Aging (albany Ny)

Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders.

[1]  Joohwee Kim,et al.  COX‐2 inhibitor NS‐398 suppresses doxorubicin‐induced p53 accumulation through inhibition of ROS‐mediated Jnk activation , 2016, Molecular carcinogenesis.

[2]  G. López-Lluch,et al.  Anti-inflammatory effect of resveratrol in old mice liver , 2015, Experimental Gerontology.

[3]  Bingshu He,et al.  Chitooligosaccharides prevent osteopenia by promoting bone formation and suppressing bone resorption in ovariectomised rats: possible involvement of COX-2 , 2015, Natural product research.

[4]  Joohwee Kim,et al.  Prostaglandin F2α receptor (FP) signaling regulates Bmp signaling and promotes chondrocyte differentiation. , 2015, Biochimica et biophysica acta.

[5]  F. Westwood,et al.  Nonproliferative and Proliferative Lesions of the Rat and Mouse Female Reproductive System , 2014, Journal of toxicologic pathology.

[6]  T. Gansukh,et al.  Increase in cyclooxygenase‐2 (COX‐2) expression in keratinocytes and dermal fibroblasts in photoaged skin , 2014, Journal of cosmetic dermatology.

[7]  Laura C. Greaves,et al.  Chronic inflammation induces telomere dysfunction and accelerates ageing in mice , 2014, Nature Communications.

[8]  R. Effros,et al.  Prostaglandin E2 Promotes Features of Replicative Senescence in Chronically Activated Human CD8+ T Cells , 2014, PloS one.

[9]  S. Hakim,et al.  Comparative immunohistochemical assessment of cutaneous cyclooxygenase‐2 enzyme expression in chronological aging and photoaging , 2014, Photodermatology, photoimmunology & photomedicine.

[10]  Hyung Keun Kim,et al.  Down-regulation of oxidative stress and COX-2 and iNOS expressions by dimethyl lithospermate in aged rat kidney , 2014, Archives of Pharmacal Research.

[11]  C. Abbadie,et al.  Cellular senescence involves an intracrine prostaglandin E2 pathway in human fibroblasts. , 2013, Biochimica et biophysica acta.

[12]  L. Donehower,et al.  REGγ deficiency promotes premature aging via the casein kinase 1 pathway , 2013, Proceedings of the National Academy of Sciences.

[13]  K. Umezawa,et al.  Enhanced NF-κB Activity Impairs Vascular Function Through PARP-1–, SP-1–, and COX-2–Dependent Mechanisms in Type 2 Diabetes , 2013, Diabetes.

[14]  Pierre Validire,et al.  The cyclooxygenase-2-prostaglandin E2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts. , 2013, American journal of respiratory and critical care medicine.

[15]  B. Jang,et al.  Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells. , 2012, International journal of molecular medicine.

[16]  Ao-Lin Hsu,et al.  Celecoxib extends C. elegans lifespan via inhibition of insulin‐like signaling but not cyclooxygenase‐2 activity , 2011, Aging cell.

[17]  A. Seluanov,et al.  Establishing primary adult fibroblast cultures from rodents. , 2010, Journal of visualized experiments : JoVE.

[18]  Y. Mishina,et al.  Embryonic Expression of Cyclooxygenase-2 Causes Malformations in Axial Skeleton* , 2010, The Journal of Biological Chemistry.

[19]  Chih‐Chung Lin,et al.  Cigarette smoke extract induces COX-2 expression via a PKCalpha/c-Src/EGFR, PDGFR/PI3K/Akt/NF-kappaB pathway and p300 in tracheal smooth muscle cells. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[20]  S. Anton,et al.  Molecular inflammation: Underpinnings of aging and age-related diseases , 2009, Ageing Research Reviews.

[21]  M. McArthur,et al.  Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. , 2008, Neoplasia.

[22]  A. Lucci,et al.  Cyclooxygenase-2 induces genomic instability, BCL2 expression, doxorubicin resistance, and altered cancer-initiating cell phenotype in MCF7 breast cancer cells. , 2008, The Journal of surgical research.

[23]  M. Q. Kemp,et al.  Cyclooxygenase-2 Promoter Activation by the Aromatic Hydrocarbon Receptor in Breast Cancer MCF-7 Cells: Repressive Effects of Conjugated Linoleic Acid , 2007, Nutrition and cancer.

[24]  W. Fu,et al.  PPARgamma inhibits osteogenesis via the down-regulation of the expression of COX-2 and iNOS in rats. , 2007, Bone.

[25]  P. Hainaut,et al.  Cross‐talks between cyclooxygenase‐2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis , 2007, International journal of cancer.

[26]  C. Camargo,et al.  Increasing United States hospital admissions for acute pancreatitis, 1988-2003. , 2007, Annals of epidemiology.

[27]  F. Cipollone,et al.  COX-2 expression in atherosclerosis: the good, the bad or the ugly? , 2007, Current medicinal chemistry.

[28]  D. Harvey,et al.  Co-morbidity is a Strong Predictor of Early Death and Multi-organ System Failure among Patients with Acute Pancreatitis , 2007, Journal of Gastrointestinal Surgery.

