Telomeres and Arterial Aging
Telomeres and Arterial Aging
The prevailing view in telomere epidemiology is that leukocyte telomere length (LTL) is
 associated with atherosclerosis and accelerated aging since it serves as a biomarker of the
 cumulative burden of inflammation and oxidative stress during adult life. Our recent results
 however, indicate that telomere length (TL) is mainly determined at birth and childhood.
 Since short telomeres ante cede atherosclerosis, the investigators hypothesize that TL is not
 just a simple marker, but a real determinant of arterial aging. That is because TL reflects
 cellular repair capacity and a short LTL denotes diminished repair reserves. This hypothesis
 cannot be tested by measurements of LTL alone, since this parameter reflects TL at birth and
 its age-dependent attrition thereafter. The investigators propose, therefore, a model that
 makes it possible to examine different elements of TL dynamics in different tissues:
 leukocytes, skeletal muscle, endothelial progenitor cells (EPCs), skin or subcutaneous fat in
 patients with or without atherosclerosis.

 Our model is based on the following premises, which are derived from observations that TL is
 synchronized (equivalent) across somatic tissues/cells of the newborn:

 -  TL in skeletal muscle mainly reflects TL at birth

 -  The difference in TL between muscle and leukocytes in adults (approximately 1.5 Kbp)
 mainly reflects LTL attrition during the growth period, i.e., childhood/adolescence

 -  TL in EPCs determines the cell proliferative ability and therefore capacity for vessels
 repair during aging.

 The general aim of the present project is to examine the links of arterial aging with TL, as
 expressed in different tissues, and LTL dynamics, as expressed in the difference between TLs
 of muscle and leukocytes.
Specific objectives:

 1. To determine whether TL during early development, which is primarily reflected in muscle
 TL, and LTL attrition during development, which is primarily expressed in the difference
 between muscle TL and LTL, are associated with indices of arterial aging.

 2. To examine the relation between EPC-TL to endothelial regenerative capacity and
 endothelial function. In order to attain this objective the investigators will perform
 two types of experiments:

 -  Measure TL in progenitor cells and relate it to clinical phenotypes of arterial
 aging and atherosclerosis, as well as markers of endothelial dysfunction

 -  Generate in vitro progenitor cells with different TL induced by the environmental
 factors (oxidative stress) and assess their phenotypes concerning inflammation and
 microvesiculation, in order to show a possible mechanistic relationship between TL
 in PC and the atherogenic and the regenerative capacities of these cells.

 The project is composed of 6 tasks:

 T1: Recruitment and sample collection (skeletal muscle, total blood) of 170 patients with
 atherosclerosis and 170 controls. Performed by surgeons and cardiologists of Marseille and
 Nancy University hospitals T2: Characterization of arterial aging in all patients (Geriatric
 Dpt, Univ. hospital Nancy, Pr Benetos and AP-HM, Internal Medicine, Marseille, Dr Rossi) T3:
 Characterization of early and late endothelial progenitor cells (EPC): laboratory of
 hematology and vascular biology and in UMR_S1076 in Marseille (Prs Dignat-George and
 Sabatier) T4: Measurements of TL in all samples (skeletal muscle, leukocytes and EPC):
 UMR_S1116 Nancy (Dr Lacolley) in collaboration with Pr Aviv (University of Medicine of New
 Jersey) T5: Characterization of inflammation markers in blood samples: UMR_S1116 and the
 UMR_S1122 (Dr Siest-Visvikis, Nancy) T6: Database construction and statistical analyses
 (UMR_S1116)

 The results of this program could completely modify the present concept on the association
 between TL and cardiovascular risk: Actually, if our concept of early determination of TL is
 valid, therefore TL could be a true determinant of the arterial aging pace, through
 limitation of repair capacity of cells.
Inclusion Criteria:

 -  Men and women, aged ≥ 20 years who are admitted for different types of surgery or for
 pacemaker/ defibrillator implantation and provide informed consent for participating
 in this study.

 Exclusion Criteria:

 Conditions which may impact telomere length:

 -  Patients undergoing surgery for cancer

 -  Patients who had had radiotherapy or chemotherapy.