• 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.

  • Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6. PubMed: 22048312. Categories: ApoptoSENS

    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

    Nature. 2011 Nov 2;479(7372):232-6.

    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

    Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM.

    Abstract

    Abstract:

    Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

  • Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011 Feb 21;192(4):547-56. PubMed: 21321098. Categories: ApoptoSENS, OncoSENS, RepleniSENS

    Four faces of cellular senescence.

    J Cell Biol. 2011 Feb 21;192(4):547-56.

    Four faces of cellular senescence.

    Rodier F, Campisi J.

    Abstract

    Abstract:

    Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

  • Naesens M. Replicative senescence in kidney aging, renal disease, and renal transplantation. Discov Med. 2011 Jan;11(56):65-75. PubMed: 21276412. Categories: ApoptoSENS

    Replicative senescence in kidney aging, renal disease, and renal transplantation.

    Discov Med. 2011 Jan;11(56):65-75.

    Replicative senescence in kidney aging, renal disease, and renal transplantation.

    Naesens M.

    Abstract

    Abstract:

    Cellular or replicative senescence is classically seen as the key element of aging. In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age. In this review, we summarize the current concepts in the molecular mechanisms of cellular senescence, and correlate these theories with the available literature on aging of native kidneys, kidney diseases, and outcome of renal allografts. Recent data illustrate the complex biology of senescence in vivo, and disprove the concept that senescence is an intrinsic injury process with immanent deleterious consequences. Senescence acts as a homeostatic mechanism that can even limit renal fibrosis, at least in animal studies. In a human setting, it remains to be investigated whether cellular senescence plays an active or a bystander role in fibrogenesis and atrophy of renal tissue.

  • 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.

  • Burton DG. Cellular senescence, ageing and disease. Age (Dordr). 2009 Mar;31(1):1-9. PubMed: 19234764. Categories: ApoptoSENS

    Cellular senescence, ageing and disease.

    Age (Dordr). 2009 Mar;31(1):1-9.

    Cellular senescence, ageing and disease.

    Burton DG.

    Abstract

    Abstract:

    Cellular senescence is the irreversible growth arrest of individual mitotic cells, which as a consequence display a radically altered phenotype that is thought to impair tissue function and predispose tissues to disease development and/or progression as they gradually accumulate. However, in the past, research into mechanisms of ageing has commonly been researched and treated separately from disease development. This may partly be due to the lack of understanding concerning mechanisms of ageing and the difficulty in implementing what was known into models of disease development. Only in the last 10 years, with increasing knowledge of the senescent phenotype and the ability to detect senescent cells in human tissues, have biologists been able to investigate the relationship between cellular senescence and disease. This review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/progression of disease.

  • 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.

  • Delarosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R. Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 2006;7(5-6):471-481. PubMed: 16957868. Categories: ApoptoSENS

    Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity.

    Biogerontology 2006;7(5-6):471-481.

    Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity.

    Delarosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R.

    Abstract

    Abstract:

    Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ''immune risk phenotype" (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

  • Lynch MD. How does cellular senescence prevent cancer? DNA Cell Biol 2006;25(2):69-78. PubMed: 16460230. Categories: ApoptoSENS

    How does cellular senescence prevent cancer?

    DNA Cell Biol 2006;25(2):69-78.

    How does cellular senescence prevent cancer?

    Lynch MD.

    Abstract

    Abstract:

    It is widely believed that cellular senescence is a tumor suppressor mechanism; however, it has not been understood why it is advantageous for organisms to retain mutant cells is a postmitotic state rather than simply eliminating them by apoptosis. It has recently been proposed that the primary role of cellular senescence is in mitotic compartments of fixed size in which spatial considerations dictate that a deleted cell is replaced by a neighboring cell. In these situations, rather than eliminating the neoplastic clone, deletion of mutant cells can paradoxically lead to their increased turnover. If mutant cells become senescent, then the compartment is instead progressively filled by senescent cells until the mutant clone is eliminated. Since most of the genetic alterations responsible for malignancy arise in stem cells, this mechanism may have particular relevance to the stem cell niche. In this article the implications of this hypothesis are examined in detail and related to experimental results. It is further proposed here that blockage of stem cell niches by senescent stem cells may account for some of the functional alterations observed in stem cell compartments at old age. Clearly, the existence of senescent stem cells is central to the proposed hypothesis, and although there is preliminary evidence for this assertion it has yet to be proven in vivo. An experimental strategy involving double labeling of stem cells with a nucleotide label is described that can address this question.

  • Wikby A, Nilsson BO, Forsey R, Thompson J, Strindhall J, Lofgren S, Ernerudh J, Pawelec G, Ferguson F, Johansson B. The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech Ageing Dev 2006;127(8):695-704. PubMed: 16750842. Categories: ApoptoSENS

    The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning.

    Mech Ageing Dev 2006;127(8):695-704.

    The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning.

    Wikby A, Nilsson BO, Forsey R, Thompson J, Strindhall J, Lofgren S, Ernerudh J, Pawelec G, Ferguson F, Johansson B.

    Abstract

    Abstract:

    In the present NONA immune longitudinal study, we further examine the previously identified T cell immune risk phenotype (IRP), relative inflammatory activity, morbidity and 2-year mortality in very old individuals >90 years. T-cell subsets as well as the inflammatory markers IL-6, IL-10, C-reactive protein, transthyretin and albumin were evaluated. IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells. The further characterisation of these exceptional individuals may allow insight into remedial approaches for those who remain in the IRP category until death.

  • Koch S, Solana R, Dela Rosa O, Pawelec G. Human cytomegalovirus infection and T cell immunosenescence: a mini review. Mech Ageing Dev 2006;127(6):538-543. PubMed: 16513159. Categories: ApoptoSENS

    Human cytomegalovirus infection and T cell immunosenescence: a mini review.

    Mech Ageing Dev 2006;127(6):538-543.

