12-15, 2021 in Osaka, Japan as a Hybrid Meeting. The conference brought together basic and translational scientists to discuss recent developments in the field of cellular senescence research. In recent years, the study of cellular senescence has become a very hot field of research. It is clear that the ICSA, founded in 2015, has played an important role in this process. The 6th ICSA conference has provided another opportunity for exchanges and new connections between basic and translational scientists. The scientific program consisted of keynote lectures, invited talks, short talks selected from abstracts, a poster session, and luncheon seminars sponsored by the Japanese Society of Anti-Aging Medicine. In the Meet the Editor session, Dr Christoph Schmitt, Editor-in-Chief of Nature Metabolism, gave a short presentation about the journal and answered questions from the audience. Being a hybrid meeting, there was only so much that could be done, but we hope that the meeting was fruitful.
    Keywords:  aging; cancer; cellular senescence
  16. J Cell Sci. 2022 Jun 20. pii: jcs.259738. [Epub ahead of print]
      Intervertebral disc degeneration (IVDD) is a complex process involving many factors, among which excessive senescence of nucleus pulposus cells (NPCs) is considered to be the main factor. Our previous study found that metformin may inhibit senescence in nucleus pulposus cells; however, its working mechanism is still largely unknown. In the current study, we found that metformin may inactivate cGAS-STING pathway during oxidative stress. Knock-down of STING may further suppress senescence, indicating metformin may exert its effect through cGAS-STING pathway. Damaged DNA is a major inducer of the activation of cGAS-STING pathway. Mechanistically, our study showed that DNA damage was reduced during metformin treatment; however, suppression of autophagy by 3-methyladenine (3MA) may compromise the effect of metformin on DNA damage. The in vivo study also showed that 3MA may recede the therapeutic effect of metformin on IVDD. Taken together, our results reveal that metformin may suppress senescence via inactivating the cGAS-STING pathway through autophagy, implying the new application of metformin in cGAS-STING pathway related diseases.
    Keywords:  Autophagy; CGAS-STING signaling pathway; Intervertebral disc degeneration; Metformin; Senescence
  17. Antioxidants (Basel). 2022 May 24. pii: 1037. [Epub ahead of print]11(6):
      Chronic hyperglycemia, the diagnostic biomarker of Type 2 Diabetes Mellitus (T2DM), is a condition that fosters oxidative stress and proinflammatory signals, both involved in the promotion of cellular senescence. Senescent cells acquire a proinflammatory secretory phenotype, called SASP, exacerbating and perpetuating the detrimental effects of hyperglycemia. Bioactive compounds can exert antioxidant and anti-inflammatory properties. However, the synergistic anti-inflammatory and antioxidant effects of the most extensively investigated natural compounds have not been confirmed yet in senescent cells and in hyperglycemic conditions. Here, we exposed young and replicative senescent HUVEC (yHUVEC and sHUVEC) to a high-glucose (HG) condition (45 mM) and treated them with Polydatin (POL), Curcumin (CUR) and Quercetin (QRC), alone or in combination (MIX), to mirror the anti-inflammatory component OxiDefTM contained in the novel nutraceutical GlicefenTM (Mivell, Italy). In both yHUVEC and sHUVEC, the MIX significantly decreased the expression levels of inflammatory markers, such as MCP-1, IL-1β and IL-8, and ROS production. Importantly, in sHUVEC, a synergistic effect of the MIX was observed, suggesting its senomorphic activity. Moreover, the MIX was able to reduce the expression level of RAGE, a receptor involved in the activation of proinflammatory signaling. Overall, our data suggest that the consumption of nutraceuticals containing different natural compounds could be an adjuvant supplement to counteract proinflammatory and pro-oxidative signals induced by both hyperglycemic and senescence conditions.
