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A first-in-human, randomized, double-blind, single- and multiple-dose, phase I study of recombinant human thymosin β4 in healthy Chinese volunteers.
J Cell Mol Med
Xinghe Wang, Long Liu, Lu Qi +8 more
The study evaluated the safety, tolerability, pharmacokinetics (PK) and anti-drug antibody (ADA) of the recombinant human thymosin β4 (NL005) for single and multiple intravenous injections in healthy subjects. Seven cohorts, with 54 healthy subjects, were given a single intravenous dose of NL005 or placebo and were observed for 28 days. The cohorts received ascending doses of either 0.05, 0.25, 0.5, 2.0, 5.0, 12.5 or 25.0 μg/kg in the single-dose trial. A total of 30 healthy subjects were randomly enrolled in the multiple-dose trial, and 3 cohorts (0.5, 2.0 and 5.0 μg/kg) were administered once human thymosin β4 daily for 10 days and observed for 28 days. The adverse events were mild to moderate in intensity. There were no dose-limiting toxicities or serious adverse events. The plasma concentration, maximum peak concentration (Cmax ) and AUC of each dose group increased with the increase in the dose. The tendency of terminal clearance in each dose group was consistent, and there was no obvious accumulation after continuous administration. Thus, the drug can be concluded to be well tolerated and safe in healthy people and suitable for use in a clinical study for the treatment of acute myocardial infarction.
Growth hormone-releasing hormone antagonistic analog MIA-690 stimulates food intake in mice.
Peptides
Lucia Recinella, Annalisa Chiavaroli, Giustino Orlando +8 more
In addition to its metabolic and endocrine effects, growth hormone-releasing hormone (GHRH) was found to modulate feeding behavior in mammals. However, the role of recently synthetized GHRH antagonist MIA-690 and MR-409, a GHRH agonist, on feeding regulation remains to be evaluated. We investigated the effects of chronic subcutaneous administration of MIA-690 and MR-409 on feeding behavior and energy metabolism, in mice. Compared to vehicle, MIA-690 increased food intake and body weight, while MR-409 had no effect. Both analogs did not modify locomotor activity, as well as subcutaneous, visceral and brown adipose tissue (BAT) mass. A significant increase of hypothalamic agouti-related peptide (AgRP) gene expression and norepinephrine (NE) levels, along with a reduction of serotonin (5-HT) levels were found after MIA-690 treatment. MIA-690 was also found able to decrease gene expression of leptin in visceral adipose tissue. By contrast, MR-409 had no effect on the investigated markers. Concluding, chronic peripheral administration of MIA-690 could play an orexigenic role, paralleled by an increase in body weight. The stimulation of feeding could be mediated, albeit partially, by elevation of AgRP gene expression and NE levels and decreased 5-HT levels in the hypothalamus, along with reduced leptin gene expression, in the visceral adipose tissue.
Growth hormone replacement may influence the biological action of thyroid hormone on liver and bone tissue.
Growth Horm IGF Res
Nigel Glynn, David J Halsall, Gerard Boran +8 more
Growth hormone (GH) replacement alters the peripheral interconversion of thyroxine (T4) and triiodothyronine (T3). However, little is known about the clinical impact of these alterations. We aimed to compare changes observed in the serum T3:T4 ratio with known biological markers of thyroid hormone action derived from different peripheral tissues.
Calorie restriction modulates neuro-immune system differently in young and aged rats.
Int Immunopharmacol
Apala Chakraborty, Soumyabrata Banerjee, Biswajit Mukherjee +2 more
Aging weakens and deregulates the immune system and plays an impact on the central nervous system (CNS). A crosstalk in between the CNS-mediated immune system and the body's overall innate immunity is often found to increase and subsequently accelerate neurodegeneration and behavioural impairment during aging. Dietary calorie restriction (CR) is found to be a beneficial non-invasive anti-aging therapy as it shows rejuvenation of stress response, brain functions and behaviour during aging. The present investigation deals with the consequence of CR diet supplementation for two different duration (one and two consecutive months) on aging-related alteration of the immune response in male albino Wistar rats at the level of (a) lymphocyte viability, proliferation, cytotoxicity, and DNA fragmentation in blood, spleen, and thymus and (b) cytokines (IL-6, IL-10, and TNF-α) in blood, spleen, thymus and different brain-regions to understand the effect of CR diet on neuroimmune system. The results depict that CR diet consumption for consecutive one and two months by the aged (18 and 24 months) rats significantly attenuated the aging-related (a) decrease of blood, splenic and thymic lymphocyte viability, proliferative activity, cytotoxicity, and IL-10 level and (b) increase of (i) blood, splenic and thymic DNA fragmentation and (ii) IL-6 and TNF-α level in those tissues and also in different brain regions. Unlike older rats, in young (4 months) rats, the consumption of CR diet under similar conditions affected those above-mentioned immune parameters reversibly and adversely. This study concludes that (a) aging significantly (p < 0.01) deregulates the above-mentioned immune parameters, (b) consecutive consumption of CR diet for one and two months is (i) beneficial (p < 0.05) to the aging-related immune system [lymphocyte viability, lymphocyte proliferation, cytotoxicity, pro (IL-6 and TNF-α)- and anti (IL-10)-inflammatory cytokines], but (ii) adverse (p < 0.05) to the immune parameters of the young rats, and (c) consumption of CR diet for consecutive two months is more potent (p < 0.05) than that due to one month.
Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans.
Hum Genet
A Kemal Topaloglu, Enver Simsek, Matthew A Kocher +8 more
Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate nucleus of the hypothalamus constitute the GnRH (gonadotropin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in-silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2's critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.
The effects of collagen peptide supplementation on body composition, collagen synthesis, and recovery from joint injury and exercise: a systematic review.
Amino Acids
Mishti Khatri, Robert J Naughton, Tom Clifford +2 more
Collagen peptide supplementation (COL), in conjunction with exercise, may be beneficial for the management of degenerative bone and joint disorders. This is likely due to stimulatory effects of COL and exercise on the extracellular matrix of connective tissues, improving structure and load-bearing capabilities. This systematic review aims to evaluate the current literature available on the combined impact of COL and exercise. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a literature search of three electronic databases-PubMed, Web of Science and CINAHL-was conducted in June 2020. Fifteen randomised controlled trials were selected after screening 856 articles. The study populations included 12 studies in recreational athletes, 2 studies in elderly participants and 1 in untrained pre-menopausal women. Study outcomes were categorised into four topics: (i) joint pain and recovery from joint injuries, (ii) body composition, (iii) muscle soreness and recovery from exercise, and (iv) muscle protein synthesis (MPS) and collagen synthesis. The results indicated that COL is most beneficial in improving joint functionality and reducing joint pain. Certain improvements in body composition, strength and muscle recovery were present. Collagen synthesis rates were elevated with 15 g/day COL but did not have a significant impact on MPS when compared to isonitrogenous higher quality protein sources. Exact mechanisms for these adaptations are unclear, with future research using larger sample sizes, elite athletes, female participants and more precise outcome measures such as muscle biopsies and magnetic imagery.
Chronic exposure to perfluorohexane sulfonate leads to a reproduction deficit by suppressing hypothalamic kisspeptin expression in mice.
J Ovarian Res
Xiaorui Yin, Tingting Di, Xinyuan Cao +3 more
Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid found as an environmental contaminant. This study aims to investigate the effects of PFHxS exposure on female reproduction and the underlying mechanism in mice.
Antimicrobial peptides: mechanism of action and lipid-mediated synergistic interactions within membranes.
Faraday Discuss
Dennis W Juhl, Elise Glattard, Christopher Aisenbrey +1 more
Biophysical and structural studies of peptide-lipid interactions, peptide topology and dynamics have changed our view of how antimicrobial peptides insert and interact with membranes. Clearly, both peptides and lipids are highly dynamic, and change and mutually adapt their conformation, membrane penetration and detailed morphology on a local and a global level. As a consequence, peptides and lipids can form a wide variety of supramolecular assemblies in which the more hydrophobic sequences preferentially, but not exclusively, adopt transmembrane alignments and have the potential to form oligomeric structures similar to those suggested by the transmembrane helical bundle model. In contrast, charged amphipathic sequences tend to stay intercalated at the membrane interface. Although the membranes are soft and can adapt, at increasing peptide density they cause pronounced disruptions of the phospholipid fatty acyl packing. At even higher local or global concentrations the peptides cause transient membrane openings, rupture and ultimately lysis. Interestingly, mixtures of peptides such as magainin 2 and PGLa, which are stored and secreted naturally as a cocktail, exhibit considerably enhanced antimicrobial activities when investigated together in antimicrobial assays and also in pore forming experiments applied to biophysical model systems. Our most recent investigations reveal that these peptides do not form stable complexes but act by specific lipid-mediated interactions and the nanoscale properties of phospholipid bilayers.
Lefty1 Ameliorates Post-infarction Fibrosis by Suppressing p-Smad2 and p-ERK1/2 Signaling Pathways.
