Judith Campisi

Buck Institute for Research on Aging, NOT, California, United States

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Publications (238)1910.43 Total impact

  • Science 09/2015; 349(6255):aaa5612-aaa5612. DOI:10.1126/science.aaa5612 · 33.61 Impact Factor
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    ABSTRACT: Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAF(V600E), the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAF(V600E)-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAF(V600E)-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.Oncogene advance online publication, 17 August 2015; doi:10.1038/onc.2015.282.
    Oncogene 08/2015; DOI:10.1038/onc.2015.282 · 8.46 Impact Factor
  • Michael C Velarde · Marco Demaria · Simon Melov · Judith Campisi
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    ABSTRACT: Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1)(20Efu/J) × Sod2(tm1Smel), that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.
    Proceedings of the National Academy of Sciences 08/2015; 112(33). DOI:10.1073/pnas.1505675112 · 9.67 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):1271-1271. DOI:10.1158/1538-7445.AM2015-1271 · 9.33 Impact Factor
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    ABSTRACT: The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
    Nature Cell Biology 07/2015; 17(8). DOI:10.1038/ncb3195 · 19.68 Impact Factor
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    ABSTRACT: Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic.
    Oncotarget 06/2015; 6(18). DOI:10.18632/oncotarget.4602 · 6.36 Impact Factor
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    ABSTRACT: DNA damage has been implicated in ageing, but direct evidence for a causal relationship is lacking, owing to the difficulty of inducing defined DNA lesions in cells and tissues without simultaneously damaging other biomolecules and cellular structures. Here we directly test whether highly toxic DNA double-strand breaks (DSBs) alone can drive an ageing phenotype using an adenovirus-based system based on tetracycline-controlled expression of the SacI restriction enzyme. We deliver the adenovirus to mice and compare molecular and cellular end points in the liver with normally aged animals. Treated, 3-month-old mice display many, but not all signs of normal liver ageing as early as 1 month after treatment, including ageing pathologies, markers of senescence, fused mitochondria and alterations in gene expression profiles. These results, showing that DSBs alone can cause distinct ageing phenotypes in mouse liver, provide new insights in the role of DNA damage as a driver of tissue ageing.
    Nature Communications 04/2015; 6:6790. DOI:10.1038/ncomms7790 · 11.47 Impact Factor
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    ABSTRACT: Human and mouse skin accumulate senescent cells in both the epidermis and dermis during aging. When chronically present, senescent cells are thought to enhance the age-dependent deterioration of the skin during extrinsic and intrinsic aging. However, when transiently present, senescent cells promote optimal wound healing. Here, we review recent studies on how senescent cells and the senescence-associated secretory phenotype contribute to different physiological and pathophysiological conditions in the skin with a focus on some of the cell autonomous and non-autonomous functions of senescent cells in the context of skin aging and wound healing.Journal of Investigative Dermatology advance online publication, 9 April 2015; doi:10.1038/jid.2015.108.
    Journal of Investigative Dermatology 04/2015; 135(7). DOI:10.1038/jid.2015.108 · 7.22 Impact Factor
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    Joana Neves · Marco Demaria · Judith Campisi · Heinrich Jasper
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    ABSTRACT: Studies in flies, mice, and human models have provided a conceptual framework for how paracrine interactions between damaged cells and the surrounding tissue control tissue repair. These studies have amassed evidence for an evolutionarily conserved secretory program that regulates tissue homeostasis. This program coordinates cell survival and proliferation during tissue regeneration and repair in young animals. By virtue of chronic engagement, however, it also contributes to the age-related decline of tissue homeostasis leading to degeneration, metabolic dysfunction, and cancer. Here, we review recent studies that shed light on the nature and regulation of this evolutionarily conserved secretory program. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 01/2015; 32(1). DOI:10.1016/j.devcel.2014.11.028 · 9.71 Impact Factor
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    ABSTRACT: Cellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the physiological role(s) of the complex senescent phenotype, we generated a mouse model in which senescent cells can be visualized and eliminated in living animals. We show that senescent fibroblasts and endothelial cells appear very early in response to a cutaneous wound, where they accelerate wound closure by inducing myofibroblast differentiation through the secretion of platelet-derived growth factor AA (PDGF-AA). In two mouse models, topical treatment of senescence-free wounds with recombinant PDGF-AA rescued the delayed wound closure and lack of myofibroblast differentiation. These findings define a beneficial role for the SASP in tissue repair and help to explain why the SASP evolved. Copyright © 2014 Elsevier Inc. All rights reserved.
    Developmental Cell 12/2014; 31(6). DOI:10.1016/j.devcel.2014.11.012 · 9.71 Impact Factor
  • Andreas Simm · Judith Campisi
    Experimental Gerontology 11/2014; 59. DOI:10.1016/j.exger.2014.11.015 · 3.49 Impact Factor
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    ABSTRACT: Mammalian aging can be delayed with genetic, dietary, and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand geroscience research directed at extending human healthspan.
    Cell 11/2014; 159(4). DOI:10.1016/j.cell.2014.10.039 · 32.24 Impact Factor
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    ABSTRACT: Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex 'senescence-associated secretory phenotype' (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest that both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain could therefore constitute novel therapeutic targets for treating age-related neuropathologies.
    Experimental Gerontology 10/2014; 68. DOI:10.1016/j.exger.2014.09.018 · 3.49 Impact Factor
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    ABSTRACT: In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.
