• age-related diseases
• aging
• alternative lengthening of telomere
• biomarkers
• cancer
• premature aging disorders
• telomerase reactivation
• telomere attrition
• therapeutics

• DNA methylation
• aging mechanisms
• cellular senescence
• epigenetic clock
• epigenetics
• healthspan extension
• senolytics

• Humans
• Epigenesis, Genetic/drug effects
• Aging/genetics
• Aging/metabolism
• Aging/drug effects
• Senotherapeutics/pharmacology
• DNA Methylation/drug effects
• Cellular Senescence/drug effects
• Cellular Senescence/genetics
• Animals

• Aging
• Autophagy
• Biomarker
• DAMP (damage-associated molecular pattern)
• DNA
• HMGB1 (high mobility group protein B1)
• Homeostasis
• Inflammation
• Redox
• Regeneration

• Humans
• HMGB1 Protein/metabolism
• Aging/metabolism
• Aging/genetics
• Homeostasis/physiology
• Animals

• SASP
• aging
• histone
• hmgs
• senescence

• DNA damage
• NAD+
• autophagy
• cardio-oncology
• fission and fusion
• mitochondrial dysfunction
• premature senescence
• telomere dysfunction

• R01 HL163857 NHLBI NIH HHS
• P30 CA016672 NCI NIH HHS
• R01 HL149303 NHLBI NIH HHS
• R01 HL134740 NHLBI NIH HHS
• U01 AI156921 NIAID NIH HHS
• R01 CA233610 NCI NIH HHS
• National Institutes of Health
• University of Texas MD Anderson Cancer Center

• cellular senescence
• monogenic diabetes
• pancreatic beta cells
• type 1 diabetes
• type 2 diabetes

• Female
• Male
• Humans
• Animals
• Mice
• Diabetes Mellitus, Type 2/therapy
• Diabetes Mellitus, Type 1
• Aging
• Cellular Senescence
• DNA Damage

• K08 DK132507 NIDDK NIH HHS
• P30 DK036836 NIDDK NIH HHS
• R01 DK132535 NIDDK NIH HHS

• SASP
• atherosclerosis
• cellular metabolism
• cellular senescence
• endothelial cells

• R01 HL134740 NHLBI NIH HHS
• R01 HL149303 NHLBI NIH HHS
• R01 HL157790 NHLBI NIH HHS
• R01 HL163857 NHLBI NIH HHS

• atherosclerosis
• disturbed flow
• endoMT
• senescence
• sumoylation

• R01 HL163857 NHLBI NIH HHS
• R01 HL166820 NHLBI NIH HHS
• U01 AI156921 NIAID NIH HHS

• Geroconversion
• Peroxynitrite
• Replication-stress
• Senescence
• Senolysis
• Superoxide

• Humans
• Chromosomal Proteins, Non-Histone/genetics
• Chromosomal Proteins, Non-Histone/metabolism
• Chromatin Assembly and Disassembly/genetics
• Neoplasms
• Chromatin
• Gene Expression

• Z01 ES071006 Intramural NIH HHS
• HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)

• cellular senescence
• chronic inflammation
• endothelial dysfunction
• inflamm-ageing
• vascular alterations

• Humans
• Vascular Diseases/metabolism
• Inflammation/metabolism
• Cellular Senescence

• Aging
• Cellular senescence
• Fibroblast
• Osteoarthritis
• Remodeling activation
• Remodeling-associated secretory phenotype (RASP)

• HIV
• SASP
• cancer
• senescence
• senolytic
• senostatic
• senotherapy

• Cancer
• Cellular senescence
• Cytokines
• Transforming growth factor

• Cellular Senescence/physiology
• Humans
• Neoplasms
• Receptors, Transforming Growth Factor beta/metabolism
• Signal Transduction/physiology
• Transforming Growth Factor beta/metabolism

