• Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J. Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab. 23(2):303-14. PubMed: 26686024. Categories: ApoptoSENS, MitoSENS

    Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

    Cell Metab. 23(2):303-14.

    Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

    Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J.

    Abstract

    Abstract:

    Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

  • Soland MA, Keyes LR, Bayne R, Moon J, Porada CD, St Jeor S, Almeida-Porada G. Perivascular stromal cells as a potential reservoir of human cytomegalovirus. Am J Transplant. 2014 Apr;14(4):820-30. doi: 10.1111/ajt.12642. Epub 2014 Mar 4 PubMed: 24592822. Categories: ApoptoSENS

    Perivascular stromal cells as a potential reservoir of human cytomegalovirus.

    Am J Transplant. 2014 Apr;14(4):820-30. doi: 10.1111/ajt.12642. Epub 2014 Mar 4

    Perivascular stromal cells as a potential reservoir of human cytomegalovirus.

    Soland MA, Keyes LR, Bayne R, Moon J, Porada CD, St Jeor S, Almeida-Porada G.

    Abstract

    Abstract:

    Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality among both solid organ and hematopoietic stem cell transplant recipients. Identification of cells throughout the body that can potentially serve as a viral reservoir is essential to dissect mechanisms of cell tropism and latency and to develop novel therapies. Here, we tested and compared the permissivity of liver-, brain-, lung (LNG)- and bone marrow (BM)-derived perivascular mesenchymal stromal cells (MSC) to HCMV infection and their ability to propagate and produce infectious virus. Perivascular MSC isolated from the different organs have in common the expression of CD146 and Stro-1. While all these cells were permissive to HCMV infection, the highest rate of HCMV infection was seen with LNG-MSC, as determined by viral copy number and production of viral particles by these cells. In addition, we showed that, although the supernatants from each of the HCMV-infected cultures contained infectious virus, the viral copy number and the quantity and timing of virus production varied among the various organ-specific MSC. Furthermore, using quantitative polymerase chain reaction, we were able to detect HCMV DNA in BM-MSC isolated from 7 out of 19 healthy, HCMV-seropositive adults, suggesting that BM-derived perivascular stromal cells may constitute an unrecognized natural HCMV reservoir.

  • Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol 2013;201(4):613-29. PubMed: 23649808. Categories: ApoptoSENS

    p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

    J Cell Biol 2013;201(4):613-29.

    p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

    Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J.

    Abstract

    Abstract:

    Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

  • Rebo J, Causey K, Zealley B, Webb T, Hamalainen M, Cook B, Schloendorn J. Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles. Rejuvenation Res. 2010 Apr-Jun;13(2-3):298-300. doi: 10.1089/rej.2009.0964. PubMed: 20426617. Categories: ApoptoSENS

    Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles.

    Rejuvenation Res. 2010 Apr-Jun;13(2-3):298-300. doi: 10.1089/rej.2009.0964.

    Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles.

    Rebo J, Causey K, Zealley B, Webb T, Hamalainen M, Cook B, Schloendorn J.

    Abstract

    Abstract:

    A major type of unwanted cells that accumulate in aging are anergic cytotoxic T cells. These cells often have virus-specific T cell receptors, as well as other surface markers that distinguish them from their youthful counterparts, and they are thought to play a major role in the decline of the immune system with age. Here we consider two surface markers thought to define these cells in mice, CD8 and Killer cell lectin-like receptor G1 (KLRG1), and a means we developed to remove these cells from the blood of aged C57BL/6 mice. Using antibodies with magnetic nanoparticles linked to their Fc domains, we first developed a method to use magnets to filter out the unwanted cells from the blood and later constructed a device that does this automatically. We demonstrated that this device could reduce the KLRG1-positive CD8 cell count in aged mouse blood by a factor of 7.3 relative to the total CD8 cell compartment, reaching a level typically seen only in very young animals.

  • de Grey ADNJ. Foreseeable pharmaceutical repair of age-related extracellular damage. Curr Drug Targets. 2006 Nov;7(11):1469-77. PubMed: 17100587. Categories: ApoptoSENS, GlycoSENS

    Foreseeable pharmaceutical repair of age-related extracellular damage.

    Curr Drug Targets. 2006 Nov;7(11):1469-77.

    Foreseeable pharmaceutical repair of age-related extracellular damage.

    de Grey ADNJ.

    Abstract

    Abstract:

    Various molecular and cellular alterations to our tissues accumulate throughout life as intrinsic side-effects of metabolism. These alterations are initially harmless, but some, which we may term "damage", are pathogenic when sufficiently abundant. The slowness of their accumulation explains why decline of tissue and organismal function generally does not appear until the age of 40 or older. Aging is thus best viewed as a two-part process in which metabolism causes accumulating damage and sufficiently abundant damage causes pathology. Hence, a promising approach to avoiding age-related pathology is periodically to repair the various types of damage and so maintain them at a sub-pathogenic level. Some examples of such types of damage are intracellular and others extracellular. Several types of intracellular damage are highly challenging--sophisticated cellular and genetic therapies will be needed to combat them, which are surely at least 20 years away and maybe much more. Extracellular damage, by contrast, generally appears more amenable to pharmaceutical repair which may be feasible in a shorter timeframe. In this article, the major types of age-related extracellular damage and promising avenues for their repair are reviewed.

  • de Grey ADNJ. Challenging but essential targets for genuine anti-ageing drugs. Expert Opin Ther Targets. 2003 Feb;7(1):1-5. PubMed: 12556198. Categories: ApoptoSENS, GlycoSENS, SENS Overviews

    Challenging but essential targets for genuine anti-ageing drugs.

    Expert Opin Ther Targets. 2003 Feb;7(1):1-5.

    Challenging but essential targets for genuine anti-ageing drugs.

    de Grey ADNJ.

    Abstract

    Abstract:

    Contrary to what one might conclude from the popular press, anti-ageing drugs do not yet exist, in the sense in which the term 'drug' is normally used. Since a drug is assumed to be effective against its target human pathology and since the vast majority of deaths in the developed world are from ageing-related causes, it is inappropriate to describe something as an anti-ageing drug unless one has good reason to believe that it will appreciably extend the life expectancy of those in the developed world who receive it. A drug that rejuvenates aspects of the aged body but does not increase life expectancy is an antifrailty drug, not an anti-ageing one. This distinction is critical for decision makers in the drug discovery sphere because, while the market for antifrailty drugs (even unproven ones) is large, that for genuine anti-ageing drugs - which, as the author explains, are now foreseeable - will certainly be far larger. In this article, the author surveys the main aspects of age-related degeneration that are believed to be essential targets for genuine anti-ageing drugs - that is, without whose amelioration human life expectancy probably cannot be greatly increased - and some promising strategies for the design of such drugs.