On telomeres long and short.

Telomeres and their shortening have been studied in the con­ text of psychiatric disorders for about 10 years. A number of studies correlating telomere length (TL) with selected psycho­ pathologies have generated intriguing and largely consistent findings: many psychiatric disorders are associated with shorter leukocyte TL. Yet, this observation can be interpreted in alternative ways, and choosing among them remains diffi­ cult owing to missing key pieces of information. Telomeres are, essentially, caps on ends of chromosomes. They consist of TTAGGG repeats that usually become shorter with each successive cell division. Their main roles are to pro­ tect chromosomes from a gradual loss of nucleotides in divid­ ing cells and to delineate DNA breakage from normal chro­ mosome ends. They also halt cell division through activation of DNA damage recognition systems in response to acute cel­ lular stress (e.g., radiation, oxidative stress), age (i.e., un­ capped short telomeres) and disruption of various telomere­ associated proteins (e.g., acquired or inherited mutations, cell signalling, toxins, drugs).1 Telomere integrity is maintained by a specialized polymerase system and various associated structural and signalling proteins; accordingly, the telomere system provides cells with information about their individual history and physiologic context. The enzyme telomerase can elongate telomeres, but does not compensate fully for the cell division–related shortening in so­ matic cells. Telomerase is not substantially active in most adult somatic cells, with the exception of the germ line cells, prolifer­ ating leukocytes and endometrium and has a limited function in stem cells. Telomerase activity declines precipitously during the teen years, while TL declines most rapidly in early de­ velop ment, with subsequent slower attrition through the rest of the life course.1 Mean TL has been associated with 7 genetic loci that correspond with genes directly involved in telomere maintenance.2 Thus, we infer that TL results from the differ­ ence between factors negatively impacting TL on one hand and telomerase activity on the other. In humans, TL is herit­ able both generally3 and in specific cases of intergenerational telomere loss leading to genetic anticipation in a particular gen etic disease.4 Telomere balance at any given time is a func­ tion of somatic growth rate, relevant genetics and epigenetics, age, environmental and physiologic context, psychological re­ sponse to the en vironment,5 and physical or mental illness and/or its treatment, which define the rate of change in mean TL at any given time. These factors combined with the herit­ ability of TL “set points,” which define early life (maximal) telomere length, determine somatic TL. Populations vary dramatically in TL, even within regions, such as Europe,6 that have traditionally been considered rela­ tively homogeneous and among people from different parts of the world.7 Likewise, TL varies among specific tissues within the same organism. This complexity is a good reminder that the telomere system is not amenable to simplistic analysis. Telomere length is typically measured in leukocytes and referred to as leukocyte TL (LTL). Most commonly, LTL is es­ timated via a ratio of telomeric repeat amplification to that of a known single copy gene in multiplex quantitative poly­ merase chain reaction (qPCR),8 although other methods have better precision and cell­type and chromosome specificity;9 qPCR ratio does not describe the many telomeres of different lengths at every chromosome end in every cell or say any­ thing about variance between cells or cell populations in the given sample. Given that very short telomeres occur ran­ domly and with increasing probability at lower average TL, association between average TL and biomolecular reality is, at best, probabilistic. In addition, the normal variation in hu­ man average TL is substantial, necessitating large cohorts to achieve sufficient statistical power for inference testing. While current techniques are sufficient for high­level descrip­ tive work, chromosome resolution, longitudinal “telomere velocity” studies will provide more useful information. Among psychiatric disorders, LTL has been found to be significantly reduced in patients with bipolar disorder, psy­ chosis, major depression and anxiety disorders. Shorter telo­ meres are commonly thought to reflect — or result from — accelerated aging processes. One proposed mechanism involves oxidative stress, negative impact of reactive oxygen species and impaired mitochondrial function. The same mechanisms may, for instance, play a role in the pathophysi­ ology of bipolar disorder and/or its progression, with recent results indicating that long­term lithium therapy leads to a detectable relative increase in LTL versus controls.10 There is clearly much to learn in this regard, as lithium therapy has not been shown to modulate leukocyte telomerase function.11 Most observations of telomere shortening in psychiatry come from investigations of leukocytes, not brain tissue. Few studies examined TL in postmortem brains. Teyssier and