    Keywords:  T2DM; aging; hyperglycemia; natural compounds; oxidative stress
  18. Biogerontology. 2022 Jun 21.
      Over the past decade, extensive efforts have focused on understanding age-associated diseases and how to prolong a healthy lifespan. The induction of dietary protocols such as caloric restriction (CR) and protein restriction (PR) has positively affected a healthy lifespan. These intervention ideas (nutritional protocols) have been the subject of human cohort studies and clinical trials to evaluate their effectiveness in alleviating age-related diseases (such as type II diabetes, cardiovascular disease, obesity, and musculoskeletal fragility) and promoting human longevity. This study summarizes the literature on the nutritional protocols, emphasizing their impacts on bone and muscle biology. In addition, we analyzed several CR studies using Gene Expression Omnibus (GEO) database and identified common transcriptome changes to understand the signaling pathway involved in musculoskeletal tissue. We identified nine novel common genes, out of which five were upregulated (Emc3, Fam134b, Fbxo30, Pip5k1a, and Retsat), and four were downregulated (Gstm2, Per2, Fam78a, and Sel1l3) with CR in muscles. Gene Ontology enrichment analysis revealed that CR regulates several signaling pathways (e.g., circadian gene regulation and rhythm, energy reserve metabolic process, thermogenesis) involved in energy metabolism. In conclusion, this study summarizes the beneficiary role of CR and identifies novel genes and signaling pathways involved in musculoskeletal biology.
    Keywords:  Aging; Dietary Interventions; Healthy Aging; Musculoskeletal
  19. Mech Ageing Dev. 2022 Jun 18. pii: S0047-6374(22)00070-7. [Epub ahead of print] 111688
      Osteoarthritis (OA) is an age-related chronic degenerative disease, and chondrocyte senescence has been established to play an important role in the pathological process. There is ample evidence to suggest that lipid metabolism plays an important role in the aging process. However, the effect of lipid metabolism on chondrocyte senescence and OA remains unclear. Accordingly, we constructed a TBHP-induced senescent chondrocytes model and a destabilization of the medial meniscus (DMM) mouse model. We found that lipid accumulation and fatty acid oxidation were enhanced in senescent chondrocytes. Interestingly, carnitine palmitoyltransferase 1A (Cpt1a), the rate-limiting enzyme for fatty acid oxidation, was highly expressed in senescent chondrocytes and murine knee cartilage tissue. Suppressing Cpt1a expression using siRNA or Etomoxir, an inhibitor of Cpt1a, could attenuate oxidative stress-induced premature senescence and OA phenotype of primary murine chondrocytes, decrease cellular ROS levels, restore mitochondrial function, and maintain mitochondrial homeostasis via activating mitophagy. In vivo, pharmacological inhibition of Cpt1a by Etomoxir attenuated cartilage destruction, relieved joint space narrowing and osteophyte formation in the DMM mouse model. Overall, these findings suggested that knockdown of Cpt1a alleviated chondrocyte senescence by regulating mitochondrial dysfunction and promoting mitophagy, providing a new therapeutic strategy and target for OA treatment.
    Keywords:  CPT1A; Chondrocyte senescence; Fatty acid oxidation; Mitochondria; Mitophagy; Osteoarthritis
  20. Ageing Res Rev. 2022 Jun 17. pii: S1568-1637(22)00116-7. [Epub ahead of print]80 101674
      The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt β-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity. However, a precise understanding of the pancreatic β-cell response in ageing is still lacking. In this review, we summarize the age-related alterations, adaptations and/or failures of β-cells at the molecular, morphological and functional levels in mouse and human. Age-associated alterations include processes such as β-cell proliferation, apoptosis and cell identity that can influence β-cell mass. Age-related changes also affect β-cell function at distinct steps including electrical activity, Ca2+ signaling and insulin secretion, among others. We will consider the potential impact of these alterations and those mediated by senescence pathways on β-cells and their implications in age-related T2D. Finally, given the great diversity of results in the field of β-cell ageing, we will discuss the sources of this heterogeneity. A better understanding of β-cell biology during ageing, particularly at older ages, will improve our insight into the contribution of β-cells to age-associated T2D and may boost new therapeutic strategies.