    EMBO Reports 10/2014; 15(11). DOI:10.15252/embr.201439245 · 9.06 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):4603-4603. DOI:10.1158/1538-7445.AM2014-4603 · 9.33 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs), small non-coding RNAs, regulate gene expression primarily at the posttranscriptional level. We previously found that miR-335 is critically involved in the regulation and differentiation capacity of human mesenchymal stem cells (hMSCs) in vitro. In this study, we investigated the significance of miR-335 for the therapeutic potential of hMSCs. Analysis of hMSCs in ex vivo culture demonstrated a significant and progressive increase in miR-335 that is prevented by telomerase. Expression levels of miR-335 were also positively correlated with donor age of hMSCs, and were increased by stimuli that induce cell senescence, such as γ-irradiation and standard O2 concentration. Forced expression of miR-335 resulted in early senescence-like alterations in hMSCs, including: increased SA-β-gal activity and cell size, reduced cell proliferation capacity, augmented levels of p16 protein, and the development of a senescent-associated secretory phenotype (SASP). Furthermore, overexpression of miR-335 abolished the in vivo chondro-osseous potential of hMSCs, and disabled their immunomodulatory capacity in a murine experimental model of lethal endotoxemia. These effects were accompanied by a severely reduced capacity for cell migration in response to proinflammatory signals and a marked reduction in Protein Kinase D1 (PRKD1) phosphorylation, resulting in a pronounced decrease of AP-1 activity. Our results demonstrate that miR-335 plays a key role in the regulation of reparative activities of hMSCs and suggests that it might be considered a marker for the therapeutic potency of these cells in clinical applications. Stem Cells 2014
    Stem Cells 08/2014; 32(8). DOI:10.1002/stem.1699 · 6.52 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) possess unique paracrine and immunosuppressive properties, which make them useful candidates for cellular therapy. Here, we address how cellular senescence influences the therapeutic potential of human MSCs (hMSCs). Senescence was induced in bone marrow-derived hMSC cultures with gamma irradiation. Control and senescent cells were tested for their immunoregulatory activity in vitro and in vivo, and an extensive molecular characterization of the phenotypic changes induced by senescence was performed. We also compared the gene expression profiles of senescent hMSCs with a collection of hMSCs used in an ongoing clinical study of Graft Versus Host Disease (GVHD). Our results show that senescence induces extensive phenotypic changes in hMSCs and abrogates their protective activity in a murine model of LPS-induced lethal endotoxemia. Although senescent hMSCs retain an ability to regulate the inflammatory response on macrophages in vitro, and, in part retain their capacity to significantly inhibit lymphocyte proliferation, they have a severely impaired migratory capacity in response to proinflammatory signals, which is associated with an inhibition of the AP-1 pathway. Additionally, expression analysis identified PLEC, C8orf48, TRPC4, and ZNF14, as differentially regulated genes in senescent hMSCs that were similarly regulated in those hMSCs which failed to produce a therapeutic effect in a GVHD trial. All the observed phenotypic alterations were confirmed in replicative-senescent hMSCs. In conclusion, this study highlights important changes in the immunomodulatory phenotype of senescent hMSCs and provides candidate gene signatures which may be useful to evaluate the therapeutic potential of hMSCs used in future clinical studies. Stem Cells 2014.
    Stem Cells 07/2014; 32(7). DOI:10.1002/stem.1654 · 6.52 Impact Factor
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    Claudio Franceschi · Judith Campisi
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    ABSTRACT: Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as “inflammaging.” Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2014; 69 Suppl 1(supplement 1):S4-9. DOI:10.1093/gerona/glu057 · 5.42 Impact Factor
  • Judith Campisi · Ladislas Robert
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    ABSTRACT: Cell senescence is one of the major paradigms of aging research. It started with the demonstration by L. Hayflick of the limited number of divisions by normal, nontransformed cells, not shown by transformed malignant cells, this processes being largely regulated by the telomere-telomerase system. A complete renewal of this discipline came from the demonstration that cells can enter senescence at any time by an anti-oncogene-triggered pathway, enabling them to escape malignancy. The senescent cell became a major actor of the aging process, among others, by the acquisition of the senescence-associated secretory phenotype. This chapter is devoted to the regulatory process involved in the acquisition of the senescent cell phenotype and its role in organismal aging. © 2014 S. Karger AG, Basel.
    05/2014; 39:45-61. DOI:10.1159/000358899
  • Christopher Wiley · Judith Campisi
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    ABSTRACT: Loss of the coenzyme NAD+, which is required for many energy-dependent cellular processes, has emerged as a potentially unifying mechanism for age-related conditions. A study in this issue of The EMBO Journal identifies a novel link between depletion of NAD+ and age-associated loss of proliferating adult neural stem/progenitor cells in the murine brain (Stein & Imai,). These data have important implications for how brain function might decline with age. Age-associated loss of NAD+ or Nampt, the rate-limiting biosynthetic step for this coenzyme, accounts for the loss of neural stem/progenitor cells self-renewal and differentiation.
    The EMBO Journal 05/2014; 33(12). DOI:10.15252/embj.201488969 · 10.43 Impact Factor

Publication Stats

23k Citations
1,910.43 Total Impact Points


  • 2004–2015
    • Buck Institute for Research on Aging
      NOT, California, United States
  • 2001–2015
    • Lawrence Berkeley National Laboratory
      • Life Sciences Division
      Berkeley, California, United States
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 1992–2014
    • University of California, Berkeley
      • • Department of Molecular and Cell Biology
      • • Lawrence Berkeley Laboratory
      Berkeley, California, United States
  • 2007
    • University of North Carolina at Chapel Hill
      • Department of Radiation Oncology
      Chapel Hill, NC, United States
  • 2002
    • University of Washington Seattle
      • Department of Pathology
      Seattle, Washington, United States
  • 1990–1992
    • Boston University
      • Department of Biochemistry
      Boston, Massachusetts, United States
  • 1989–1991
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1986
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 1981–1985
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1982–1984
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States