DRUDIS-1645; No of Pages 5 Please cite this article in press as: Bersani, F.S. et al. Telomerase activation as a possible mechanism of action for psychopharmacological interventions, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.06.016 feature Telomerase activation as a possible mechanism of action for psychopharmacological interventions Francesco S. Bersani 1,2 , Daniel Lindqvist 1,3 , Synthia H. Mellon 4 , Brenda W.J.H. Penninx 5 , Josine E. Verhoeven 5 , Do ´ ra Re ´ve ´sz 5 , Victor I. Reus 1 and Owen M. Wolkowitz 1,* , Owen.Wolkowitz@ucsf.edu Originally studied in relation to aging and cancer research, telomerase is now also investigated in relation to psychiatric disorders and treatments. Based on emerging clinical and preclinical data, we hypothesise that telomerase activation could represent a novel element mediating the mechanism of action of certain psychopharmacological interventions (e.g. antidepressants, lithium and antipsychotics). The modulation of intracellular Wnt/b-catenin or PI3K/Akt signalling pathways, the interaction with BDNF and 5-HT, and the antioxidant properties could represent possible mechanisms by which the different types of psychiatric medications could modulate telomerase activity. The potential of telomerase in promoting cellular survival and/or function in the brain and in the periphery could, in turn, represent a neurobiological substrate through which the enzyme can mediate the therapeutic effect of such interventions. Introduction Telomeres consist of tandem repeats of hex- americ sequence units (TTAGGG) that, together with bound protective proteins, cap chromo- somal ends and promote chromosomal stability and genomic integrity [1]. When somatic cells divide, telomeres might not be fully replicated owing to the ‘end replication problem’ [1]. When telomeres shorten sufficiently, cells can become senescent and cellular mechanisms are activated that promote growth arrest, mitochondrial damage, inflammation, apoptosis and/or geno- mic instability. In addition to mitotic divisions, oxidation and inflammation appear to be strong telomere shortening stimuli [1]. Average human telomere length (TL) [often assessed in leukocytes or peripheral blood mononuclear cells (PBMCs)] generally shortens with age unless acted upon by telomerase, the major telomere-lengthening enzyme, or by al- ternative telomere-lengthening mechanisms [1]. This, plus the fact that short leukocyte telomere length (LTL) is associated with somatic morbidity and premature mortality, suggests that LTL could represent a biomarker of biological or cellular aging [1,2]. However, there are caveats in inter- preting LTL, including issues with measurement errors and alterations in the proportions of specific leukocyte subpopulations [3]. Telomerase exerts its protective action by adding DNA sequence repeats (TTAGGG) onto the 3 0 telomeric ends [1]. This highly regulated telomeric DNA synthesising action of telomerase is an important pathway responsible for lengthening, repairing and protecting telomeres, and thereby maintaining cellular viability [1]. Telomerase has two major components: the functional telomerase RNA component (TERC), which serves as a template for telomeric DNA synthesis; and the catalytic protein component with telomerase reverse transcriptase (TERT) activity, which adds the telomeric repeats [1]. In addition to its canonical effects on telomere maintenance, telomerase has a variety of TL- independent actions that promote cellular sur- vival and/or function [4,5]. Although originally studied in relation to ag- ing and cancer, telomerase activity (TA) has recently been investigated in relation to psy- chiatric disorders and treatments. An increasing number of studies suggest that several mental Features  PERSPECTIVE Drug Discovery Today  Volume 00, Number 00  July 2015 PERSPECTIVE 1359-6446/ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2015.06.016 www.drugdiscoverytoday.com 1