    Human cytomegalovirus infection and T cell immunosenescence: a mini review.

    Koch S, Solana R, Dela Rosa O, Pawelec G.

    Abstract

    Abstract:

    The mammalian immune system defends the organism against pathogens, and possibly cancer, but is known to become dysregulated with increasing age. This results in greater morbidity and mortality due to infectious disease in old people. The most important changes occur in T cell immunity, manifested sometimes dramatically as altered clonal expansions of cells of limited antigen specificity and a marked shrinkage of the T cell antigen receptor repertoire. At the same time, it was independently reported that CMV seropositivity was associated with many of the same T cell changes that were being identified as biomarkers of immune ageing. It has now become clear that CMV is commonly the driving force behind the oligoclonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. These changes are much less obvious in centenarians and most extreme in people whom longitudinal studies have shown to possess an "immune risk profile". This is a cluster of immunological parameters of which CMV seropositivity is one component and which predicts incipient mortality in an elderly population. Taken together, these findings suggest the hypothesis that persistence of CMV as a chronic antigenic stressor is a major contributor to immunosenescence and associated mortality.

  • Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB. Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol 2006;177(1):450-458. PubMed: 16785542. Categories: ApoptoSENS

    Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection.

    J Immunol 2006;177(1):450-458.

    Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection.

    Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB.

    Abstract

    Abstract:

    CMVs are beta herpesviruses that establish lifelong latent infection of their hosts. Acute infection of C57BL/6 mice with murine CMV elicits a very broad CD8 T cell response, comprising at least 24 epitopes from 18 viral proteins. In contrast, we show here that the CD8 T cell response in chronically infected mice was dominated by only five epitopes. Altogether, four distinct CD8 T cell kinetic patterns were evident. Responses to some epitopes, including M45, which dominates the acute response, contracted sharply after day 7 and developed into stable long-term memory. The response to m139 underwent rapid expansion and contraction, followed by a phase of memory inflation, whereas the response to an M38 epitope did not display any contraction phase. Finally, responses against two epitopes encoded by the immediate early gene IE3 were readily detectable in chronically infected mice but near the limit of detection during acute infection. CD8 T cells specific for the noninflationary M45 epitope displayed a classic central memory phenotype, re-expressing the lymph node homing receptor CD62L and homeostatic cytokine receptors for IL-7 and IL-15, and produced low levels of IL-2. Responses to two inflationary epitopes, m139 and IE3, retained an effector memory surface phenotype (CD62L(low), IL-7Ralpha(-), IL-15Rbeta(-)) and were unable to produce IL-2. We suggest that immunological choices are superimposed on altered viral gene expression profiles to determine immunodominance during chronic murine CMV infection.

  • Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, thor Straten P, Wikby A. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol 2006;176(4):2645-2653. PubMed: 16456027. Categories: ApoptoSENS

    Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly.

    J Immunol 2006;176(4):2645-2653.

    Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly.

    Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, thor Straten P, Wikby A.

    Abstract

    Abstract:

    The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.

  • Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science 2006;311(5765):1257. PubMed: 16456035. Categories: ApoptoSENS

    Cellular senescence in aging primates.

    Science 2006;311(5765):1257.

    Cellular senescence in aging primates.

    Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM.

    Abstract

    Abstract:

    The aging of organisms is characterized by a gradual functional decline of all organ systems. Mammalian somatic cells in culture display a limited proliferative life span, at the end of which they undergo an irreversible cell cycle arrest known as replicative senescence. Whether cellular senescence contributes to organismal aging has been controversial. We investigated telomere dysfunction, a recently discovered biomarker of cellular senescence, and found that the number of senescent fibroblasts increases exponentially in the skin of aging baboons, reaching >15% of all cells in very old individuals. In addition, the same cells contain activated ataxia-telangiectasia mutated kinase and heterochromatinized nuclei, confirming their senescent status.

  • McElhaney JE. The unmet need in the elderly: designing new influenza vaccines for older adults. Vaccine 2005;23(Suppl 1):S10-S25. PubMed: 15908062. Categories: ApoptoSENS

    The unmet need in the elderly: designing new influenza vaccines for older adults.

    Vaccine 2005;23(Suppl 1):S10-S25.

    The unmet need in the elderly: designing new influenza vaccines for older adults.

    McElhaney JE.

    Abstract

    Abstract:

    Influenza is a serious illness and probably the single most important cause of excess disability and mortality during the winter months. In spite of limited efficacy in older adults, influenza vaccination is nevertheless a cost-saving medical intervention since it does reduce hospitalisation and death rates due to pneumonia, exacerbations of heart failure and, surprisingly, heart attacks and strokes. Yet hospitalisation and death rates for acute respiratory illnesses continue to rise in spite of widespread vaccination programs. As a person ages, the immune response to antigenic stimulation with the influenza virus shifts toward T helper type 2 cytokine production. This is associated with a relative reduction in cytotoxic T-cell activity and a reduced capacity to destroy infected host cells and clear the virus from infected lung tissue. Breakthrough strategies to improve the current influenza vaccines are required to avoid a crisis in health care. A targeted approach will develop vaccines that can reverse these age-related changes in T-cell responses, particularly the functions of cytotoxic T lymphocytes.

  • Effros RB, Dagarag M, Spaulding C, Man J. The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 2005;205:147-157. PubMed: 15882351. Categories: ApoptoSENS

    The role of CD8+ T-cell replicative senescence in human aging.

    Immunol Rev 2005;205:147-157.

    The role of CD8+ T-cell replicative senescence in human aging.

    Effros RB, Dagarag M, Spaulding C, Man J.

