A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan.

Winicki NM, Nanavati AP, Morrell CH, Moen JM, Axsom JE, Krawczyk M, Petrashevskaya NN, Beyman MG, Ramirez C, Alfaras I, Mitchell SJ, Juhaszova M and 8 more

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Riordon DR, Wang M, Zhang J, Cerami A, Brines M, Sollott SJ, de Cabo R, Lakatta EG

Frontiers in cardiovascular medicine18 Jan 2023Cited by 3 (Europe PMC)

PMID36741836PMCIDPMC9889362DOI10.3389/fcvm.2022.1096887PepBankPUB-36741836

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Summary

BackgroundAging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age?MethodsWe conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan-Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions.ResultsChronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life.ConclusionAdministration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

12 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, chronic ARA290 mitigated the age-related increase in the cardiac non-myocyte to myocyte ratio versus saline.
In plain wordsIn aged rats, ARA290 reduced the age-related rise in non-muscle cells in the heart compared with saline.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseCardiac non-myocyte to myocyte ratio
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183601
02AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, chronic ARA290 mitigated the age-related increase in infiltrating leukocytes and monocytes in the heart.
In plain wordsIn aged rats, ARA290 reduced the age-related rise of immune cells in the heart compared with saline.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseInfiltrating leukocytes and monocytes in heart
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183602
03AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, chronic ARA290 mitigated the age-related increase in pro-inflammatory cytokines in the heart.
In plain wordsIn aged rats, ARA290 reduced the age-related rise of inflammatory signals in the heart compared with saline.
Peptide
Cibinetide (ARA-290)
Outcome
DecreasePro-inflammatory cytokines in heart
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183603
04AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, chronic ARA290 mitigated the age-related increase in total NF-κB in the heart.
In plain wordsIn aged rats, ARA290 reduced the age-related rise of the inflammation protein NF-κB in the heart.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseTotal NF-κB in heart
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183604
05AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, chronic ARA290 mitigated the age-related increase in p-NF-κB in the heart.
In plain wordsIn aged rats, ARA290 reduced the age-related rise of active NF-κB in the heart.
Peptide
Cibinetide (ARA-290)
Outcome
DecreasePhosphorylated NF-κB (p-NF-κB) in heart
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183605
06AnimalAnimal study (in vivo)Mechanism
In aged rats, ARA290 treatment enhanced cardiomyocyte autophagy flux.
In plain wordsIn aged rats, ARA290 increased the clearing of damaged material in heart muscle cells.
Peptide
Cibinetide (ARA-290)
Outcome
IncreaseCardiomyocyte autophagy flux
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated
Source sentences
Summary
Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183606
07AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, ARA290 treatment reduced cellular accumulation of lipofuscin in cardiomyocytes.
In plain wordsIn aged rats, ARA290 reduced build-up of an ageing pigment in heart cells.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseCardiomyocyte lipofuscin accumulation
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated
Source sentences
Summary
reduced cellular accumulation of lipofuscin.
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183607
08AnimalAnimal study (in vivo)Mechanism
In cardiomyocytes from aged rats, chronic ARA290 desensitized the mitochondrial permeability transition pore response to oxidant stress.
In plain wordsIn aged rats, ARA290 made heart cell mitochondria less sensitive to damage from oxidant stress.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseMitochondrial permeability transition pore response to oxidant stress
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment.
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183608
09AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, ARA290 significantly blunted the age-associated elevation in blood pressure.
In plain wordsIn aged rats, ARA290 reduced the age-related rise in blood pressure compared with saline.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseAge-associated elevation in blood pressure
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Blood pressure · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183609
10AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, ARA290 preserved the left ventricular ejection fraction.
In plain wordsIn aged rats, ARA290 kept the heart's pumping fraction better than saline.
Peptide
Cibinetide (ARA-290)
Outcome
IncreaseLV ejection fraction
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
preserved the LV ejection fraction.
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183610
11AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, ARA290 preserved body weight.
In plain wordsIn aged rats, ARA290 helped keep body weight compared with saline.
Peptide
Cibinetide (ARA-290)
Outcome
IncreaseBody weight at end of life
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Finally, ARA290 preserved body weight
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183611
12AnimalAnimal study (in vivo)Efficacy outcome
In aged rats, ARA290 significantly reduced other markers of organism-wide frailty at the end of life.
In plain wordsIn aged rats, ARA290 lowered several signs of frailty late in life compared with saline.
Peptide
Cibinetide (ARA-290)
Outcome
DecreaseMarkers of organism-wide frailty
Study
Fischer 344 x Brown Norway ratn: not reported in source
Aged (18-month-old) rats given chronic ARA290 or saline
Comparator
Saline
Outcome group
Aging markers · Aging and longevity
Studied dose
Dose not stated
Source sentences
Summary
significantly reduced other markers of organism-wide frailty at the end of life.
1 context sentence(design, population, supporting numbers)
Summary · context
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline.
Show in the study text Report a problemFND-3674183612

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Version 2Current
10 Oct 2026, 10:21 UTC
Study results updated
Version 1
9 Oct 2026, 03:13 UTC
First added · source update from Europe PMC

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