Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model

Athanase Benetos; Simon Toupance; Sylvie Gautier; Carlos Labat; Masayuki Kimura; Pascal M Rossi; Nicla Settembre; Jacques Hubert; Luc Frimat; Baptiste Bertrand; Mourad Boufi; Xavier Flecher; Nicolas Sadoul; Pascal Eschwege; Michèle Kessler; Irene P Tzanetakou; Ilias P Doulamis; Panagiotis Konstantopoulos; Aspasia Tzani; Marilina Korou; Anastasios Gkogkos; Konstantinos Perreas; Evangelos Menenakos; Georgios Samanidis; Michail Vasiloglou-Gkanis; Jeremy D Kark; Serguei Malikov; Simon Verhulst; Abraham Aviv

doi:10.1161/CIRCRESAHA.117.311751

Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model

Circ Res. 2018 Feb 16;122(4):616-623. doi: 10.1161/CIRCRESAHA.117.311751. Epub 2017 Dec 14.

Authors

Athanase Benetos¹, Simon Toupance², Sylvie Gautier², Carlos Labat², Masayuki Kimura², Pascal M Rossi², Nicla Settembre², Jacques Hubert², Luc Frimat², Baptiste Bertrand², Mourad Boufi², Xavier Flecher², Nicolas Sadoul², Pascal Eschwege², Michèle Kessler², Irene P Tzanetakou², Ilias P Doulamis², Panagiotis Konstantopoulos², Aspasia Tzani², Marilina Korou², Anastasios Gkogkos², Konstantinos Perreas², Evangelos Menenakos², Georgios Samanidis², Michail Vasiloglou-Gkanis², Jeremy D Kark², Serguei Malikov², Simon Verhulst², Abraham Aviv²

Affiliations

¹ From the INSERM UMRS 1116 (A.B., S.T., C.L.), Department of Geriatric Medicine, CHRU de Nancy (A.B., S.G.), Department of Vascular Surgery, CHRU de Nancy (N.S., S.M.), Department of Urology, CHRU de Nancy (J.H., P.E.), Department of Nephrology, CHRU de Nancy (L.F., M.K.), and Department of Cardiology, CHRU de Nancy (N.S.), Université de Lorraine, Nancy, France; Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark (M.K., A.A.); Department of Internal Medicine, North Hospital, APHM, and UMR-S1076 (P.M.R.) and Department of Plastic Surgery, Conception Hospital, APHM and UMR-S1076 (B.B.), Aix-Marseille University, France; Department of Vascular Surgery (M.B.) and Department of Orthopedic Surgery (X.F.), North Hospital, APHM, Marseille, France; Laboratory for Experimental Surgery and Surgical Research "NS Christeas", National and Kapodistrian University of Athens, Greece (I.P.T., I.P.D., P.K., A.T., M.K., A.G., G.S.); European University of Cyprus, School of Sciences, Engomi (I.P.T.); First Department of Adult Cardiac Surgery, Onassis Cardiac Surgery Center, Athens, Greece (K.P., G.S.); Department of Surgery, Hippokration Hospital and Medical School of Athens, National and Kapodistrian University of Athens, Greece (E.M.); Department of Surgery, Iaso General Hospital, Athens, Greece (M.V.-G.); Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel (J.D.K.); and Groningen Institute for Evolutionary Life Sciences, University of Groningen, The Netherlands (S.V.). a.benetos@chru-nancy.fr.
² From the INSERM UMRS 1116 (A.B., S.T., C.L.), Department of Geriatric Medicine, CHRU de Nancy (A.B., S.G.), Department of Vascular Surgery, CHRU de Nancy (N.S., S.M.), Department of Urology, CHRU de Nancy (J.H., P.E.), Department of Nephrology, CHRU de Nancy (L.F., M.K.), and Department of Cardiology, CHRU de Nancy (N.S.), Université de Lorraine, Nancy, France; Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark (M.K., A.A.); Department of Internal Medicine, North Hospital, APHM, and UMR-S1076 (P.M.R.) and Department of Plastic Surgery, Conception Hospital, APHM and UMR-S1076 (B.B.), Aix-Marseille University, France; Department of Vascular Surgery (M.B.) and Department of Orthopedic Surgery (X.F.), North Hospital, APHM, Marseille, France; Laboratory for Experimental Surgery and Surgical Research "NS Christeas", National and Kapodistrian University of Athens, Greece (I.P.T., I.P.D., P.K., A.T., M.K., A.G., G.S.); European University of Cyprus, School of Sciences, Engomi (I.P.T.); First Department of Adult Cardiac Surgery, Onassis Cardiac Surgery Center, Athens, Greece (K.P., G.S.); Department of Surgery, Hippokration Hospital and Medical School of Athens, National and Kapodistrian University of Athens, Greece (E.M.); Department of Surgery, Iaso General Hospital, Athens, Greece (M.V.-G.); Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel (J.D.K.); and Groningen Institute for Evolutionary Life Sciences, University of Groningen, The Netherlands (S.V.).

Abstract

Rationale: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue.

Objective: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD.

Methods and results: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTL_A) was longer than LTL and the LTL-MTL_A gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTL_A (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTL_A) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTL_A) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals.

Conclusions: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.

Keywords: aging; atherosclerosis; biopsy; leukocytes; muscle; telomere.

Publication types

Controlled Clinical Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Atherosclerosis / genetics*
Atherosclerosis / pathology
Female
Humans
Leukocytes / metabolism
Male
Middle Aged
Muscle Fibers, Skeletal / metabolism
Telomere Shortening*

Associated data

ClinicalTrials.gov/NCT02176941

Abstract

Publication types

MeSH terms

Associated data

Grants and funding