    Abstract

    Abstract:

    The strict limit in proliferative potential of normal human somatic cells - a process known as replicative senescence - is highly relevant to the immune system, because clonal expansion is fundamental to adaptive immunity. CD8(+) T cells that undergo extensive rounds of antigen-driven proliferation in cell culture invariably reach the end stage of replicative senescence, characterized by irreversible cell-cycle arrest and a critically short telomere length. Cultures of senescent CD8(+) T cells also show resistance to apoptosis, permanent loss of CD28 expression, altered cytokine profiles, reduced ability to respond to stress, and various functional changes. Cells with similar characteristics accumulate during normal aging as well as in younger persons infected with human immunodeficiency virus, suggesting that the process of replicative senescence is not an artifact of cell culture but is also occurring in vivo. Interestingly, in elderly persons, the presence of high proportions of CD8(+) T cells with characteristics of replicative senescence is correlated with reduced antibody responses to vaccines as well as with osteoporotic fractures. CD8(+)CD28(-) T cells also accumulate in patients with certain types of cancer. The emerging picture is that senescent CD8(+) T cells may modulate both immune and non-immune functions, contributing not only to reduced anti-viral immunity but also to diverse age-related pathologies.

  • Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A. Human immunosenescence: is it infectious? Immunol Rev 2005;205:257-268. PubMed: 15882359. Categories: ApoptoSENS

    Human immunosenescence: is it infectious?

    Immunol Rev 2005;205:257-268.

    Human immunosenescence: is it infectious?

    Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A.

    Abstract

    Abstract:

    Morbidity and mortality due to infectious disease is greater in the elderly than in the young, at least partly because of age-associated decreased immune competence, which renders individuals more susceptible to pathogens. This susceptibility is particularly evident for novel infectious agents such as in severe acute respiratory syndrome but is also all too apparent for common pathogens such as influenza. Many years ago, it was noted that the elderly possessed oligoclonal expansions of T cells, especially of CD8(+) cells. At the same time, it was established that cytomegalovirus (CMV) seropositivity was associated with many of the same phenotypic and functional alterations to T-cell immunity that were being reported as biomarkers associated with aging. It was discovered that CMV was the prime driving force behind most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells. Independently, longitudinal studies of a free-living population of the very old in Sweden over the past decade have led to the emerging concept of an 'immune risk phenotype' (IRP), predicting mortality, which was itself found to be associated with CMV seropositivity. These findings support our hypothesis that the manner in which CMV and the host immune system interact is critical in determining the IRP and hence is predictive of mortality. In this sense, then, we suggest that immunosenescence is contagious.

  • Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, Salmon M, Rustin MH, Akbar AN. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 2005;175(12):8218-8225. PubMed: 16339561. Categories: ApoptoSENS

    Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion.

    J Immunol 2005;175(12):8218-8225.

    Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion.

    Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, Salmon M, Rustin MH, Akbar AN.

    Abstract

    Abstract:

    Repeated antigenic encounter drives proliferation and differentiation of memory T cell pools. An important question is whether certain specific T cells may be driven eventually to exhaustion in elderly individuals since the human life expectancy is increasing. We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors.

  • Wang SS, Brownell KD. Public policy and obesity: the need to marry science with advocacy. Psychiatr Clin North Am 2005;28(1):235-252. PubMed: 15733621. Categories: ApoptoSENS, Beyond the Bench

    Public policy and obesity: the need to marry science with advocacy.

    Psychiatr Clin North Am 2005;28(1):235-252.

    Public policy and obesity: the need to marry science with advocacy.

    Wang SS, Brownell KD.

    Abstract

    Abstract:

    No abstract available.

  • Khan N, Hislop A, Gudgeon N, Cobbold M, Khanna R, Nayak L, Rickinson AB, Moss PA. Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol 2004;173(12):7481-7489. PubMed: 15585874. Categories: ApoptoSENS

    Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection.

    J Immunol 2004;173(12):7481-7489.

    Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection.

    Khan N, Hislop A, Gudgeon N, Cobbold M, Khanna R, Nayak L, Rickinson AB, Moss PA.

    Abstract

    Abstract:

    Aging in humans is associated with increased infections and the reduced proliferative capacity of T cells, part of the more global phenomenon termed immune senescence. The etiology of immune senescence is unknown but the accumulation of virus-specific memory T cells may be a contributory factor. We have examined CD8 T cell responses to two persistent herpesvirus infections, CMV and EBV, and to a recurrent virus infection, influenza, in different age cohorts of healthy donors using HLA-peptide tetramers and intracellular cytokine detection. Of these, CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging.

  • Markert ML, Alexieff MJ, Li J, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA. Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood 2004;104(8):2574-2581. PubMed: 15100156. Categories: ApoptoSENS

    Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome.

    Blood 2004;104(8):2574-2581.

    Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome.

    Markert ML, Alexieff MJ, Li J, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA.

    Abstract

    Abstract:

    Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppression followed by postnatal thymus transplantation would lead to T-cell function in 6 infant patients who had host T cells at the time of transplantation. All infants had fewer than 50 recent thymic emigrants (CD3(+)CD45RA(+)CD62L(+)) per cubic millimeter (mm(3)) and all had some proliferative response to the mitogen phytohemagglutinin. Four infants had rash, lymphadenopathy, and oligoclonal populations of T cells in the periphery. Five of 6 patients are alive at the follow-up interval of 15 months to 30 months. The 5 surviving patients developed a mean of 983 host CD3(+) T cells/mm(3) (range, 536/mm(3)-1574/mm(3)), a mean of 437 recent thymic emigrants/mm(3) (range, 196/mm(3)-785/mm(3)), and normal proliferative responses to phytohemaglutinin (follow-up from day 376 to day 873). The TCR repertoire became polyclonal in patients who presented with oligoclonal T cells. All patients had thymopoiesis on allograft biopsy. Postnatal thymus transplantation after treatment with Thymoglobulin shows promise as therapy for infants with complete DiGeorge syndrome who have significant proliferative responses to mitogens or who develop rash, lymphadenopathy, and oligoclonal T cells.

  • Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, Mohammed BS. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med. 2004;350(25):2549-2557. PubMed: 15201411. Categories: ApoptoSENS

    Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease.