    Keywords:  Ageing; Diabetes; Insulin secretion; Pancreatic beta-cell function; Pancreatic beta-cell mass; Senescence
  21. FASEB J. 2022 May;36 Suppl 1
      BACKGROUND: Alcohol-related liver disease (ALD) is a worldwide health problem without successful treatment. Aging is associate with obesity, which are known a risk factor that aggravate ALD. We and others have previously demonstrated that chronic plus binge alcohol increases adipose tissue lipolysis and promotes alcohol-induced liver injury through the adipose-liver crosstalk. In the present study, we investigated the role of autophagy receptor protein SQSTM1/p62 in adipose-liver crosstalk and the effects of aging and obesity in ALD.METHODS: Whole-body p62 knockout (KO) and their matched wild type young (2-3 months) and aged (13-15 months) mice were subjected to chronic plus binge (Gao-binge) alcohol model.  Adipose and liver tissues were collected for biochemical and histological analysis.
    RESULTS: p62 KO mice developed mature-onset obesity in aged mice with increased both white and brown adipose tissue mass. Gao-binge alcohol feeding decreased both the white and adipose mass regardless of the age and genotypes of mice. Alcohol feeding increased levels of serum free fatty acids regardless of the genotypes of the mice although the serum levels of glycerol only significantly increased in alcohol fed aged p62 KO mice. Alcohol feeding increased levels of serum ALT and hepatic triglyceride (TG) in both young and aged WT and p62 KO mice, but no significant differences were found among the young WT and p62 KO mice as well as aged WT vs young WT mice. However, alcohol-fed aged p62 KO mice had significantly higher levels of serum ALT and hepatic TG as well as fibrosis and inflammation markers than alcohol-fed aged WT mice. Mechanistically, aged p62 KO mice had increased de novo lipogenesis and senescence with increased senescence associated secretory phenotype with similar increased oxidative stress compared with matched WT mice.
    CONCLUSION: We established a genetic obesity/metabolic syndrome mouse model with alcohol consumption. Loss of p62 in aged mice leads to obesity with metabolic syndrome that exacerbates alcohol-induced liver injury via increased de novo lipogenesis and senescence.
  22. Neurol Neurochir Pol. 2022 Jun 23.
      Changes in the immune system associated with ageing are known as immunosenescence. This is characterised by a decline in immune response, chronic inflammation and an increased risk of autoimmune diseases. A chronic inflammatory process with persistent production of proinflammatory mediators increases the risk for morbidity and mortality related to age, and has been dubbed 'inflamm-ageing'. Immunosenescence is associated with a decrease in the number of naive T and B cells, NK cells and disruption of the pro- and anti-inflammatory balance by changes in the production of cytokines. In fact, ageing of the immune system has a complex network of underlying causes which include not only natural mechanisms of senescence but also chronic disorders, lifestyle, environmental and epigenetic factors, and infections. Moreover, immunosenescence has an influence on the course of chronic diseases which have an onset in young adults, such as multiple sclerosis (MS). Current disease modifying therapies (DMTs) in MS aim to reduce the frequency of relapses and to slow disease progression, but they do not necessarily stop the accumulation of disability related to disease progression. Some features of immunosenescence found in aged healthy controls are already observed in MS patients at a younger age. The older population is characterised by an increased susceptibility to infections, a poor response to vaccinations, and a higher risk of developing cancer, vascular diseases and neurodegeneration. Immunosenescence is an important factor influencing the course of MS, and the safety and effectiveness of DMTs. The relationship between the pathogenic process underlying the development of MS and immunosenescence requires further investigation.
