Changing Direction: From Therapeutic Telomerase Inhibition to Activation?

Abstract

High telomerase expression is a hallmark of most types of cancer, and, therefore, strategies to inhibit telomerase as an anticancer treatment have been pursuit for many years. In contrast to cancer, short telomeres and lack of telomerase are associated with aging and age-related disease, including heart disease. Consequently, pharmacological telomerase activation can delay aging and also provides cardioprotection. In this viewpoint, we briefly summarized the 2 faces of telomerase in cancer and during aging. We discuss why we see the therapeutic future in telomerase activation rather than its inhibition, for the treatment of cardiac disease and possibly even in the context of cancer. Cardiovascular disease is a worldwide epidemic and represents the most common cause of morbidity and mortality in the western world. Significant advances in health care have led to a steadily rising life expectancy and consequently to a dramatically increased incidence of age-related diseases, such as cancer and heart disease. One of the main reasons for the high incidence of heart failure (HF) is an extremely low regeneration capacity of mammalian cardiomyocytes. Hence, the only effective way to replace lost cardiomyocytes in humans to date, for instance after myocardial infarction, is heart transplantation, which emphasizes the need for novel intervention and prevention strategies Intensive research provided insights into the cellular and molecular mechanisms of aging. Among others (eg, cellular senescence, genomic instability, stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations), telomere attrition, in particular, has emerged as a main driver of aging and age-related diseases, such as HF.1 Telomeres are dynamic nucleoprotein structures which form a protective cap to conceal the ends of chromosomes from the DNA repair machinery, thus providing chromosomal and cellular integrity.2 However, telomeres are sensitive to aging because telomerase ( TERT [telomere reverse transcriptase]), the enzyme that maintains telomere length, is repressed in …