    N Engl J Med. 2004;350(25):2549-2557.

    Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease.

    Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, Mohammed BS.

    Abstract

    Abstract:

    BACKGROUND: Liposuction has been proposed as a potential treatment for the metabolic complications of obesity. We evaluated the effect of large-volume abdominal liposuction on metabolic risk factors for coronary heart disease in women with abdominal obesity. METHODS: We evaluated the insulin sensitivity of liver, skeletal muscle, and adipose tissue (with a euglycemic-hyperinsulinemic clamp procedure and isotope-tracer infusions) as well as levels of inflammatory mediators and other risk factors for coronary heart disease in 15 obese women before and 10 to 12 weeks after abdominal liposuction. Eight of the women had normal glucose tolerance (mean [+/-SD] body-mass index, 35.1+/-2.4), and seven had type 2 diabetes (body-mass index, 39.9+/-5.6). RESULTS: Liposuction decreased the volume of subcutaneous abdominal adipose tissue by 44 percent in the subjects with normal glucose tolerance and 28 percent in those with diabetes; those with normal oral glucose tolerance lost 9.1+/-3.7 kg of fat (18+/-3 percent decrease in total fat, P=0.002), and those with type 2 diabetes lost 10.5+/-3.3 kg of fat (19+/-2 percent decrease in total fat, P<0.001). Liposuction did not significantly alter the insulin sensitivity of muscle, liver, or adipose tissue (assessed by the stimulation of glucose disposal, the suppression of glucose production, and the suppression of lipolysis, respectively); did not significantly alter plasma concentrations of C-reactive protein, interleukin-6, tumor necrosis factor alpha, and adiponectin; and did not significantly affect other risk factors for coronary heart disease (blood pressure and plasma glucose, insulin, and lipid concentrations) in either group. CONCLUSIONS: Abdominal liposuction does not significantly improve obesity-associated metabolic abnormalities. Decreasing adipose tissue mass alone will not achieve the metabolic benefits of weight loss.

  • Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G. Dysfunctional CMV-specific CD8+ T cells accumulate in the elderly. Exp Gerontol 2004;39(4):607-613. PubMed: 15050296. Categories: ApoptoSENS

    Dysfunctional CMV-specific CD8+ T cells accumulate in the elderly.

    Exp Gerontol 2004;39(4):607-613.

    Dysfunctional CMV-specific CD8+ T cells accumulate in the elderly.

    Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G.

    Abstract

    Abstract:

    Large clonal expansions of peripheral CD8(+) T cells carrying receptors for single epitopes of CMV are common in the elderly and may be associated with an immune risk phenotype predicting mortality. To study the effect of ageing on the ability of CMV-specific CD8(+) T cells to produce type 1- and type 2-cytokines, interferon-gamma-and IL-10-producing, CD8(+) T cell responses in the presence of CMV peptide antigen were measured in CMV-seropositive old and young donors. We found that large expansions of A2/NLV-specific CD8(+) T lymphocytes in the elderly are accompanied by a partial loss of antigen responsiveness as reflected in a greatly decreased frequency of antigen-specific IFN-gamma-and IL-10-producing cells. Thus, despite carrying specific antigen receptors, the majority of the clonally expanded CMV-specific CD8(+) cells in the elderly was dysfunctional according to these criteria. Our data indicated a bias towards a more anti-inflammatory response in the elderly. The accumulation of dysfunctional CMV-specific cells might fill the 'immunological space' and decrease the available repertoire of T cells for novel antigens. This might account for the increased incidence of many infectious diseases in the elderly.

  • Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med 2004;200(12):1613-1622. PubMed: 15611289. Categories: ApoptoSENS

    Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses.

    J Exp Med 2004;200(12):1613-1622.

    Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses.

    Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L.

    Abstract

    Abstract:

    With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.

  • Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R, Unger RH. Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci USA 2004;101(7):2058-2063. PubMed: 14769942. Categories: ApoptoSENS

    Rapid transformation of white adipocytes into fat-oxidizing machines.

    Proc Natl Acad Sci USA 2004;101(7):2058-2063.

    Rapid transformation of white adipocytes into fat-oxidizing machines.

    Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R, Unger RH.

    Abstract

    Abstract:

    Adenovirus-induced hyperleptinemia rapidly depletes body fat in normal rats without increasing free fatty acids and ketogenesis, implying that fat-storing adipocytes are oxidizing the fat. To analyze the ultrastructural changes of adipocytes accompanying this functional transformation, we examined the fat tissue by electron microscopy. After 14 days of hyperleptinemia, adipocytes had become shrunken, fatless, and encased in a thick basement-membrane-like matrix. They were crowded with mitochondria that were much smaller than those of brown adipocytes. Their gene expression profile revealed striking up-regulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (an up-regulator of mitochondrial biogenesis not normally expressed in white fat), increased uncoupling proteins-1 and -2, and down-regulation of lipogenic enzymes. Phosphorylation of both acetyl CoA carboxylase and AMP-activated protein kinase was increased, thus explaining the increase in fatty acid oxidation. The ability to transform adipocytes into unique fat-burning cells may suggest novel therapeutic strategies for obesity.

  • Messaoudi I, Lemaoult J, Guevara-Patino JA, Metzner BM, Nikolich-Zugich J. Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J Exp Med 2004;200(10):1347-1358. PubMed: 15545358. Categories: ApoptoSENS

    Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense.

    J Exp Med 2004;200(10):1347-1358.

    Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense.

    Messaoudi I, Lemaoult J, Guevara-Patino JA, Metzner BM, Nikolich-Zugich J.

