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

Abstract

Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. This demographic also often suffers from post-injury symptomologies that may persist for months. Telomere length (TL) has previously been used as a marker for outcomes following repetitive mild TBI (RmTBI) and it may be possible that telomere elongation can reduce post-traumatic behavioral impairments. Telomerase activator-65 (TA-65) is a telomerase small-molecule activator purified from the root of Chinese herbs that has been anecdotally reported to have anti-aging and life-extending potential. We hypothesized that RmTBI would shorten TL but administration of TA-65 would reverse RmTBI-induced telomere shortening and behavioral deficits. Male and female Sprague-Dawley rats were orally administered TA-65 or a placebo substance for 30 consecutive days [postnatal day (P) 25-55]. Following the injury protocol (mTBIs on P33, 36, and 40), rats went through a behavioral test battery designed to examine symptomologies commonly associated with mTBI (balance and motor coordination, exploratory behavior, short-term working memory, and anxiety-and depressive-like behaviors). TL in ear and brain tissue (prefrontal cortex and hippocampus) and relative expression of TERT and Tep1 via qPCR were assessed 15 days following the last injury. We observed a heterogenous response between males and females, with TA65 administration resulting in increased mRNA expression of TERT and Tep1 in female rats that experienced RmTBI, which was accompanied by some functional recovery on motor behavior and footslips in the beam walk task and depressive-like behavior in the forced swim task.

The Safety of Oral Telomerase Activator in UV-Induced Skin Cancer with A Review of Telomerase in Aging and Skin Carcinogenesis

“…Mice fed TA-65 -and not the control -exhibited significant alterations in the subcutaneous fat layer and more proliferation of epidermis [3]. Also, female Sprague-Dawley rats increased mRNA levels of TERT and telomerase associated protein (Tep1) in the cerebral prefrontal cortex and hippocampus after oral supplementation with TA-65 following repetitive traumatic brain injury; unsupplemented controls showed no increase [59]. Another demonstration of tissue distribution of TA-65 after oral supplementation was shown in a transgenic mouse model of Parkinson's disease [40]: Oral TA-65 increased TERT protein in the brain neocortex and hippocampus, resulting in decreased -synuclein protein levels and improvement of motor functions.…”

“…This is indeed encouraging because a possible adverse effect of dietary telomerase might have been the enhancement of tumorigenesis. In fact, many researchers (who have themselves demonstrated the efficacy of TA-65 in slowing age-related diseases and cellular senescence and possibly even mortality) realize the importance of ensuring "that administration of a telomerase activator does not increase susceptibility to / or risk for cancer or cancer related diseases" [59]. Because skin cancer is by far the most common human cancer, the absence of any change in the magnitude of skin cancer incidence with oral TA-65 attests to the safety of this supplement.…”

Nutrition and neutraceutical interventions as therapeutic strategies to aid recovery from mild traumatic brain injuries

“…The small molecule Telomerase activator-65 (TA-65, also known as cycloastragenol) is derived from various legume species in the genus Astragalus and is a potent telomerase activator that can lengthen telomeres. Treatment with TA-65 improved motor coordination and reduced depressive-like behaviour in female, but not male, rats that sustained repeated mTBI, and increased mRNA expression of telomere-length related genes telomerase reverse transcriptase (TERT) and telomerase-associated protein-1 (Tep1) (Eyolfson et al, 2020). Further studies should be conducted to establish links between the prognostic outcomes of TBIs, cellular aging, telomere length and NAM/vitamin B3 as a putative therapy for TBI-induced pathologies.…”

Telomerase in Brain: The New Kid on the Block and Its Role in Neurodegenerative Diseases

“…These results are similar to those described by Eyolfson and co-authors who treated rats for one month with TA-65 before inflicting a brain injury. The authors found an increase in Tert expression as well as an improvement in motor coordination in the treated rats compared to controls [ 68 ].…”