[29]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[30]  G. Castellani,et al.  Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans , 2007, Mechanisms of Ageing and Development.

[31]  Raymond N DuBois,et al.  NSAIDs and cancer prevention: targets downstream of COX-2. , 2007, Annual review of medicine.

[32]  H. Majewski,et al.  Age-related changes in monocyte and platelet cyclooxygenase expression in healthy male humans and rats. , 2006, Translational research : the journal of laboratory and clinical medicine.

[33]  L. Boscá,et al.  Cyclooxygenase 2: understanding the pathophysiological role through genetically altered mouse models. , 2006, Frontiers in bioscience : a journal and virtual library.

[34]  A. Mancini,et al.  Prostaglandin E2 Stimulates p53 Transactivational Activity through Specific Serine 15 Phosphorylation in Human Synovial Fibroblasts , 2006, Journal of Biological Chemistry.

[35]  P. Kirkpatrick,et al.  Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis: Effects of Telomerase and Oxidative Stress , 2006, Circulation research.

[36]  M. Hansen,et al.  Overexpression of COX-2 in human osteosarcoma cells decreases proliferation and increases apoptosis. , 2006, Cancer research.

[37]  J. Campisi Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors , 2005, Cell.

[38]  Zaineb R Razak,et al.  Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate. , 2004, Carcinogenesis.

[39]  L. Minghetti Cyclooxygenase‐2 (COX‐2) in Inflammatory and Degenerative Brain Diseases , 2004, Journal of neuropathology and experimental neurology.

[40]  Ji Hyun Han,et al.  Selective COX-2 inhibitor, NS-398, inhibits the replicative senescence of cultured dermal fibroblasts , 2004, Mechanisms of Ageing and Development.

[41]  A. Melk,et al.  Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. , 2004, Kidney international.

[42]  P. Lacelle,et al.  Epidermal COX-2 induction following ultraviolet irradiation: suggested mechanism for the role of COX-2 inhibition in photoprotection. , 2003, The Journal of investigative dermatology.

[43]  J. Clària Cyclooxygenase-2 biology. , 2003, Current pharmaceutical design.

[44]  N. Santoro,et al.  Age-related decline in fertility. , 2003, Endocrinology and metabolism clinics of North America.

[45]  J. Campisi Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes , 2003, Experimental Gerontology.

[46]  S. Donell,et al.  The role of chondrocyte senescence in osteoarthritis , 2002, Aging cell.

[47]  E. Schwarz,et al.  Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. , 2002, The Journal of clinical investigation.

[48]  G. Pasinetti,et al.  Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. , 2002, The Journal of pharmacology and experimental therapeutics.

[49]  J. Hoeijmakers,et al.  Premature Aging in Mice Deficient in DNA Repair and Transcription , 2002, Science.

[50]  S. Welle Cellular and molecular basis of age-related sarcopenia. , 2002, Canadian journal of applied physiology = Revue canadienne de physiologie appliquee.

[51]  Stephen N. Jones,et al.  p53 mutant mice that display early ageing-associated phenotypes , 2002, Nature.

[52]  P. Worley,et al.  Age-Dependent Cognitive Deficits and Neuronal Apoptosis in Cyclooxygenase-2 Transgenic Mice , 2001, The Journal of Neuroscience.

[53]  C. Zouboulis,et al.  Chronological ageing and photoageing of the human sebaceous gland , 2001, Clinical and experimental dermatology.

[54]  H. Chung,et al.  Gene expression of cyclooxygenase in the aging heart. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[55]  James A. Clark,et al.  Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[56]  H. J. Kim,et al.  The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation. , 2000, Free radical biology & medicine.

[57]  P. Lipsky,et al.  Cyclooxygenase in biology and disease , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  S. Meydani,et al.  Enhanced expression of inducible cyclooxygenase with age in murine macrophages. , 1997, Journal of immunology.

[59]  S. Abramson,et al.  Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. , 1997, The Journal of clinical investigation.

[60]  J. L. Thompson,et al.  Acute Pancreatitis of Unknown Etiology in the Elderly , 1993, Annals of surgery.

[61]  G. Olivetti,et al.  [The aging of the heart: weight and structural changes in the left ventricle with age]. , 1991, Giornale italiano di cardiologia.

[62]  W. Jee,et al.  The role of prostaglandins in bone in vivo. , 1990, Prostaglandins, leukotrienes, and essential fatty acids.

[63]  D. Harrison,et al.  Biomarkers of aging: Tissue markers. Future research needs, strategies, directions and priorities , 1988, Experimental Gerontology.

[64]  B. Waller The old‐age heart: Normal aging changes which can produce or mimic cardiac disease , 1988, Clinical cardiology.

[65]  R. Marks,et al.  Tissue measurements in senile sebaceous gland hyperplasia , 1988, The British journal of dermatology.

[66]  L. Minghetti Role of COX-2 in inflammatory and degenerative brain diseases. , 2007, Sub-cellular biochemistry.

[67]  Zaineb R Razak,et al.  Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate. , 2004, Carcinogenesis.

[68]  R. Veerhuis,et al.  Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain , 2000, Acta Neuropathologica.

[69]  Gary A. Boorman,et al.  Pathology of the Mouse: Reference and Atlas , 1999 .