Are aging biomarkers clinically relevant in oncogeriatrics?

https://doi.org/10.1016/j.critrevonc.2012.08.004Get rights and content

Abstract

Immunosenescence and inflammaging have been depicted for long as age-related heterogeneous blood phenotypic changes (“immunoaging”). Some of them can be reproduced in animal models either by accelerating telomere shortening or by forcing DNA damage response. According to these models, “immunoaging” is the consequence of replicative senescence of hematopoietic stem cells.

This increasing knowledge may impact oncogeriatrics in the future since (1) an increasing evidence links hematopoietic and cancer stem cells regulations; (2) immunosenescence may be linked to cancer immunotolerance and the increasing rate of cancer incidence with age; (3) immunoaging has a major consequence during cancer treatment, since it explains increased hematological toxicities observed in the elderly and (4) it favors secondary cancers and mainly hemopathies.

For all these reasons, aging biomarkers, among which are telomere length peripheral blood sampling but also analyses of telomere-linked proteins like shelterin complex or DNA-damage markers will probably be clinically relevant in the future.

Section snippets

Defining aging biomarkers

Aging is associated with a progressive decline in the functional reserve of multiple organ systems [1]. As aging is heterogeneous, this decline has to be assessed individually in the elderly and care adapted not solely on chronological age. Nowadays this assessment is clinical and based upon a geriatric evaluation. In the context of a biological assessment, aging biomarkers could be defined as easily accessible biological markers predictive of the loss of functional reserve, estimated through

Aging is associated in vivo with the accumulation of senescent cells

One of the main characteristics during aging both in vivo and in vitro is the accumulation of DNA damage. In cell culture, this results in an exponential accumulation of senescent cells [10]. Senescence represents a response to DNA damage signaling, inducing a permanent growth arrest. Senescence can be induced by the stepwise accumulation of DNA damage as a consequence of cell divisions and telomere shortening (replicative senescence). Moreover, senescence can also abruptly be induced by

Aging biomarkers in oncogeriatrics

Therapeutic decisions in oncogeriatrics are usually elaborated upon benefit/risk ratio and an evaluation of patients’ general health, estimated through different algorithms [1]. Another challenging question, in the context of adjuvant treatments, is the estimation of the expected survival, again nowadays estimated upon clinical scores [57]. Good aging biomarkers should, on the basis of what was previously developed, (1) give a better estimation of patients’ general health and expected survival,

Biomarkers of DNA damage, telomere dysfunction, and senescence

Considering the above described evidences, following classes of markers could be evaluated as biomarkers for aging and an increased cancer risk: (1) accumulation of DNA damage indicated by upstream markers of DNA damage (γH2AX, 53BP1, MDC1, etc.), (2) markers of telomere dysfunction (telomere shortening, altered expression of proteins of the shelterin, anaphase bridges and chromosomal imbalances), (3) downstream components of DNA damage signaling and senescence induction (p21, p16 and SA-βGAL),

Controversies and limits of the concept of aging biomarkers

However, all the previously described pieces of evidence on biomarkers of aging stay a matter of debate. One must emphasize that, although senescent cells are usually described in vitro, they are hardly detectable in vivo. Two hypotheses for that phenomenon are that the cells generally do not arrive to the senescent state or are recognized and destroyed by the immune system. As a consequence, the harmful impact of senescent cells, through the impairment of tissue renewal, the senescence

Conclusion – perspectives

Since oncogeriatrics treatment decisions depend not only on the tumor characteristics but also on the ability of the patient to tolerate treatments and on the benefit/risk ratio, tools are needed in order to assess risk factors and to predict outcome and therapeutic benefits for elderly cancer patients. Aging biomarkers could become a quantitative, reproducible and quick help for treatment decisions. Nevertheless, prospective data are still sparse and the current challenge is to integrate

Reviewers

Hans Wildiers, MD, PhD, University Hospital Gasthuisberg, Dept. of Medical Oncology, Herestraat 49, B-3000 Leuven, Belgium.