    Abstract

    Abstract:

    Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8+ T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results in reduced CD8+, but not CD4+, T cell diversity, and in functional inability to mobilize parts of the CD8+ T cell repertoire affected by TCE. In the model of herpes simplex virus (HSV)-1 infection of B6 mice, >90% of the responding CD8+ T cells use Vbeta10 or Vbeta8 and are directed against a single glycoprotein B (gB498-505) epitope, gB-8p. We found that old animals bearing CD8+ TCE within Vbeta10 or Vbeta8 families failed to mount an effective immune response against HSV-1, as judged by reduced numbers of peptide-major histocompatibility complex tetramer+ CD8 T cells and an absence of antiviral lytic function. Furthermore, Vbeta8 TCE experimentally introduced into young mice resulted in lower resistance to viral challenge, whereas Vbeta5+ TCE induced in a similar fashion did not impact viral resistance. These results demonstrate that age-related TCE functionally impair the efficacy of antiviral CD8+ T cell immunity in an antigen-specific manner, strongly suggesting that TCE are not the mere manifestation of, but are also a contributing factor to, the immunodeficiency of senescence.

  • 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.

  • Jonasson L, Tompa A, Wikby A. Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection. J Intern Med. 2003;254(5):472-478. PubMed: 14535969. Categories: ApoptoSENS

    Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection.

    J Intern Med. 2003;254(5):472-478.

    Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection.

    Jonasson L, Tompa A, Wikby A.

    Abstract

    Abstract:

    OBJECTIVES: The nature of the immune response in coronary artery disease (CAD) is not fully defined. One pathogen that has been linked to atherogenesis, cytomegalovirus (CMV), is known to exert strong and long-lasting effects on peripheral T cells. In the present study, we investigated the effect of prior CMV infection on the immune system in CAD patients. SUBJECTS: Patients with stable angina and angiographically verified CAD (n=43) and clinically healthy controls (n=69) were included. METHODS: The expression of CD57 and CD28 on peripheral CD4+ and CD8+ T cells was evaluated with three-colour flow cytometry. The findings were related to serological markers of inflammation, T-cell activation and CMV seropositivity. RESULTS: An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets. CONCLUSION: A pronounced shift in peripheral T-cell homeostasis was observed in CAD patients. Primarily CMV infection but also CAD per se contributed to the expansion of CD8+ T-cell subsets. The T-cell changes were not related to a systemic inflammatory response but should rather be considered as markers of a chronic antigen exposure and/or immunosenescence in CAD.

  • Karrer U, Sierro S, Wagner M, Hengel H, Koszinowski UH, Phillips RE, Klenerman P. Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J Immunol 2003;170(4):2022-2029. PubMed: 12574372. Categories: ApoptoSENS

    Memory inflation: continuous accumulation of antiviral CD8+ T cells over time.

    J Immunol 2003;170(4):2022-2029.

    Memory inflation: continuous accumulation of antiviral CD8+ T cells over time.

    Karrer U, Sierro S, Wagner M, Hengel H, Koszinowski UH, Phillips RE, Klenerman P.

    Abstract

    Abstract:

    CD8+ T lymphocytes play an important role in the control of intracellular pathogens during both acute and persistent infections. This is particularly true in the case of persistent herpesviruses such as human CMV, which are typified by large virus-specific CD8+ T cell populations during viral latency. To understand the origin of these populations and the factors shaping them over time, we investigated the CD8+ T cell response after murine CMV (MCMV) infection. The kinetics of the acute response were characterized by rapid expansion of activated T cells, followed by a contraction phase. Thereafter, we observed a striking pattern, where MCMV-specific memory CD8+ T cells steadily accumulated over time, with 20% of all CD8+ T cells at 1 year specific for one MCMV epitope. Accumulation of MCMV-specific CD8+ T lymphocytes was seen in all organs tested and was associated with continuous activation of specific CD8+ T lymphocytes, primarily within lymph nodes. The pattern of accumulation was observed in only two of five epitopes tested, and was accompanied by a gradual restriction in usage of the variable region of the TCR beta-chain over time. This novel pattern of a virus-specific CD8+ T cell response suggests that continuous or repetitive exposure to Ag can slowly mold memory T cell populations over time. This may be relevant for understanding the evolution of the large human CMV-specific CD8+ T cell populations seen in humans.

  • Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, Muller CA, Pircher H, Pawelec G. Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol 2003;38(8):911-920. PubMed: 12915213. Categories: ApoptoSENS

    Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1).

    Exp Gerontol 2003;38(8):911-920.

    Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1).

    Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, Muller CA, Pircher H, Pawelec G.

    Abstract

    Abstract:

    Large clonal expansions of peripheral CD8+ T cells carrying receptors for single epitopes of CMV and EBV are common in the elderly and may be associated with an immune risk phenotype predicting mortality. Here we show that the frequency of CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1), a marker of cells unable to undergo further clonal expansion, was markedly elevated in CD8+ T cells from old donors. Moreover, tetramer staining revealed that the elevated frequency of CMV-specific CD8+ T cells in the elderly was due to an accumulation of cells bearing this dominant negative receptor. The fraction of CMV-specific T cells able to secrete interferon-gamma after specific antigenic stimulation was significantly lower in the elderly than in the young, although the total number of functional cells was comparable. Therefore, the majority of the clonally expanded virus-specific CD8+ cells in the elderly was dysfunctional. Thus, T cell responses are altered in the aged by an accumulation of replicatively senescent dysfunctional T cells carrying receptors for persistent herpes viruses. The presence of clonal expansions of such virus-specific cells may shrink the available repertoire for other antigens and contribute to the increased incidence of infectious disease in the elderly.

  • Trzonkowski P, Mysliwska J, Szmit E, Wieckiewicz J, Lukaszuk K, Brydak LB, Machala M, Mysliwski A. Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. Vaccine 2003;21(25-26):3826-3836. PubMed: 12922116. Categories: ApoptoSENS

    Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence.

    Vaccine 2003;21(25-26):3826-3836.

    Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence.

    Trzonkowski P, Mysliwska J, Szmit E, Wieckiewicz J, Lukaszuk K, Brydak LB, Machala M, Mysliwski A.