J Cardiovasc Transl Res
Chang-Yi Li, Jing-Rui Zhang, Xin-Xin Li +4 more
Transforming growth factor-β1 signaling pathways are known to involve in the development of post-infarction fibrosis, a process characterized by the aberrant activation, proliferation, and differentiation of fibroblasts, as well as the unbalanced turnover of extracellular matrix proteins. Recent studies have shown that Lefty1, a novel member of TGF-β superfamily, acts as a brake on the TGF-β signaling pathway in non-cardiac tissues. However, its role in myocardial infarction (MI)-induced fibrosis and left ventricular remodeling has not been fully elucidated. Here, for the first time, we reported that Lefty1 alleviated post-MI fibroblast proliferation, differentiation, and secretion through suppressing p-Smad2 and p-ERK1/2 signaling pathways in vivo and in vitro. In MI mice or TGF-β1-treated neonatal rat cardiac fibroblasts (CFBs), the expression of Lefty1 was upregulated. Adenovirus-mediated overexpression of Lefty1 significantly attenuated TGF-β1-induced CFBs' proliferation, differentiation, and collagen production. Using the adeno-associated virus approach, we confirmed that Lefty1 attenuates MI-induced cardiac injury, as evidenced by the decreased infarct size and preserved cardiac function. These results highlight the importance of Lefty1 in the prevention of post-MI fibrosis and may help identify potential targets for therapeutic intervention of cardiac fibrosis. Graphical abstract.
Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism.
Neuroendocrinology
Ali Abbara, Pei Chia Eng, Maria Phylactou +14 more
Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH.
The immunosuppressive effects of low molecular weight chitosan on thymopentin-activated mice bearing H22 solid tumors.
Int Immunopharmacol
Hai-Yu Ji, Chao Liu, Ke-Yao Dai +3 more
In the present study, the low molecular weight of chitosan (CS) was prepared and its activity on thymopentin-activated mice bearing H22 solid tumors was further researched. The purity and molecular weight of CS were determined by UV and HPGPC spectra, and its immunosuppressive effects on H22 tumor-bearing mice were evaluated through determination on immune organs, cells and cytokines. Results showed that CS contained little impurities with the average molecular weight of 1.20 × 104 Da. The in vivo antitumor experiments demonstrated that CS facilitated to destroy immune organs (thymuses and spleens), suppress immune cells (lymphocytes, macrophages and NK cells) activities and reduce immune-related cytokines (TNF-α, IFN-γ, IL-2 and IL-4) expressions of H22 tumor-bearing mice even with simultaneous TP5 stimulation. Our data suggested that CS could not be applied to improve immune response in cancer-bearing patients, but might be employed for treatments on autoimmune diseases or organ transplant patients.
Bremelanotide for Treatment of Female Hypoactive Sexual Desire.
Neurol Int
Amber N Edinoff, Nicole M Sanders, Kyle B Lewis +4 more
Hypoactive sexual desire disorder (HSDD) is a persistent deficiency or absence of sexual fantasies and desire resulting in significant distress or interpersonal difficulty. Women with this disorder may display a lack of motivation for sexual activity, reduced responsiveness to erotic cues, a loss of interest during sexual activity, and avoidance of situations that could lead to sexual activity. The pathophysiology of HSDD is thought to be centered around inhibitory and excitatory hormones, neurotransmitters, and specific brain anatomy. Due to the multifactorial nature of HSDD, treatment can be complex and must attempt to target the biological and psychosocial aspects of the disorder. Bremelanotide is a melanocortin receptor agonist and has been recently approved by the FDA to treat HSDD. Bremelanotide is administered intranasally or as a subcutaneous injection. The recommended dosage of bremelanotide is 1.75 mg injected subcutaneously in the abdomen or thigh at least 45 min before sexual activity. Studies showed improvements in desire, arousal, and orgasm scores when 1.75 mg of bremelanotide was administered before sexual activity compared to a placebo. Bremelanotide is a promising way to treat HSDD.
The two-faced effects of nerves and neuropeptides in corneal diseases.