    Keywords:  DMTs; immunosenescence; inflamm-ageing; multiple sclerosis
  23. Front Cardiovasc Med. 2022 ;9 910580
      Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Factors associated with the atherosclerotic process, including oxidative stress, inflammation, and calcium-regulating factors, are closely linked to senescence in VSMCs. A number of experimental studies using traditional cellular aging markers have suggested that anti-aging biochemical agents could be used to treat atherosclerosis. However, doubt has recently been cast on such potential due to the increasingly apparent complexity of VSMCs status and an incomplete understanding of the role that these cells play in the atherosclerosis process, as well as a lack of specific or spectrum-limited cellular aging markers. The utility of anti-aging drugs in atherosclerosis treatment should be reevaluated. Promotion of a healthy lifestyle, exploring in depth the characteristics of each cell type associated with atherosclerosis, including VSMCs, and development of targeted drug delivery systems will ensure efficacy whilst evaluation of the safety and tolerability of drug use should be key aims of future anti-atherosclerosis research. This review summarizes the characteristics of VSMC senescence during the atherosclerosis process, the factors regulating this process, as well as an overview of progress toward the development and application of anti-aging drugs.
    Keywords:  SASP; VSMCs; atheroscelorsis; senescence; sentherapeutic
  24. Int J Mol Sci. 2022 Jun 10. pii: 6538. [Epub ahead of print]23(12):
      The identification of compounds and natural ingredients that can counteract tissue stress and dysfunction induced by aging in skin cells is warranted. Here, we investigated the activity of the secretion from the snail Cryptomphalus aspersa (SCA®), an active compound with well-established beneficial effects on skin integrity and aging. To determinate its senescence-regulation mechanisms, we used a model where damage was induced by hydrogen peroxide (H2O2). The results showed that SCA® positively modulated factors involved in cell senescence such as β-galactosidase and cell morphology, secretory efficiency markers (SIRT1/6 and carboxymethyl-lysine), and metabolic and redox homeostasis (mTOR and ROS). This study demonstrated a novel compound that is activity-modulating, reduces cell senescence, and increases longevity to maintain skin homeostasis and functionality.
    Keywords:  Cryptomphalus aspersa secretion (SCA®); cell senescence; mTOR; metabolic homeostasis; skin aging
  25. Front Cell Dev Biol. 2022 ;10 902857
      Aging of mice can be tracked by DNA methylation changes at specific sites in the genome. In this study, we used the recently released Infinium Mouse Methylation BeadChip to compare such epigenetic modifications in C57BL/6 (B6) and DBA/2J (DBA) mice. We observed marked differences in age-associated DNA methylation in these commonly used inbred mouse strains, indicating that epigenetic clocks for one strain cannot be simply applied to other strains without further verification. In B6 mice age-associated hypomethylation prevailed with focused hypermethylation at CpG islands, whereas in DBA mice CpG islands revealed rather hypomethylation upon aging. Interestingly, the CpGs with highest age-correlation were still overlapping in B6 and DBA mice and included the genes Hsf4, Prima1, Aspa, and Wnt3a. Notably, Hsf4 and Prima1 were also top candidates in previous studies based on whole genome deep sequencing approaches. Furthermore, Hsf4, Aspa, and Wnt3a revealed highly significant age-associated DNA methylation in the homologous regions in human. Subsequently, we used pyrosequencing of the four relevant regions to establish a targeted epigenetic clock that provided very high correlation with chronological age in independent cohorts of B6 (R 2 = 0.98) and DBA (R 2 = 0.91). Taken together, the methylome differs extensively between B6 and DBA mice, while prominent age-associated changes are conserved among these strains and even in humans. Our new targeted epigenetic clock with 4 CpGs provides a versatile tool for other researchers analyzing aging in mice.