    Abstract

    Abstract:

    We assessed association between prior cytomegalovirus (CMV) infection, proinflammatory status and effectiveness of the anti-influenza vaccination. We examined 154 individuals during the epidemic season dividing them according to the age, response to the vaccine and the Senieur Protocol (SP). The anti-hemagglutinins (HI), tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6, IL10, ACTH/cortisol axis, anti-CMV antibodies and CD28+CD57- lymphocytes were assessed. Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known to be associated with CMV carrier status) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol. The anti-influenza vaccine induced increase in TNFalpha and IL10 in the all non-responders, while cortisol increased only in the young. Concluding, CMV carrier status eliciting elevated proinflammatory potential could contribute to unresponsiveness to the anti-influenza vaccine.

  • Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 2002;169(4):1984-1992. PubMed: 12165524. Categories: ApoptoSENS

    Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals.

    J Immunol 2002;169(4):1984-1992.

    Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals.

    Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA.

    Abstract

    Abstract:

    The deterioration in immune function with aging is thought to make a major contribution to the increased morbidity and mortality from infectious disease in old age. One aspect of immune senescence is the reduction in CD8 T cell repertoire as due to the accumulation of oligoclonal, memory T cells and a reduction in the naive T cell pool. CD8 T cell clonal expansions accumulate with age, but their antigenic specificity remains unknown. In this study, we show that in elderly individuals seropositivity for human CMV leads to the development of oligoclonal populations of CMV-specific CTL that can constitute up to one-quarter of the total CD8 T cell population. Furthermore, CMV-specific CTL have a highly polarized membrane phenotype that is typical of effector memory cells (CD28(-), CD57(+), CCR7(-)). TCR analyses show that CMV-specific CTL have highly restricted clonality with greater restriction in the larger expansions. Clonal analysis of the total CD8 T cell repertoire was compared between CMV-seropositive and CMV-seronegative donors. Thirty-three percent more clonal expansions were observed in CMV-seropositive donors in comparison with seronegative individuals. These data implicate CMV as a major factor in driving oligoclonal expansions in old age. Such a dramatic accumulation of virus-specific effector CTL might impair the ability to respond to heterologous infection and may underlie the negative influence of CMV seropositivity on survival in the very elderly.

  • Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 2000;121(1-3):187-201. PubMed: 11164473. Categories: ApoptoSENS

    Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study.

    Mech Ageing Dev 2000;121(1-3):187-201.

    Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study.

    Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG.

    Abstract

    Abstract:

    Results from the previous times (Times 1-3) of the Swedish longitudinal OCTO immune study indicated that a combination of high CD8 and low CD4 percentages and poor T-cell proliferation in PBL was associated with a higher 2-year mortality in a sample of very old Swedish individuals. The combination of immune parameters was closely related to an inverted CD4/CD8 ratio. In the present study at Time 4 (T4) results are reported from the final follow-up of this longitudinal study, 8 years after it was initiated in 1989. An additional goal at this time point was to examine the immune system alterations in the very old in relation to evidence of lymphocyte activation and cytomegalovirus antibody status. In the present study immune system changes were identified that suggest a loss of T-cell homeostasis, as reflected by a decrease in the number of CD4 cells and a very significant increase in the number of CD8 cells in individuals with an inverted CD4/CD8 ratio. When considered over the duration of the OCTO study the inversion occurred in a high percentage (32%) of the individuals included in the original sample and was associated with non-survival. At T4 the changes were apparent in a number of the T-cell subsets, but particularly in the CD8+CD28-and CD57+ subsets. T-cell activation was significantly associated with the inversion of the CD4/CD8 ratio. In this very old sample the subset alterations were associated with evidence of cytomegalovirus (CMV) infection.

  • Wei W, Sedivy JM. Differentiation between senescence (M1) and crisis (M2) in human fibroblast cultures. Exp Cell Res 1999;253(2):519-522. PubMed: 10585275. Categories: ApoptoSENS

    Differentiation between senescence (M1) and crisis (M2) in human fibroblast cultures.

    Exp Cell Res 1999;253(2):519-522.

    Differentiation between senescence (M1) and crisis (M2) in human fibroblast cultures.

    Wei W, Sedivy JM.

    Abstract

    Abstract:

    Normal human fibroblasts undergo only a limited number of divisions in culture and eventually enter a nonreplicative state designated senescence or mortality stage 1 (M1). Expression of certain viral oncogenes, such as the SV40 large T antigen (SV40 T-Ag), can elicit a significant extension of replicative life span, but these cultures eventually also cease dividing. This proliferative decline has been designated crisis or mortality stage 2 (M2). BrdU incorporation assays are commonly used to distinguish between senescence (<5% labeling index) and crisis (>30% labeling index). It has not been possible, however, to ascertain whether the high labeling index, indicative of ongoing DNA replication, was caused by the presence of T-Ag. We used gene targeting to knock out both copies of the p21(CIP1/WAF1) gene in presenescent human fibroblasts. p21 -/- cells displayed an extended life span but eventually entered a nonproliferative state. In their terminally nonproliferative state both p21 +/+ and p21 -/- cultures were positive for the senescence-associated beta-galactosidase (SA-beta-gal) activity; in contrast, the labeling index of p21 +/+ cells was low (<5%) whereas the labeling index of p21 -/- cells was high (>30%). The observation that p21 -/- and SV40 T-Ag-expressing cells behave identically with respect to life span extension as well as the high labeling index in the terminally nonproliferative state indicates that crisis is not a phenomenon induced solely by viral oncogenes, but a physiological state resulting from the bypass of normal senescence mechanisms. The widely used biomarker for senescence, SA-beta-gal, cannot distinguish between senescence and crisis. We propose that all SA-beta-gal-positive cultures should be further examined for their BrdU labeling index.

  • Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J Clin Invest 1998;101(7):1353-1361. PubMed: 9525977. Categories: ApoptoSENS

    Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.

    J Clin Invest 1998;101(7):1353-1361.

    Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.

    Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L.