Prog Retin Eye Res
Romina Mayra Lasagni Vitar, Paolo Rama, Giulio Ferrari
Corneal nerves are instrumental to maintain cornea integrity through regulation of key physiological functions such as tear secretion, blink reflex, and neuropeptide turnover. Corneal nerve injury/stimulation can follow many insults including mechanical/chemical trauma, infections and surgeries. Nerve disruption initiates a process named neurogenic inflammation which leads to edema, pain, and recruitment and activation of leukocytes. Interestingly, leukocyte influx in the cornea can further damage nerves by releasing inflammatory mediators-including neuropeptides. The clinical outcome of neuroinflammation can be beneficial or detrimental to corneal integrity. On one side, it ensures prompt wound healing and prevents infections. On the other, prolonged and/or deranged neuroinflammation can permanently disrupt corneal integrity and impair vision. The cornea is an ideal site to study peripheral neuroinflammation and neurogenic inflammation since it receives the highest density of sensory nerves of the entire body. We will review the corneal nerve anatomy and neurochemistry, discuss the beneficial and detrimental effects of neurogenic inflammation in corneal wound healing, inflammatory processes, and pain. We will also examine the emerging remote impact of corneal nerve disruption on the trigeminal ganglion and the brain, highlighting the key role of neuropeptide Substance P. Finally, we will discuss the clinical relevance of such neuroinflammatory network in the context of severe and highly prevalent ocular diseases, including potential treatments.
Sedative-Hypnotic Agents That Impact Gamma-Aminobutyric Acid Receptors: Focus on Flunitrazepam, Gamma-Hydroxybutyric Acid, Phenibut, and Selank.
J Clin Pharmacol
Cassandra R Doyno, C Michael White
There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues.
Effect of metformin treatment on memory and hippocampal neurogenesis decline correlated with oxidative stress induced by methotrexate in rats.
Biomed Pharmacother
Nataya Sritawan, Kornrawee Suwannakot, Salinee Naewla +6 more
Metformin is currently used as a first-line drug to treat patients with type 2 diabetes. Previous studies have demonstrated that metformin has antioxidant properties and reduces neuroinflammation and hippocampal neuronal cell loss, which eventually improves memory. Methotrexate (MTX) is an antimetabolite chemotherapeutic agent reported to activate cognitive impairment found in many patients. Moreover, MTX negatively affects the spatial working memory, related to neurogenesis reduction in animal models. Therefore, the present study aimed to investigate the antioxidant effect of metformin on the reduction of memory and neurogenesis caused by MTX. Male Sprague-Dawley rats were divided into four groups: control, MTX, metformin, and MTX+metformin. MTX (75 mg/kg, i.v.) was administered on days 7 and 14. Rats were administered metformin (200 mg/kg, i.p.) for 14 days. Memory was determined using novel object location (NOL) and novel object recognition (NOR) tests. Furthermore, cell cycle arrest was quantified by p21 immunostaining. Levels of neuronal protein expression, scavenging enzymes activity, and malondialdehyde (MDA) level changes in the hippocampus and prefrontal cortex were investigated. Rats receiving only MTX showed memory impairment. Decreases in scavenging enzyme activity and BDNF, DCX, and Nrf2 protein expressions levels were detected in the MTX-treated rats. In addition, MTX significantly increased p21-positive cell numbers and MDA levels. However, these adverse MTX effects were counteracted by co-administration with metformin. These results demonstrate that metformin can improve memory impairments, increase BDNF, DCX and Nrf2 protein expressions and antioxidant capacities, and decrease MDA levels in MTX-treated rats.
Effects of growth hormone-releasing hormone agonistic analog MR-409 on insulin-secreting cells under cyclopiazonic acid-induced endoplasmic reticulum stress.
Mol Cell Endocrinol
Karina Rodrigues-Dos-Santos, Gabriela M Soares, Dimitrius S P S F Guimarães +9 more
The endoplasmic reticulum (ER) stress is one of the mechanisms related to decreased insulin secretion and beta cell death, contributing to the progress of type 2 diabetes mellitus (T2D). Thus, investigating agents that can influence this process would help prevent the development of T2D. Recently, the growth-hormone-releasing hormone (GHRH) action has been demonstrated in INS-1E cells, in which it increases cell proliferation and insulin secretion. As the effects of GHRH and its agonists have not been fully elucidated in the beta cell, we proposed to investigate them by evaluating the role of the GHRH agonist, MR-409, in cells under ER stress. Our results show that the agonist was unable to ameliorate or prevent ER stress. However, cells exposed to the agonist showed less oxidative stress and greater survival even under ER stress. The mechanisms by which GHRH agonist, MR-409, leads to these outcomes require further investigation.
Protection effect of thymosin β4 on ethanol injury in corneal stromal keratocyte.
BMC Ophthalmol
Jinghua Liu, Chen Guo, Peng Hao +4 more
To investigate the protective effects of thymosin β4 (Tβ4) on ethanol injured human corneal keratocytes (HCKs).
Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics.
