Humanin

Assessment of mitochondrial peptide humanin in women with polycystic ovary syndrome: serum and skeletal muscle profile.

Irem Sonmezoglu Kutuk, Senay Akin, Haydar Demirel +3 more

Redox-sensitive miRNAs and Humanin could mediate effects of exercise and astaxanthin on oxidative stress and inflammation in type 2 diabetes.

Aref Basereh, Karen Khoramipour, Najmeh Hosseini +4 more

Type 2 diabetes mellitus (T2DM) is driven by oxidative stress (OS) and inflammation (IF), accelerating disease progression. This study examined whether combined aerobic and resistance training (CT) and astaxanthin (AST) supplementation synergistically improve oxidant and inflammatory status as well as metabolic indices in T2DM, focusing on the mediatory role of Humanin (HN) and microRNAs (miRNA-122, miRNA-126-3p, and miRNA-146a). Ninety women with T2DM were randomly assigned to six groups (n = 15 each): control (C), placebo (P), AST supplementation (S), combined training (CT), CT + placebo (CT + P), and CT + AST supplementation (CT + S). CT, CT + P and CT + S groups underwent an 8-week training program (eight exercises, three sessions per week). Groups and CT + S groups received 8 mg/day of AST. OS markers, inflammatory cytokines, HN levels, miRNAs expression, fasting blood glucose (FBG), insulin resistance (HOMA-IR), lipid profile, and hemoglobin A1c (HbA1c) were assessed. Both CT and AST enhanced antioxidant defenses and reduced IF, with CT + S showing the best effects. HN levels increased significantly in CT and CT + S (p < 0.05). MiRNA-126-3p and miRNA-146a were upregulated, while miRNA-122 was downregulated in CT + S compared to other groups. Lipid profile improved with both interventions, with CT + S yielding the highest increases in HDL and triglycerides. FBG, IR, and HbA1c improved significantly in CT groups but remained unchanged with S group. The metabolic and anti-inflammatory benefits of CT and AST in T2DM may mediated by the effects of HN on mitochondrial function and insulin signaling, together with miRNA-mediated regulation of lipid metabolism, endothelial health, and innate immunity. Targeting these molecular pathways may improve therapeutic strategies for diabetes management.

A Review on the Potential Role of Humanin Peptide and its Analogs in the Regulation of Autophagy Pathways for Therapeutic Application in Metabolic Disorders.

Hira Moin, Rizwan Ashraf, Batool Butt +3 more

Autophagy is a self-eating cellular process in which the cell breaks down worn-out organelles, damaged/defective proteins, and toxins. Impaired autophagy is a significant factor in the development of various metabolic disorders, along with oxidative stress, inflammation, mitochondrial and endoplasmic reticulum dysfunction. These disorders pose a significant health and economic burden on the global human population, owing to their steadily rising prevalence. Therefore, modulating the expression of proteins involved in the autophagy-related pathways can be a promising avenue for curbing the development and progression of these disorders. Humanin (HN) is a 24-amino acid mitochondrial-derived peptide. It possesses anti-oxidant, anti-inflammatory, and pro-apoptotic properties. The analogs of HN can be generated by replacing specific amino acids in the polypeptide chain, thereby functionally modifying the peptide. Among these, humanin- glycine (HNG) is the most widely studied analog in both in vivo and in vitro disease models. It is far more potent than HN, with a potency that is 1000 times greater. To the best of our knowledge, this review is the first to discuss and examine the available evidence regarding the potential involvement of HN or its analogs in regulating autophagy pathways. The review primarily highlights that HN is an autophagy inducer, which can promote cell survival in the presence of metabolic and oxidative stress, particularly the HNG analog. Future research is imperative to comprehensively evaluate the effects of HN and its analogs on autophagy. Further investigations are needed to correlate its levels with various autophagic markers in different metabolic diseases, offering the potential for groundbreaking discoveries in understanding disease mechanisms and developing novel therapeutic strategies.

The neuroprotective role of Humanin in Alzheimer's disease: The molecular effects.

Saad Misfer Alqahtani, Hayder M Al-Kuraishy, Ali I Al-Gareeb +6 more

Humanin (HN) is an endogenous micropeptide also known as a mitochondria-derived peptide. It has a neuroprotective effect against Alzheimer's disease (AD) and other neurodegenerative diseases by improving hippocampal acetylcholine and attenuating the development of oxidative stress and associated neurotoxicity. HN protects the neuron from the toxic effects of amyloid beta (Aβ). HN is regarded as a biomarker of mitochondrial stress. Interestingly, aging reduces brain expression of HN, leading to cognitive impairment and elevating the risk of neurodegeneration, including AD. However, in old subjects and AD patients, circulating HN levels increase as a compensatory mechanism to reduce neurodegeneration and mitochondrial dysfunction in AD. Conversely, other studies demonstrated a reduction in circulating HN levels in AD. These findings indicated controversial points regarding the precise mechanistic role of HN in AD. Therefore, the aim of this review was to discuss the exact role of HN in AD neuropathology and also to discuss the molecular mechanisms of HN in AD.

