Telomerase Activation to reverse Immunosenescence in elderly patients with Acute Coronary Syndrome

Abstract

Introduction: Immune ageing is characterised by lymphopenia, expansion of pro-inflammatory T lymphocytes and reduced telomere length. Acute coronary syndrome (ACS) evokes an intense inflammatory response and leads to accelerated immune ageing, reflected by an increase in CD8+ terminally differentiated T lymphocytes (CD8+ TEMRA). While activation of telomerase enhances lymphocyte proliferation in-vitro and reverses tissue degeneration in aged mice, its potential benefit in patients recovering from ACS is unknown. Methods: This randomized, double-blinded controlled study aimed to evaluate the safety and efficacy of the oral telomerase activator TA-65 in 90 MI patients aged over of 65 years, which is the average onset age for immune ageing. Patients were randomised to either TA-65 (16 mg daily, n=45) or placebo (n=45) for 12 months. Immune phenotyping was performed by flow cytometry at baseline, 6 months and 12 months. The pre-defined primary endpoint was the proportion of CD8+ T-lymphocytes which were CD8+ TEMRA, a marker of immune cell ageing. Secondary endpoints included high-sensitivity C-reactive protein (hsCRP) and adverse events. A linear mixed effects model was used to calculate the treatment effect. Results: The median age of participants was 71 years and 17% were women. Most patients received percutaneous coronary intervention (87%). The proportion of CD8+ TEMRA did not differ between the 2 treatment groups at 12 months, but increased significantly only in the placebo group (+2.2 %, 95% CI 0.14-4.24). Total adverse events were 30% lower in the treatment group (n=130 vs n=185). High-sensitivity CRP was 62% lower in the TA-65 group compared to placebo (1.1 vs. 2.9 mg/L). There was a 14% increase in mean lymphocyte count in the TA-65 group (+240 cells/µl, 95% CI: 109 – 374), driven by significant increases from baseline in all major lymphocyte populations: CD3+ (+14%), CD4+ (+14%), CD8+ T lymphocytes (+14%), B-lymphocytes (+14%) and natural killer cells (+16%), while major lymphocyte populations did not increase in the placebo group. Conclusion: While TA-65 did not significantly alter CD8+ TEMRA ,it increased all major lymphocyte subsets and reduced hsCRP in elderly patients with MI at 12 months. TA-65 may be a novel agent to reduce inflammation and improve age-related decline in major lymphocyte populations after MI.