Telomerase Activation Improves Microvascular Function and Reduces Blood Pressure with Advancing Age

Introduction: Advancing age is associated with declines in overall cardiovascular health, including elevations in blood pressure (BP), reduced microvascular function and is an immutable risk factor in development of coronary artery disease (CAD). Previous ex vivo evidence has demonstrated that CAD is associated with reductions in telomerase, and loss of nitric oxide (NO) mediated dilation in the microvasculature that is rescued by increasing telomerase activity. We hypothesized that increasing telomerase activity would improve age-associated declines in microvascular function in vivo and reduce BP in both older humans and rats. Methods: Human Model: Brachial BP was assessed via oscillometry. One intradermal microdialysis fiber was placed in the skin of the forearm of 5 older adults (3F/2M; 74±4 yrs; BMI 26.3±1.9) for local delivery of Ringer’s solution and the NO synthase inhibitor L-NAME (20 mM). Cutaneous vascular conductance (CVC, quotient of red blood cell flux and brachial mean arterial pressure) was measured over by laser Doppler flowmetry during local heating to 39°C. After a stable plateau in CVC, L-NAME (20 mM) was infused to block production of NO. Following a plateau in the L-NAME response, local heaters were increased to 43°C and 54mM of sodium nitroprusside was infused to elicit maximal cutaneous vasodilation. Subjects then underwent 28 days of supplementation with TA-65® (250 U/day), a commercially available activator of telomerase. Following the supplementation period, assessment of BP and cutaneous microvascular function was repeated. Cutaneous vascular conductance presented as a percent of maximal CVC (%CVCmax). Percent NO contribution (%NO) to CVC was calculated as the difference between the local heating plateau and the post-L-NAME plateau x 100.Rodent Model: Female Fisher-344 rats (95-100 weeks; n=5-8) were fed Cycloastragenol (CAG) obtained from King-Tiger Pharm-Chem. Tech for 28-days (active ingredient of TA-65®; 25-30 mg/kg body weight). BP and coronary microvascular dilation to acetylcholine was evaluated via pressure myography. Data presented as % of maximal diameter. Significance was defined as p<0.05. Results: Supplementation with TA-65 reduced MAP (97±12 vs. 87±8 mmHg; p<0.05) and improved peak CVC to local heating (p<0.05), but did not significantly improve plateau responses (p=0.08), L-NAME responses (p=0.46) or the contribution of NO (p=0.07). In the rodent model, increasing telomerase activity reduced diastolic BP (Pre-CAG: 90±16 mmHg vs. Post-CAG: 73±7 mmHg; p<0.05) and enhanced coronary artery endothelial-dependent responses to acetylcholine (% Max Diameter, Older Control: 23.3±9.7% vs. Older+CAG: 82.7±22.7%; p<0.05). Conclusion: Our data demonstrate that increasing telomerase activity promotes reductions in BP and enhanced coronary microvascular function. Together, these results suggest increased telomerase activity may be promising for prevention of age-associated declines in cardiovascular health. Funded by NHLBI K99 HL161491-01 (WEH), R01-HL133029-02 (AMB), R01 AG053585, R01 DE030103, and P30 ES030283; and a grant from the Gheens Foundation (AJL). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.