    Keywords:  aging; conserved; epigenetics; homology; human; methylation; mice; predictor
  26. J Intern Med. 2022 Jun 20.
      Numerous studies have shown that epigenetic age-an individual's degree of aging based on patterns of DNA methylation-can be computed and is associated with an array of factors including diet, lifestyle, genetics, and disease. One can expect that still further associations will emerge with additional aging research, but to what end? Prediction of age was an important first step, but-in our view-the focus must shift from chasing increasingly accurate age computations to understanding the links between the epigenome and the mechanisms and physiological changes of aging. Here, we outline emerging areas of epigenetic aging research that prioritize biological understanding and clinical application. First, we survey recent progress in epigenetic clocks, which are beginning to predict not only chronological age but aging outcomes such as all-cause mortality and onset of disease, or which integrate aging signals across multiple biological processes. Second, we discuss research that exemplifies how investigation of the epigenome is building a mechanistic theory of aging and informing clinical practice. Such examples include identifying methylation sites and the genes most strongly predictive of aging-a subset of which have shown strong potential as biomarkers of neurodegenerative disease and cancer; relating epigenetic clock predictions to hallmarks of aging; and using longitudinal studies of DNA methylation to characterize human disease, resulting in the discovery of epigenetic indications of type 1 diabetes and the propensity for psychotic experiences.
    Keywords:  CpG; aging; epigenetics; longevity; methylation
  27. Front Aging Neurosci. 2022 ;14 888292
      The concept of "aging" is defined as the set of gradual and progressive changes in an organism that leads to an increased risk of weakness, disease, and death. This process may occur at the cellular and organ level, as well as in the entire organism of any living being. During aging, there is a decrease in biological functions and in the ability to adapt to metabolic stress. General effects of aging include mitochondrial, cellular, and organic dysfunction, immune impairment or inflammaging, oxidative stress, cognitive and cardiovascular alterations, among others. Therefore, one of the main harmful consequences of aging is the development and progression of multiple diseases related to these processes, especially at the cardiovascular and central nervous system levels. Both cardiovascular and neurodegenerative pathologies are highly disabling and, in many cases, lethal. In this context, melatonin, an endogenous compound naturally synthesized not only by the pineal gland but also by many cell types, may have a key role in the modulation of multiple mechanisms associated with aging. Additionally, this indoleamine is also a therapeutic agent, which may be administered exogenously with a high degree of safety. For this reason, melatonin could become an attractive and low-cost alternative for slowing the processes of aging and its associated diseases, including cardiovascular and neurodegenerative disorders.
    Keywords:  aging; cardiovascular diseases; inflammation; melatonin; mitochondria; neurodegenerative disease; oxidative stress
  28. J Transl Med. 2022 Jun 21. 20(1): 278
      BACKGROUND: Adipose tissue homeostasis is at the heart of many metabolic syndromes such as diabetes. Previously it has been demonstrated that adipose tissues from diabetic patients are senescent but whether this contributes to diabetic cardiomyopathy (DCM) remains to be elucidated.METHODS: The streptozotocin (STZ) type 1 diabetic mice were established as animal model, and adult mouse ventricular myocytes (AMVMs) isolated by langendorff perfusion as well as neonatal mouse ventricular myocytes (NMVMs) were used as cell models. Senescent associated β galactosidase (SA-β-gal) staining and RT-qPCR were used to identify the presence of adipose senescence in diabetic adipose tissue. Senescent adipose were removed either by surgery or by senolytic treatment. Large extracellular vesicles (LEVs) derived from adipose tissue and circulation were separated by ultracentrifugation. Cardiac systolic and diastolic function was evaluated through cardiac ultrasound. Cardiomyocytes contraction function was evaluated by the Ionoptix HTS system and live cell imaging, mitochondrial morphology and functions were evaluated by transmission electron microscope, live cell fluorescent probe and seahorse analysis. RNA-seq for AMVMs and miRNA-seq for LEVs were performed, and bioinformatic analysis combined with RT-qPCR and Western blot were used to elucidate underlying mechanism that senescent adipose derives LEVs exacerbates myocardial metabolism.
