Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.Work in the VA laboratory is supported by the Spanish Ministerio de Ciencia
e Innovación (MCIN) (PID2019-108489RB-I00) and the Instituto de Salud
Carlos III (ISCIII) (AC17/00067) with co-funding from the European Regional
Development Fund (ERDF, “Una manera de hacer Europa”), and the Progeria
Research Foundation (Award PRF 2019–77). The CNIC is supported by the
ISCIII, the MCIN, and the Pro CNIC Foundation. I. Spyridopoulos is funded by the
British Heart Foundation (PG/18/25/33587) and National Institute for Health
Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle
upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work
of J. Haendeler and J. Altschmied is in part supported by the Deutsche Forschungsgemeinschaft
(DFG) SFB1116, A04 (J. Haendeler and J. Altschmied),
HA2868/14-1 (J. Haendeler) and AL288/5-1 (J. Altschmied). The views expressed
are those of the author(s) and not necessarily those of the NHS, the
NIHR or the Department of Health’. I. Spyridopoulos also receives a grant from
TA-Science for the TACTIC trial (Telomerase Activator to Reverse Immunosenescence
in Acute Coronary Syndrome).S
