Sexually Dimorphic Behavioral and Genetic Outcomes Associated With Administration of TA65 (A Telomerase Activator) Following Repetitive Traumatic Brain Injury: A Pilot Study

Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.

Traumatic brain injury (TBI) has long been recognized to be a risk factor for dementia. This association has, however, only recently gained widespread attention through the increased awareness of 'chronic traumatic encephalopathy' (CTE) in athletes exposed to repetitive head injury. Originally termed 'dementia pugilistica' and linked to a career in boxing, descriptions of the neuropathological features of CTE include brain atrophy, cavum septum pellucidum, and amyloid-β, tau and TDP-43 pathologies, many of which might contribute to clinical syndromes of cognitive impairment. Similar chronic pathologies are also commonly found years after just a single moderate to severe TBI. However, little consensus currently exists on specific features of these post-TBI syndromes that might permit their confident clinical and/or pathological diagnosis. Moreover, the mechanisms contributing to neurodegeneration following TBI largely remain unknown. Here, we review the current literature and controversies in the study of chronic neuropathological changes after TBI.

An ageing world population has fueled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signaling activation in vivo 1. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure, and impaired tissue injury responses1. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-Estrogen Receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice display short dysfunctional telomeres and sustain increased DNA damage signaling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signaling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, DCX+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of SVZ neural progenitors in generation and maintenance of olfactory bulb interneurons2, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk1,3 and the dramatic reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.