    RESULTS: SA-β-gal staining and RT-qPCR identified the presence of adipose tissue senescence in STZ mice. Through surgical as well as pharmacological means we show that senescent adipose tissue participates in the pathogenesis of DCM in STZ mice by exacerbates myocardial metabolism through secretion of LEVs. Specifically, expression of miRNA-326-3p was up-regulated in LEVs isolated from senescent adipose tissue, circulation, and cardiomyocytes of STZ mice. Up-regulation of miRNA-326-3p coincided with myocardial transcriptomic changes in metabolism. Functionally, we demonstrate that miRNA-326-3p inhibited the expression of Rictor and resulted in impaired mitochondrial and contractile function in cardiomyocytes.
    CONCLUSION: We demonstrate for the first time that senescent adipose derived LEVs exacerbates myocardial metabolism through up-regulated miRNA-326-3p which inhibits Rictor in cardiomyocytes. Furthermore, reducing senescence burden in adipose tissue is capable of relieving myocardial metabolism disorder in diabetes mellitus.
    Keywords:  Adipose tissue; Cardiomyocytes; Diabetic cardiomyopathy; Extracellular vesicles; Senescence
  29. Genes (Basel). 2022 Jun 01. pii: 994. [Epub ahead of print]13(6):
      Cellular senescence (CS) is a major homeostatic biological process, which plays a key role in normal tissue development and provides protection from stressful cell insults. The role of CS in mammary-gland development and breast cancer is not well understood. While there is a lack of experimental data on the role of CS in the development of the pre-pubertal mammary gland, there is evidence for a biphasic senescence response in adult normal-mammary-epithelial cells, where the bypass of the first senescence barrier (M0) seems to be a key step in the development of premalignant lesions, with genetic abnormalities that resemble in situ breast carcinoma. Further, there is accumulating evidence for the role of cellular senescence in breast-cancer response, regarding treatment and patient outcome. Here, we review the current literature on cellular senescence, in epithelial-mammary cells, breast-cancer cells, and breast-tumor-microenvironment-resident cells. Furthermore, we discuss its putative role in breast-cancer response, regarding treatment and disease progression. In addition, we provide preliminary evidence of CS in breast-cancer-microenvironment cells, such as tumor-associated fibroblasts and tumor-infiltrating lymphocytes, by employing the novel GL13 lipofuscin stain, as a marker of cellular senescence.
    Keywords:  GL13; IHC; breast cancer; cellular senescence; chemotherapy; mammary gland
  30. Science. 2022 Jun 24. 376(6600): 1466-1470
      Is senescence inevitable and universal for all living organisms, as evolutionary theories predict? Although evidence generally supports this hypothesis, it has been proposed that certain species, such as turtles and tortoises, may exhibit slow or even negligible senescence-i.e., avoiding the increasing risk of death from gradual deterioration with age. In an extensive comparative study of turtles and tortoises living in zoos and aquariums, we show that ~75% of 52 species exhibit slow or negligible senescence. For ~80% of species, aging rates are lower than those in modern humans. We find that body weight positively relates to adult life expectancy in both sexes, and sexual size dimorphism explains sex differences in longevity. Unlike humans and other species, we show that turtles and tortoises may reduce senescence in response to improvements in environmental conditions.
  31. Front Immunol. 2022 ;13 901671
      Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role in shaping the tumor microenvironment through a comprehensive analysis of multiple datasets, including 2,072 ccRCC samples. Unsupervised consensus clustering identified three senescence subtypes, and we found that the senescence-activated subtype survived the worst, even in the condition of targeted therapy and immunotherapy. The activated senescence program was correlated to increased genomic instability, unbalanced PBMR1/BAP1 mutations, elevated immune cell infiltration, and enhanced immune inhibitory factors (cancer-associated fibroblasts, immune suppression, immune exclusion, and immune exhaustion signaling). A senescence score based on nine senescence-related genes (i.e., P3H1, PROX1, HJURP, HK3, CDKN1A, AR, VENTX, MAGOHB, and MAP2K6) was identified by adaptive lasso regression and showed robust prognostic predictive power in development and external validation cohorts. Notably, we found that the senescence score was correlated to immune suppression, and the low-score subgroup was predicted to respond to anti-PD-1 therapy, whereas the high-score subgroup was predicted to respond to Sunitinib/Everolimus treatment. Collectively, senescence acted as an active cancer hallmark of ccRCC, shaped the immune microenvironment, and profoundly affected tumor prognosis and drug treatment response.