• 2020/37/B/NZ5/00100 Narodowe Centrum Nauki

A newly developed UVC LED source with an emission wavelength of 233 nm was proved on bactericidal efficacy and skin tolerability. The bactericidal efficacy was qualitatively analysed using blood agar test. Subsequently, quantitative analyses were performed on germ carrier tests using the MRSA strain DSM11822, the MSSA strain DSM799, S. epidermidis DSM1798 with various soil loads. Additionally, the compatibility of the germicidal radiation doses on excised human skin and reconstructed human epidermis was proved. Cell viability, DNA damage and production of radicals were assessed in comparison to typical UVC radiation from discharge lamps (222 nm, 254 nm) and UVB (280–380 nm) radiation for clinical assessment. At a dose of 40 mJ/cm², the 233 nm light source reduced the viable microorganisms by a log₁₀ reduction (LR) of 5 log₁₀ levels if no soil load was present. Mucin and protein containing soil loads diminished the effect to an LR of 1.5–3.3. A salt solution representing artificial sweat (pH 8.4) had only minor effects on the reduction. The viability of the skin models was not reduced and the DNA damage was far below the damage evoked by 0.1 UVB minimal erythema dose, which can be regarded as safe. Furthermore, the induced damage vanished after 24 h. Irradiation on four consecutive days also did not evoke DNA damage. The radical formation was far lower than 20 min outdoor visible light would cause, which is classified as low radical load and can be compensated by the antioxidant defence system.

The treatment options for cancer include surgery, radiotherapy and chemotherapy. However, the traditional approach of high-dose chemotherapy brings tremendous toxic side effects to patients, as well as potentially causing drug resistance. Drug resistance affects cell proliferation, cell senescence and apoptosis. Cellular senescence refers to the process in which cells change from an active proliferative status to a growth-arrested status. There are multiple factors that regulate this process and cellular senescence is activated by various pathways. Senescent cells present specific characteristics, such as an increased cell volume, flattened cell body morphology, ceased cell division and the expression of β-galactosidase. Tumor senescence can be categorized into replicative senescence and premature senescence. Cellular senescence may inhibit the occurrence and development of tumors, serving as an innovative strategy for the treatment of cancer. The present review mainly focuses on senescent biomarkers, methods for the induction of cellular senescence and its possible application in the treatment of cancer.

• p53
• pRb. senescent biomarker
• treatment
• tumor cell senescence

• Oncology
• Prostate cancer

Cellular senescence is now recognized as one of the hallmarks of aging. Herein, we examine current findings on senescence of the vascular endothelium and its impacts on age-related vascular diseases. Endothelial senescence can result in systemic metabolic changes, implicating senescence in chronic diseases such as diabetes, obesity and atherosclerosis. Senolytics, drugs that eliminate senescent cells, afford new therapeutic strategies for control of these chronic diseases.

• age-related disease
• aging
• endothelium
• senescence
• vascular dysfunction

• Acute lung injury
• Acute respiratory distress syndrome
• Senescence

• Classification of states
• Markov chain
• Probability generating function
• Stationary distribution
• Telomere maintenance mechanisms
• Telomeres

• Amniochorion
• Cytokines
• EMT
• Exosome
• Fetal membranes
• Inflammation
• Mesenchymal cells
• Progesterone
• p38MAPK

• Immune system aging
• evolution
• human
• immune cells
• immunosenescence
• inflammaging
• senescent cells.

Colon cancer represents one of the most common cancers diagnosed in older adults worldwide. The standard of care in resected stage II and stage III colon cancer continues to evolve. While there is unequivocal evidence to suggest both disease free and overall survival benefits with the use of combination chemotherapy in patients with stage III colon cancer, data regarding its use in patients with stage II colon cancer are less clear. Further, although colon cancer is a disease that affects older adults, there is considerable debate on the value of adjuvant chemotherapy in the aging population. In particular, many older patients are undertreated when compared to their younger counterparts. In this review, we will describe the clinical trials that contributed to the current adjuvant chemotherapy approach in colon cancer, discuss representation of older adults in trials and the specific challenges associated with the management of this sub-population, and highlight the role of comprehensive geriatric assessments. We will also review how real-world evidence complements the data gaps from clinical trials of early stage colon cancer.