Tamas Fulop, MD, PhD, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Department of medicine, IUGS, Pavillon Argyll, Sherbrooke, Quebec J1J 3H5, Canada.

Claire Falandry, MD, PhD acquired a specialization in oncology then in geriatrics. She was graduated in molecular biology in Pr E. Gilson's “Epigenetic and telomeric regulations” team. She acquired a post-doctoral experience in the Institute of Molecular Medicine and Max Planck Department on Stem Cell Aging headed by Pr K.L. Rudolph. She was the scientific coordinator of several elderly specific multicentric trials.

References (101)

  • S. Pereira et al.

    Hgps and related premature aging disorders: from genomic identification to the first therapeutic approaches

    Mechanisms of Ageing and Development

    (2008)
  • T.J. Vulliamy et al.

    Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation

    Blood

    (2006)
  • B.P. Alter et al.

    Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita

    Blood

    (2007)
  • B. Dykstra et al.

    Long-term propagation of distinct hematopoietic differentiation programs in vivo

    Cell Stem Cell

    (2007)
  • G.A. Challen et al.

    Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1

    Cell

    (2010)
  • R.H. Cho et al.

    A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells

    Blood

    (2008)
  • I. Roeder et al.

    Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: a model-based approach

    Blood

    (2008)
  • D.J. Rossi et al.

    Stems cells and the pathways to aging and cancer

    Cell

    (2008)
  • B. Grubeck-Loebenstein et al.

    The aging of the immune system

    Advances in Immunology

    (2002)
  • N.P. Weng

    Aging of the immune system: how much can the adaptive immune system adapt?

    Immunity

    (2006)
  • T. Jefferson et al.

    Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review

    Lancet

    (2005)
  • P.V. Targonski et al.

    Immunosenescence: role and measurement in influenza vaccine response among the elderly

    Vaccine

    (2007)
  • M.R. Shurin et al.

    Aging and the dendritic cell system: implications for cancer

    Critical Reviews in Oncology/Hematology

    (2007)
  • M.S. Aapro et al.

    Eortc guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours

    European Journal of Cancer

    (2006)
  • M.S. Aapro et al.

    2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours

    European Journal of Cancer

    (2011)
  • R. Greil et al.

    Hematopoietic growth factors: ESMO recommendations for the applications

    Annals of Oncology

    (2008)
  • M. Puzianowska-Kuznicka et al.

    Genetic alterations in accelerated ageing syndromes. Do they play a role in natural ageing?

    International Journal of Biochemistry and Cell Biology

    (2005)
  • H. Vaziri et al.

    From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging

    Experimental Gerontology

    (1996)
  • C.W. Greider et al.

    The telomere terminal transferase of tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity

    Cell

    (1987)
  • C.M. Counter

    The roles of telomeres and telomerase in cell life span

    Mutation Research

    (1996)
  • R.M. Cawthon et al.

    Association between telomere length in blood and mortality in people aged 60 years or older

    Lancet

    (2003)
  • C. Martin-Ruiz et al.

    Assessment of a large panel of candidate biomarkers of ageing in the newcastle 85+ study

    Mechanisms of Ageing and Development

    (2011)
  • M.T. Hemann et al.

    The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability

    Cell

    (2001)
  • M.J. Giraud-Panis et al.

    Structural identity of telomeric complexes

    FEBS Letters

    (2010)
  • A. Augereau et al.

    Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation

    Blood

    (2011)
  • X. Zhang et al.

    The atm/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells

    Journal of Biological Chemistry

    (2005)
  • J. Munro et al.

    Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock

    Experimental Cell Research

    (2004)
  • Y. Liu et al.

    Expression of p16(ink4a) prevents cancer and promotes aging in lymphocytes

    Blood

    (2011)
  • B. Vandenberk et al.

    P16 ink4a: a central player in cellular senescence and a promising aging biomarker in elderly cancer patients

    Journal of Geriatric Oncology

    (2011)
  • L. Claude et al.