    Keywords:  cellular senescence; immune checkpoint blockade; prognostic signature; targeted therapy; tumor microenvironment
  32. Stem Cell Reports. 2022 Jun 03. pii: S2213-6711(22)00269-7. [Epub ahead of print]
      Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein LIN28A remained existent in neural progenitor cells and granule neurons in the adult hippocampus and that it decreased with aging. Lin28a knockout inhibited the responsiveness of neural progenitor cells to niche Wnt agonists and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that LIN28A regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis and related cognitive functions.
    Keywords:  LIN28A; Wnt; adult neurogenesis; aging; hippocampus
  33. FEBS J. 2022 Jun 21.
      Obesity and aging predispose to numerous, yet overlapping chronic diseases. For example, metabolic abnormalities, including insulin resistance (IR) and type 2 diabetes (T2D) are important causes of morbidity and mortality. Low-grade chronic inflammation of tissues, such as the liver, visceral adipose tissue and neurological tissues, is considered a significant contributor to these chronic diseases. Thus, it is becoming increasingly important to understand what drives this inflammation in affected tissues. Recent evidence, especially in the context of obesity, suggests that the intestine plays an important role as the gatekeeper of inflammatory stimuli that ultimately fuel low-grade chronic tissue inflammation. In addition to metabolic diseases, abnormalities in the intestinal mucosal barrier have been linked to a range of other chronic inflammatory conditions, such as neurodegeneration and aging. The flow of inflammatory stimuli from the gut is in part controlled by local immunological inputs impacting the intestinal barrier. Here, we will review the impact of obesity and aging on the intestinal immune system and its downstream consequences on gut barrier function, which is strongly implicated in the pathogenesis of obesity and age-related diseases. In particular, we will discuss the effects of age-related intestinal dysfunction on neurodegenerative diseases.
    Keywords:  aging; barrier function; immune system; intestine; obesity
  34. Brain Sci. 2022 May 30. pii: 709. [Epub ahead of print]12(6):
      The microbiota-gut-brain axis has attracted significant attention with respect to studying the mechanisms of brain aging; however, the specific connection between gut microbiota and aging remains unclear. The abnormal expression and mutation of proteins belonging to the P4-ATPase family, including Atp11b, results in a variety of neurological diseases. The results of our analysis demonstrate that there was a shift in the abundance of certain gut microbiota in Atp11b-knockout (KO) mice. Specifically, there was an increase in pro-inflammatory bacteria that accelerate aging and a decrease in probiotics that delay aging. Consequently, an enhanced oxidative stress response was observed, which was characterized by a reduction in the superoxide dismutase (SOD) activity and an increase in malondialdehyde (MDA) and reactive oxygen species (ROS) levels. In addition, our data demonstrate that there was a decrease in the number of cells in the dentate gyrus (DG) region of the hippocampus, and aggravation of aging-related pathological features such as senescence β-galactosidase (SA-β-Gal), p-HistoneH2AX (Ser139), and p16INK4. Moreover, KO mice show typical aging-associated behavior, such as memory impairment and slow pain perception. Taken together, we demonstrate a possible mechanism of aging induced by gut microbiota in Atp11b-KO mice, which provides a novel perspective for the treatment of aging through the microbiota-gut-brain axis.
    Keywords:  Atp11b; aging pathology; brain aging; gut microbiota; microbiota-gut-brain axis