• Colon cancer
• Older adults
• Adjuvant chemotherapy
• Real-world evidence

• Anticancer target
• Lipid accumulation
• Lipid peroxidation
• Lipidomics
• Mitochondrial dysfunction
• Oxidative stress

• Apoptosis
• Chondrocytes
• Follistatin-like protein 1
• Osteoarthritis

Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy.

Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-β-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration.

Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort.

These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment.

This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovación y Universidades, Spain, Plan Estatal 2013–2016 and Fondo Europeo de Desarrollo Regional (FEDER), “Una manera de hacer Europa”, PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Economía y Competitividad, by grants of the National Instiutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank FOREUM Foundation for Research in Rheumatology for their support.

• Ageing
• Autophagy
• Osteoarthritis
• Screening
• Senescence
• Therapeutics

T cell “exhaustion” describes a state of late-stage differentiation usually associated with active prevention of functionality via ligation of negative signaling receptors on the cell surface, and which can be reversed by blocking these interactions. This contrasts with T cell “senescence,” which has been defined as a state that is maintained by intrinsic internal cell signaling (caused by DNA damage or other stresses) and which can be reversed pharmacologically. Interventions to alleviate these two different categories of inhibitory pathways may be desirable in immunotherapy for cancer and possibly certain infectious diseases, but reciprocally inducing and maintaining these states, or some properties thereof, may be beneficial in organ transplantation and autoimmunity. Even under physiological non-pathological conditions, T cell exhaustion and senescence may play a role in the retention of T cell clones required for immunosurveillance, and prevent their loss via elimination at the Hayflick limit. This essay briefly reviews T cell exhaustion in contrast to replicative senescence, and circumstances under which their modulation may be beneficial.

• Hayflick limit
• T cell exhaustion
• cancer immunity
• cancer immunotherapy
• cell senescence
• immunosurveillance
• organ transplantation

• aging
• chromatin
• epigenetics
• histone
• senescence

• Aging/physiology
• Cellular Senescence/physiology
• Epigenesis, Genetic
• Epigenomics
• Gene Expression Regulation
• Humans

• aging
• cancer
• cancer-associated fibroblasts
• cellular senescence
• modulation of protein synthesis
• senescence-associated secretory phenotype
• senolytic compounds
• stress-induced premature senescence

• cancer
• cellular degradation
• cellular robustness
• cooperation
• negligible senescence

• Age-related disease
• Cancer
• Extracellular matrix
• Fibrosis
• Senescence
• Tissue repair

• Genome stability
• Neoblasts
• Regeneration
• Self-renewal
• Stem cells
• Tumour suppressor

• Age
• Aging
• MicroRNA
• SASP
• Senescence
• p16
• p21
• p53

• Animals
• Biomarkers/metabolism
• Cellular Senescence/genetics
• Disease
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Models, Biological
• Signal Transduction/genetics

• Z01 AG000391 Intramural NIH HHS

• Aging
• C. elegans
• Drosophila
• Progeroid syndromes
• Yeast
• mTOR

• Aging/physiology
• Animals
• Disease Models, Animal
• Humans
• Models, Biological
• Signal Transduction/physiology

• breathing
• epidermis
• molecular
• pranayama
• skin aging
• yoga

Oxidative stress in skin plays a major role in the aging process. This is true for intrinsic aging and even more for extrinsic aging. Although the results are quite different in dermis and epidermis, extrinsic aging is driven to a large extent by oxidative stress caused by UV irradiation. In this review the overall effects of oxidative stress are discussed as well as the sources of ROS including the mitochondrial ETC, peroxisomal and ER localized proteins, the Fenton reaction, and such enzymes as cyclooxygenases, lipoxygenases, xanthine oxidases, and NADPH oxidases. Furthermore, the defense mechanisms against oxidative stress ranging from enzymes like superoxide dismutases, catalases, peroxiredoxins, and GSH peroxidases to organic compounds such as L-ascorbate, α-tocopherol, beta-carotene, uric acid, CoQ10, and glutathione are described in more detail. In addition the oxidative stress induced modifications caused to proteins, lipids and DNA are discussed. Finally age-related changes of the skin are also a topic of this review. They include a disruption of the epidermal calcium gradient in old skin with an accompanying change in the composition of the cornified envelope. This modified cornified envelope also leads to an altered anti-oxidative capacity and a reduced barrier function of the epidermis.