    Abstract

    Abstract:

    Hyperinsulinemia and increased visceral/abdominal fat (VF) are common features of human aging. To examine the relationships among VF, peripheral, and hepatic insulin sensitivity, we studied 4- and 18-mo-old male Sprague-Dawley rats (n = 42) fed ad libitum (4 AL and 18 AL) or moderately calorie restricted (18 CR) up to 18 mo of age. Total fat mass (FM) and VF were decreased in 18 CR to approximately one-third of that of 18 AL (P < 0.001), while lean body mass (LBM) was unchanged. Most important, 18 CR had more FM (65+/-6 vs. 45+/-6 g) but less VF (7.8+/-0.6 vs. 12.3+/-3.3 g) compared with 4 AL (P < 0.01 for both). Thus, the effects of variable VF on HIS could be assessed, independent of FM and age. Marked hepatic insulin resistance ensued with aging (18 AL) and CR restored hepatic insulin sensitivity to the levels of young rats, while peripheral insulin sensitivity remained unchanged (by insulin clamp of 18 mU/kg/min). In fact, the rates of insulin infusion required to maintain basal hepatic glucose production in the presence of pancreatic clamp were 0.75+/-0.10, 1.41+/-0.13, and 0.51+/-0.12 mU/kg . min, in 4 AL, 18 AL, and 18 CR, respectively (P < 0.01 between all groups), and in 18 CR rats infused with insulin at similar rates as in the 18 AL (1.4 mU/kg/min) hepatic glucose production was decreased by 32% (P < 0. 005). Furthermore, when 18 CR rats were fed AL for 14 d, VF rapidly and selectively increased and severe hepatic insulin resistance was induced. We propose that in this animal model the age-associated decrease in hepatic (rather than peripheral) insulin action is the major determinant of fasting hyperinsulinemia and that increased visceral adiposity plays the major role in inducing hepatic insulin resistance. Thus, interventions designed to prevent the accumulation of VF are likely to represent an effective mean to improve carbohydrate metabolism in aging.

  • Westerterp-Plantenga MS, Saris WH, Hukshorn CJ, Campfield LA. er JR, Pan J, Cheung Y, Zhang DK, Liu Y, Wong SC, Wan TS, Tsao SW. Expression profile of senescence-associated beta-galactosidase and activation of telomerase in human ovarian surface epithelial cells undergoing immortalization. Int J Oncol 1998;13(5):951-956. PubMed: 9772284. Categories: ApoptoSENS

    Expression profile of senescence-associated beta-galactosidase and activation of telomerase in human ovarian surface epithelial cells undergoing immortalization.

    Int J Oncol 1998;13(5):951-956.

    Expression profile of senescence-associated beta-galactosidase and activation of telomerase in human ovarian surface epithelial cells undergoing immortalization.

    Westerterp-Plantenga MS, Saris WH, Hukshorn CJ, Campfield LA. er JR, Pan J, Cheung Y, Zhang DK, Liu Y, Wong SC, Wan TS, Tsao SW.

    Abstract

    Abstract:

    Senescence is a specific physiological stage of cells characterized by long population doubling time. It accounts for the inability of normal somatic cells to undergo indefinite cell division. As the number of population doublings increase, cell cycle regulatory mechanisms come into play and signal cells to exit the cell cycle and become senescent. Senescence has been implicated in the aging process and may function as a tumor suppressor mechanism in human cells. The ability to measure the degree of cellular senescence is important in understanding the biological processes regulating cell aging and immortalization. Senescent cells exhibit an enzyme termed senescence-associated histochemical staining. Cells immortalized by viral oncogenes often enter a stage of crisis at the early phase of immortalization. The cells at crisis have a long population doubling time. Cells at the crisis stage resemble senescent cells and the expression of SA- beta-Gal may be used to monitor the process of immortalization. In this study the expression profile of SA-beta-Gal was examined in human ovarian surface epithelial cells (HOSE 6-3) undergoing immortalization by the human papilloma viral oncogene E6 and E7 (HPV E6 and E7). Our results showed a low percentage (12.0%) of HOSE 6-3 cells expressing SA-beta-Gal activity at the pre-crisis stage. The percentage of HOSE 6-3 cells expressing SA-beta-Gal activity was highest (39.2%) at the crisis stage. When HOSE 6-3 cells achieved immortalized status there was a sharp decrease in cells (1. 3%) expressing SA-beta-Gal activity. In addition, an inverse relationship between the expression of SA-beta-Gal activity and telomerase activity was noted in cells undergoing immortalization. The results confirm that the SA-beta-Gal enzyme is a good marker for monitoring the population of cells undergoing senescence at different stages of immortalization and that telomerase activation is a characteristic feature of post-crisis cells.

  • Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O'Doherty R, Newgard CB, Unger RH. Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci USA 1996;93(25):14795-14799. PubMed: 8962134. Categories: ApoptoSENS

    Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy.

    Proc Natl Acad Sci USA 1996;93(25):14795-14799.

    Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy.

    Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O'Doherty R, Newgard CB, Unger RH.

    Abstract

    Abstract:

    Sustained hyperleptinemia of 8 ng/ml was induced for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin). Hyperleptinemic rats exhibited a 30-50% reduction in food intake and gained only 22 g over the experimental period versus 115-132 g in control animals that received saline infusions or a recombinant virus containing the beta-galactosidase gene (AdCMV-beta Gal). Body fat was absent in hyperleptinemic rats, whereas control rats pair-fed to the hyperleptinemic rats retained approximately 50% body fat. Further, plasma triglycerides and insulin levels were significantly lower in hyperleptinemic versus pair-fed controls, while fatty acid and glucose levels were similar in the two groups, suggestive of enhanced insulin sensitivity in the hyperleptinemic animals. Thus, despite equivalent reductions in food intake and weight gain in hyperleptinemic and pair-fed animals, identifiable fat tissue was completely ablated only in the former group, raising the possibility of a specific lipoatrophic activity for leptin.

