Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging

Abstract

Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.

Keywords: Aging; Antidepressant; Anxiety; Bipolar affective disorder; Depression; Disease; Early life adversity; Inflammation; Leukocytes; Major depressive disorder; Manic-depression; Mortality; Neurotrophic; Oxidative stress; Post-traumatic stress disorder; Psychosis; Schizophrenia; Stress; Telomerase; Telomeres.

Conflict of interest statement

DISCLOSURES

JL is a consultant to Telomere Diagnostics Inc., formerly Telome Health, and owns stock in the company. The company had no role in this research or in writing this review. The remaining authors report no current disclosures or conflicts of interest.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Fig. 1. Telomeres and Telomerase

Telomeres [1] are protective caps at the ends of linear DNA strands. In humans, telomeres are comprised of multiple non-coding repeats of the nucleotide sequence, TTAGGG, and at birth, human telomeres are approximately 10,000 nucleotides long (Okuda et al., 2002). Telomeres lose approximately 50–100 nucleotides per DNA replication cycle (unless acted upon by telomerase) due to the so-called “end-replication problem” and can lose even more due to oxidative damage. The end replication problem arises during DNA replication or extension because DNA polymerase can only synthesize DNA in one direction (5’ → 3’). On the 5’ → 3’ leading strand [2], this route is continuous, but on the lagging strand [3], it is discontinuous, synthesized in fragments that require a RNA primer molecule [4] to provide a 5’ initiation point. As each fragment on the lagging strand (called “Okazaki fragments”) is completed, the RNA primer translocates to initiate the synthesis of additional fragments. Since the RNA primer must always attach prior to the synthesis of the lagging strand fragments, and since the RNA primer must base pair to complementary nucleotides on the leading strand, the 5’ end of lagging strand will always be shorter than the 3’ end of the leading strand, and thus is incompletely replicated. Shortened telomeres can be rebuilt by telomerase [5], which is comprised of the telomerase reverse transcriptase (TERT) enzyme and a telomerase RNA component (TERC) that serves as a template for new complementary telomeric DNA construction along the leading strand. As telomerase advances along the leading telomeric DNA strand, new nucleotides are added to it, providing additional room for extension of the lagging strand (Chakhparonian and Wellinger, 2003).

Fig. 2. Critical Shortening of Telomeres Can Lead to Apoptosis, Cell Cycle Arrest or Genomic Instability

When telomere length is sufficiently shortened [1] or when telomere integrity is sufficiently challenged, classic DNA damage responses (DDR’s) [2] are initiated. A major effector of the DDR is the tumor suppressor protein p53 [3], which is activated upon telomere damage. This can lead to cell cycle arrest (“replicative senescence”), cellular senescence and apoptosis; this is most likely to affect cells turning over rapidly, such as blood cells (Sahin et al., 2011). Cellular death and senescence can give rise to stem cell dysfunction, degenerative diseases and tissue death. Were it not for p53 activation, telomere-damaged cells could survive, and their genomic instability could give rise to cancerous cells. Activation of p53 can also damage cells turning over slowly, such as those in heart and brain, by directly decreasing the expression of peroxisome proliferator-activated receptor gamma, coactivator-1 α and β (PGC-1α and PGC-1β) [4] the master regulators of mitochondrial function and biogenesis (Sahin et al., 2011). Such effects on mitochondrial number and function can also decrease cellular viability by decreasing cellular energy production and by releasing excessive amounts of free radicals such as reactive oxygen species (ROS) [5], which further damage telomeres and other cellular components. Figure adapted from Kelly et al. (Kelly, 2011), commentary on Sahin et al. (Sahin et al., 2011).