    Lymphopenia: a new independent prognostic factor for survival in patients treated with whole brain radiotherapy for brain metastases from breast carcinoma

    Radiotherapy and Oncology

    (2005)
  • E. Cretel et al.

    Immune profile of elderly patients admitted in a geriatric short care unit

    La Revue de Médecine Interne

    (2011)
  • A. Wikby et al.

    Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the swedish longitudinal octo-immune study

    Mechanisms of Ageing and Development

    (1998)
  • F.A. Huppert et al.

    Survival in a population sample is predicted by proportions of lymphocyte subsets

    Mechanisms of Ageing and Development

    (2003)
  • P. Trzonkowski et al.

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

    Vaccine

    (2003)
  • H.Y. Chung et al.

    Molecular inflammation: underpinnings of aging and age-related diseases

    Ageing Research Reviews

    (2009)
  • P. Lencel et al.

    Inflammaging: the driving force in osteoporosis?

    Medical Hypotheses

    (2011)
  • L. Balducci et al.

    Management of cancer in the older person: a practical approach

    Oncologist

    (2000)
  • Z. Ju et al.

    Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment

    Nature Medicine

    (2007)
  • M. Jylha et al.

    Interleukin-1 receptor antagonist, interleukin-6, and c-reactive protein as predictors of mortality in nonagenarians: the vitality 90+ study

    Journals of Gerontology. Series A, Biological Sciences and Medical Sciences

    (2007)
  • S. Giovannini et al.

    Interleukin-6, c-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals

    Journal of the American Geriatrics Society

    (2011)
  • Cited by (30)

    • Do neutrophil to lymphocyte ratio and platelet to lymphocyte ratio associate with frailty in elderly inpatient with comorbidity?

      2022, Experimental Gerontology
      Citation Excerpt :

      The mechanism of lymphocytes and muscular function, frailty is indefinite yet. Previous studies have shown that total lymphocyte count in blood in the immune system reduced with aging (Falandry et al., 2013; Brodin and Davis, 2017). Janus kinase-Signal Transducer and Activator of Transcription proteins (JAK-STAT) pathway is a canonical signaling pathway of cell proliferation, Samson LD et al. found that frailer men showing lower pSTAT5 responses in CD4+ and CD8+ T cells and lower IL-10- induced pSTAT3 responses in men were related to higher frailty scores levels (Samson et al., 2022).

    • Biomarkers to identify and isolate senescent cells

      2016, Ageing Research Reviews
      Citation Excerpt :

      Only single-cell markers of senescence will be discussed. Detailed reviews on systemic aging markers have been published previously (Falandry et al., 2013; Pallis et al., 2014). While cellular senescence has been linked to a number of predictable phenotypic traits and representative biomarkers (Table 1), senescent cells are still a heterogeneous population, and this fact significantly complicates a search for a robust senescence biomarker.

    • Cancer and Aging: General Principles, Biology, and Geriatric Assessment.

      2016, Clinics in Geriatric Medicine
      Citation Excerpt :

      However, a direct mechanistic link between these inflammatory and coagulation markers and functional decline has not been clearly established. Furthermore, in patients with cancer, when the tumor has not been removed, these markers are often produced by the actual cancer itself, resulting in difficulties for accurate interpretation of correlation with overall functional age.61 Therefore, chronic inflammatory markers or markers of coagulation may have potentially better utility in the setting of early stage cancer when the tumors have been completely removed.

    View all citing articles on Scopus

    Claire Falandry, MD, PhD acquired a specialization in oncology then in geriatrics. She was graduated in molecular biology in Pr E. Gilson's “Epigenetic and telomeric regulations” team. She acquired a post-doctoral experience in the Institute of Molecular Medicine and Max Planck Department on Stem Cell Aging headed by Pr K.L. Rudolph. She was the scientific coordinator of several elderly specific multicentric trials.

    View full text