Front Med Technol
Hiroshi Ueda
Tyrosine-arginine (kyotorphin), an opioid analgesic dipeptide, was discovered more than 40 years ago in 1979. The evidence accumulated during this period has established the physiological significance of kyotorphin as a neuromodulating peptide, and pharmacological applications. Some of the following important findings have been discussed in this review: (1) kyotorphin is unevenly distributed in the brain; it is found in high concentrations in the pain pathway, which involves the regions associated with morphine analgesia; (2) kyotorphin is subcellularly localized in the synaptosome fraction or nerve-ending particles; (3) a specific synthetase generates kyotorphin from tyrosine and arginine; (4) kyotorphin may be also processed from calpastatin by a novel calcium-activated neutral protease or calpain; (5) kyotorphin preloaded into the synaptosome is released by high K+ depolarization in a Ca2+-dependent manner; (6) kyotorphin has a specific G protein coupled receptor, which mediates the activation of phospholipase C (PLC) and inhibition of adenylyl cyclase through Gi; (7) leucine-arginine works as a specific kyotorphin receptor antagonist; 8) membrane-bound aminopeptidase or excretion through a peptide transporter, PEPT2, may contribute to the inactivation of kyotorphin; and (9) kyotorphin causes increased Met-enkephalin release from brain and spinal slices. It is also known that the opening of plasma membrane Ca2+ channels through a conformational coupling of the InsP3 receptor with the transient receptor potential C1, which is downstream of the kyotorphin receptor-mediated activation of Gi and PLC, could be a potential underlying mechanism of Met-enkephalin release. Considering these findings, translational research is an exciting domain that can be explored in the future. As kyotorphin is a small molecule, we could design function-added kyotorphin derivatives. These studies would include not only the brain-permeable kyotorphin derivatives but also hybrid kyotorphin derivatives conjugated with small compounds that have additional pharmacological actions. Further, since there are reports of kyotorphin being involved in either the etiology or treatment of Alzheimer's disease, epilepsy, inflammation, and chronic pain, studies on the beneficial effects of kyotorphin derivatives should also be expected in the future.
[Multimodal therapeutic strategies in the treatment of cerebrovascular disease].
Zh Nevrol Psikhiatr Im S S Korsakova
A I Fedin, E N Saverskaya, K R Badalyan
The review presents the scientific substantiation of the relationship between age-related cerebrovascular changes and dysregulation of cerebral perfusion, blood-brain barrier (BBB) function and neurovascular units. The ischemic cascade in cerebrovascular disease (CVD) is considered, the main links of which are glutamate excitoxicosis, oxidative stress and neuroinflammation. Endothelial dysfunction and increased BBB permeability play an important role in the development of neuroinflammation. The use of multifunctional drugs aimed at various pathological targets of acute and chronic cerebral ischemia for the purpose of neuroprotection has been substantiated. These drugs include the peptide Cortexin (cattle cerebral cortex polypeptides). Experimental data on the study of its molecular partners in the brain are presented. The clinical efficacy of Cortexin as a neuroprotective drug in CVD has been established in many studies.
Improvement of cardiac and systemic function in old mice by agonist of growth hormone-releasing hormone.
J Cell Physiol
Pingping Xiang, Wangwei Jing, Yinuo Lin +9 more
Age-related diseases such as cardiovascular diseases portend disability, increase health expenditures, and cause late-life mortality. Synthetic agonists of growth hormone-releasing hormone (GHRH) exhibit several favorable effects on heart function and remodeling. Here we assessed whether GHRH agonist MR409 can modulate heart function and systemic parameters in old mice. Starting at the age of 15 months, mice were injected subcutaneously with MR409 (10 µg/day, n = 8) or vehicle (n = 7) daily for 6 months. Mice treated with MR409 showed improvements in exercise activity, cardiac function, survival rate, immune function, and hair growth in comparison with the controls. More stem cell colonies were grown out of the bone marrow recovered from the MR409-treated mice. Mitochondrial functions of cardiomyocytes (CMs) from the MR409-treated mice were also significantly improved with more mitochondrial fusion. Fewer β-gal positive cells were observed in endothelial cells after 10 passages with MR409. In Doxorubicin-treated H9C2 cardiomyocytes, cell senescence marker p21 and reactive oxygen species were significantly reduced after cultured with MR409. MR409 also improved cellular ATP production and oxygen consumption rate in Doxorubicin-treated H9C2 cells. Mitochondrial protein OPA1 long isoform was significantly increased after treatment with MR409. The effects of MR409 were mediated by GHRH receptor and protein kinase A (PKA). In short, GHRH agonist MR409 reversed the aging-associated changes with respect of heart function, mobility, hair growth, cellular energy production, and senescence biomarkers. The improvement of heart function may be related to a better mitochondrial functions through GHRH receptor/cAMP/PKA/OPA1 signaling pathway and relieved cardiac inflammation.