• Humans
• Oxidative Stress
• Skin/enzymology
• Skin/metabolism
• Skin/radiation effects
• Skin Aging

• Apoptosis
• Cartilage
• Chondrosenescence
• Hallmark
• Osteoarthritis

Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome (SAS) supports cell transformation, we asked whether SAS factor(s) would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pretransformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling of CMS-exposed pretransformed cells indicated a paracrine autoregulatory loop of SAS factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with and depended on MYC upregulation and massive changes in gene regulation. Senescent cell-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIP_L, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL-sensitizing effect on pretransformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) will not only provide a mechanistic insight into the acquisition of TRAIL sensitivity but may lead to novel concepts for apoptogenic therapies of premalignant and TRAIL-resistant tumors.

• Myc
• TRAIL
• apoptosis
• secretome
• senescence
• tumor

• Bioinformatics
• Cancer
• DNA damage pathway
• Growth arrest.
• Induced senescence
• Mortalin staining pattern
• p16INK4A
• shRNA screening

Eukaryotic initiation factor 5A (eIF5A), the only known cellular protein containing the amino acid hypusine, is an essential component of translation elongation. eIF5A2, one of the two isoforms in the eIF5A family, is reported to be a novel oncogenic protein in many types of human cancer. Both in vitro and in vivo studies showed that eIF5A2 could initiate tumor formation, enhance cancer cell growth, and increase cancer cell motility and metastasis by inducing epithelial-mesenchymal transition. Accumulatied evidence suggests that eIF5A2 is a useful biomarker in the prediction of cancer prognoses and serves as an anticancer molecular target. In this review, we will focus on updating current knowledge of the EIF5A2 gene in human cancers. The molecular mechanisms of EIF5A2 related to tumorigenesis will also be discussed.

• Cancer
• Epithelial-mesenchymal transition
• Eukaryotic initiation factor 5A2
• Metastasis.

Cellular senescence is an irreversible state of proliferation arrest evoked by a myriad of stresses including oncogene activation, telomere shortening/dysfunction and genotoxic insults. It has been associated with tumor activation, immune suppression and aging, owing to the secretion of proinflammatory mediators. The bacterial genotoxin colibactin, encoded by the pks genomic island is frequently harboured by Escherichia coli strains of the B2 phylogenetic group. Mammalian cells exposed to live pks+ bacteria exhibit DNA-double strand breaks (DSB) and undergo cell-cycle arrest and death. Here we show that cells that survive the acute bacterial infection with pks+ E. coli display hallmarks of cellular senescence: chronic DSB, prolonged cell-cycle arrest, enhanced senescence-associated β-galactosidase (SA-β-Gal) activity, expansion of promyelocytic leukemia nuclear foci and senescence-associated heterochromatin foci. This was accompanied by reactive oxygen species production and pro-inflammatory cytokines, chemokines and proteases secretion. These mediators were able to trigger DSB and enhanced SA-β-Gal activity in bystander recipient cells treated with conditioned medium from senescent cells. Furthermore, these senescent cells promoted the growth of human tumor cells. In conclusion, the present data demonstrated that the E. coli genotoxin colibactin induces cellular senescence and subsequently propel bystander genotoxic and oncogenic effects.

• Animals
• Cell Cycle Checkpoints
• Cell Line
• Cellular Senescence
• DNA Damage
• Epithelial Cells/microbiology
• Epithelial Cells/pathology
• Escherichia coli/physiology
• Escherichia coli Infections/genetics
• Escherichia coli Infections/metabolism
• Escherichia coli Infections/microbiology
• Escherichia coli Infections/pathology
• Fibroblasts/microbiology
• Fibroblasts/pathology
• Gene Expression Regulation
• Host-Pathogen Interactions
• Humans
• Peptides/genetics
• Peptides/metabolism
• Polyketides/metabolism
• Rats
• beta-Galactosidase/genetics

Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model.

An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of eIF-5A2 in aging.

Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p < 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice.

These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.