ARA290, A Small Non‐Hematopoietic Peptide Derived From Erythropoietin, Prolongs Healthspan And Attenuates Age‐Associated Declines In The Heart's Structure And Function
Authors: Nanavati Alay , Moen Jack , Axsom Jessie , Krawczyk Melissa , Petrashevskaya Natalia , Beyman Max , Ramirez Christopher , Alfaras Irene , Mitchell Sarah , Bernier Michel , Morrell Christopher , Sollott Steven , Juhaszova Magdalena , deCabo Rafael , Lakatta Edward 
Published: June 2021

Background

Chronic inflammation is linked to age‐associated declines in heart structure and function that contribute to increased risks for cardiovascular mortality and frailty, a state of high vulnerability to adverse health outcomes, and to reduced healthspan.

Objective

To determine whether a novel anti‐inflammatory, erythropoietin‐derived synthetic peptide, ARA290, can improve healthspan and delay deteriorations in heart function.

Methods

18 mo Fischer 344 × Brown Norway male rats (n = 50) were randomized to bi‐weekly injections of ARA290 or saline. Body weight (BW) was recorded every 2 weeks until death. Echocardiograms (ECHO), to measure ejection fraction (EF), and electrocardiograms (ECG), to measure heart rate (HR) before (BHR) and during a double autonomic blockade (IHR), were performed at 18, 22, 26, 30, and 33 mo, when a 33‐item frailty index (FI), scored on a scale of 0 to 1 (least to most frail), assessed health deficits in integument, musculoskeletal, vestibulocochlear, ocular, neurological, digestive, and respiratory systems. Linear mixed effects models assessed changes in cardiac markers over time, and joint models predicted the overall risk of death based on those changes and survival data.

Results

ARA290 slowed the decline in BHR that accompanied aging (p < 0.03): between 18 and 33 mo BHR decreased from 327 to 276 beats per minute (BPM) in ARA290 and 314 to 261 BPM in the control; between 27 and 33 mo BHR plateaued in ARA290 but continued to decline in the control. IHR declined non‐linearly from 254 BPM to 240 BPM between 18 and 33 mo (p < 0.003), but did not differ by treatment. The difference between BHR and IHR (ΔHR), an index of autonomic modulation on HR, declined from 58 to 17 BPM in the control and from 73 to 38 BPM in ARA290 between 18 and 33 mo. Between 22 and 33 mo ΔHR was preserved in ARA290, but not control(p < 0.02). EF in ARA290 declined from 82.4% to 76.8% at a rate of 0.469% per month slower than the control, in which EF declined from 84.6% to 70.3% (p < 0.005). At 33 months EF was 7.5% greater in ARA290 (p < 0.004). BW decreased from 534 to 486 g between 25.5 and 33.0 months in ARA290 and from 529 to 442 g between 24.3 and 33.0 months in the control. ARA290 retarded the reduction in BW by 0.04 grams/month2 (p < 0.02). FI score was significantly lower in ARA290 (0.22) compared to the control (0.30) (p < 0.001). Joint model predictions show higher risks of death by 1.2% for a 1 BPM decrease in BHR (p < 0.0001), by 1.5% for a 1 BPM decrease in IHR (p < 0.0001), by 1.1% for a 1 BPM decrease in ΔHR (p < 0.12), and by 11.9% for a 1% decrease in EF (p < 0.0001).

Conclusions

Reduced frailty of ARA290 in advanced age is consistent with improved healthspan. Concurrent ARA290 preservation in autonomic modulation of HR and EF are reflected by changes in BHR, IHR, ΔHR, and EF with age. Because a unit decrease in any of these markers predicted significantly higher risks for mortality, the impact of ARA290 on cardiac aging may contribute to the observed improvement in healthspan.

Support or Funding Information

Research was supported by the National Institute of Health/National Institute on Aging Intramural Researc program.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.