  • Yang X, Stedra J, Cerny J. Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice. J Exp Med 1996;183(3):959-970. PubMed: 8642299. Categories: ApoptoSENS

    Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice.

    J Exp Med 1996;183(3):959-970.

    Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice.

    Yang X, Stedra J, Cerny J.

    Abstract

    Abstract:

    The immune system of aged individuals often produces antibodies that have lower affinity and are less protective than antibodies from young individuals. Recent studies in mice suggested that antibodies produced by old individuals may be encoded by distinct immunoglobulin (Ig) genes and that the somatic hypermutation process in these individuals is compromised. The present study employed Ighb scid mice reconstituted with normal lymphocytes from young (2-3-mo-old) and aged (20-25-mo-old) donors and immunized with a protein conjugate of the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) to determine whether the molecular changes in antibody repertoire reflect senescence in the B cells or whether they are mediated by the aging helper T lymphocytes. The NP-reactive B cells from splenic germinal centers (GC) were recovered by microdissection of frozen tissue sections and their rearranged Ig heavy chain variable region (VH) genes of the V186.2/V3 families were sequenced. It was found that the VH gene repertoire of the GC B cells was strongly influenced by the source of the CD4+ T cells. When T cells were donated by young mice, the anti-NP response in GC was dominated by the canonical V186.2 gene, even if the responder B cells came from aged donors. However, when the mice were reconstituted with T cells from aged donors, the expression of the V186.2 gene by young B cells was diminished and the response was dominated by the C1H4 gene, another member of the V186.2/V3 family. In contrast, the somatic hypermutation process in the GC B cells followed a different pattern. The mutation frequencies in the animals that were reconstituted with both B and T cells from young donors (1/50 to 1/150 bp) were comparable to the frequencies previously reported for NP-immunized intact young/adult mice. However, when either lymphocyte subset was donated by the aged mice, the mutation frequencies declined. Thus, mice reconstituted with T cells from the aged and B cells from the young had severely compromised mutational mechanism. Likewise, the recipients of aged B and young T cells had diminished mutations even though the repertoire of their anti-NP response was dominated by the canonical V186.2 gene. It appears that the change in germine-encoded repertoire and the decrease of somatic hypermutation represent distinct mechanisms of immunosenescence and that the aging of helper T cells plays a pivotal role in both of these processes.

  • Cefalu WT, Wang ZQ, Werbel S, Bell-Farrow A, Crouse JR 3rd, Hinson WH, Terry JG, Anderson R. Contribution of visceral fat mass to the insulin resistance of aging. Metabolism 1995;44(7):954-959. PubMed: 7616857. Categories: ApoptoSENS

    Contribution of visceral fat mass to the insulin resistance of aging.

    Metabolism 1995;44(7):954-959.

    Contribution of visceral fat mass to the insulin resistance of aging.

    Cefalu WT, Wang ZQ, Werbel S, Bell-Farrow A, Crouse JR 3rd, Hinson WH, Terry JG, Anderson R.

    Abstract

    Abstract:

    Recent studies have shown that central obesity (increased waist to hip ratio [WHR]) is related to insulin resistance and aging. Furthermore, in central-obesity states, the intraabdominal fat (IAF) depot has been postulated to contribute most to the development of insulin resistance. Therefore, the observed insulin resistance of aging may be related more to changes in body composition than to aging per se. The purpose of this study was to explore the association of IAF with age and insulin sensitivity (SI) after controlling for obesity. We examined 60 healthy nondiabetic subjects (normal 75-g oral glucose tolerance test, aged 23 to 83, 15 men and 45 women). We chose subjects so that those < or = 125% and greater than 125% of ideal body weight were equally represented in each age decade. We quantified total and subcutaneous abdominal fat and IAF at the umbilicus using a validated magnetic resonance imaging (MRI) scanning technique and determined SI using a modified minimal model. IAF correlated significantly with age (r = .49, P = .0001) in the group as a whole, as well as in men (r = .58, P = .022) and women (r = .48, P = .0008) separately. In all subjects, SI was significantly related to IAF (r = -.50, P < .0001) but was not related to age (r = .00, P = .98). In multivariate analysis for various combinations of age, sex, and measures of fat distribution, WHR accounted for 28% and IAF for 51% of the variance in SI, whereas age, sex, and interactions of age and sex accounted for only 1%.

  • McVoy MA, Adler SP. Immunologic evidence for frequent age-related cytomegalovirus reactivation in seropositive immunocompetent individuals. J Infect Dis 1989;160(1):1-10. PubMed: 2543705. Categories: ApoptoSENS

    Immunologic evidence for frequent age-related cytomegalovirus reactivation in seropositive immunocompetent individuals.

    J Infect Dis 1989;160(1):1-10.

    Immunologic evidence for frequent age-related cytomegalovirus reactivation in seropositive immunocompetent individuals.

    McVoy MA, Adler SP.

    Abstract

    Abstract:

    Immunoblot analysis using mouse monoclonal antibody to human IgM detected IgM to cytomegalovirus (CMV)-specific proteins (150, 42, 38, 32, and 28 kDa) in 74 (38%) of 197 seropositive serum samples from 197 individuals in three subject groups: 43 surgical patients, 31 patients with solid tumors, and 123 healthy individuals. Logistic regression analysis revealed that the presence of IgM to CMV proteins was not associated with a specific subject group but was associated with age (P less than .0001), gender (P less than .005), and IgG titer (P less than .03). The rate of IgM positivity increased from 15% (8 of 54) for those less than 20 y to 63% (37 of 59) for those greater than 60 y. Twenty-three (29%) of 80 males were IgM-positive compared with 49 (44%) of 111 females. Immunoglobulin G titers to CMV were significantly associated with age, gender, and IgM positivity. These data suggest that CMV reactivation in immunocompetent seropositive individuals may occur frequently and increase with age.