Hepatic and Pancreatic Cellular Response to Early Life Nutritional Mismatch.

Shubhamoy Ghosh, Amit Ganguly, Manal Habib +4 more

To determine the basis for perinatal nutritional mismatch causing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus, we examined adult phenotype, hepatic transcriptome, and pancreatic β-islet function. In prenatal caloric-restricted rats with intrauterine growth restriction (IUGR) and postnatal exposure to high fat with fructose (HFhf) or high carbohydrate, we investigated male and female IUGR-HFhf and IUGR-high carbohydrate, vs HFhf and control offspring. Males more than females displayed adiposity, glucose intolerance, insulin resistance, hyperlipidemia, and hepatomegaly with hepatic steatosis. Male hepatic triglyceride synthesis, de novo lipogenesis genes increased, while female lipolysis, β-oxidation, fatty acid efflux, and FGF21 genes increased. IUGR-HFhf males demonstrated reduced β-islet insulin and humanin, and type 1 diabetes mellitus human amniotic fluid increased humanin. Humanin suppression disabled glucose stimulated insulin, ATP production, with apoptotic diminished β-islet viability. Humanin and FGF21 may reverse perinatal nutritional mismatched phenotype by restoring functional β islets and preventing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus.

SHLP6: a novel NLRP3 and Cav1 modulating agent in Cu-induced oxidative stress and neurodegeneration.

H Thamarai Kannan, Suganiya Umapathy, Ieshita Pan

Copper sulfate exposure induces oxidative stress by triggering excessive reactive oxygen species (ROS) production, leading to inflammatory responses, neuroinflammation, and cellular dysfunction. Small humanin-like peptide-6 (SHLP-6), a mitochondria-derived peptide with anti-aging and anti-cancer properties, has not been explored for its protective effects against copper sulfate toxicity. This study investigates the antioxidant, anti-inflammatory, and neuroprotective potential of SHLP-6 in zebrafish larvae exposed to copper sulfate.

The Effect of Chronic Endurance Exercise on Serum Levels of MOTS-c and Humanin in Professional Athletes.

Maha Alser, Manjunath Ramanjaneya, Najeha Rizwana Anwardeen +7 more

Humanin and the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are mitochondrial encoded peptides involved in energy metabolism, cytoprotection, longevity, insulin sensitivity and their expression decrease with age. Levels of these molecules have been shown to respond to acute exercise, however little is known about their modulation under different chronic exercise conditions. In this study, we aim to compare levels of Humanin and MOTS-c in non-athletes vs professional (moderate and high endurance) athletes.

Cardio-protective role of Humanin in myocardial ischemia-reperfusion.

Zhenwei Gong, Eric Goetzman, Radhika H Muzumdar

Mitochondria-derived peptides (MDPs) are bioactive peptides encoded by and secreted from the mitochondria. To date, a few MDPs including humanin, MOTS-c and SHLP1-6, and their diverse biological functions have been identified. The first and most studied MDP is humanin, a 24-amino-acid poly peptide. It was first identified in 2001 in the surviving neurons of patient with Alzheimer's disease, and since then has been well characterized for its neuro-protective effect through inhibition of apoptosis. Over the past two decades, humanin has been reported to play critical roles in aging as well as multiple diseases including metabolic disorders, cardiovascular diseases, and autoimmune disease. Humanin has been shown to modulate multiple biological processes including autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. A role for humanin has been shown in a wide range of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and myocardial fibrosis. In this minireview, we will summarize the literature demonstrating a role for humanin in cardio-protection following myocardial ischemia-reperfusion induced injury and the potential mechanisms that mediate it.

Mitochondrial-derived peptides and exercise.

Jonathan S T Woodhead, Troy L Merry

Acute exercise, and in particular aerobic exercise, increases skeletal muscle energy demand causing mitochondrial stress, and mitochondrial-related adaptations which are a hallmark of exercise training. Given that mitochondria are central players in the exercise response, it is imperative that they have networks that can communicate their status both intra- and inter-cellularly. Peptides encoded by short open-reading frames within mitochondrial DNA, mitochondrial-derived peptides (MDPs), have been suggested to form a newly recognised branch of this retrograde signalling cascade that contribute to coordinating the adaptive response to regular exercise. Here we summarise the recent evidence that acute high intensity exercise in humans can increase concentrations of the MDPs humanin and MOTS-c in skeletal muscle and plasma, and speculate on the mechanisms controlling MDP responses to exercise stress. Evidence that exercise training results in chronic changes in MDP expression within tissues and the circulation is conflicting and may depend on the mode, duration, intensity of training plan and participant characteristics. Further research is required to define the effect of these variables on MDPs and to determine whether MDPs other than MOTS-c have exercise mimetic properties. MOTS-c treatment of young and aged mice improves exercise capacity/performance and leads to adaptions that are similar to that of being physically active (weight loss, increased antioxidant capacity and improved insulin sensitivity), however, studies utilising a MOTS-c inactivating genetic variant or combination of exercise + MOTS-c treatment in mice suggest that there are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits. Overall, MOTS-c, and potentially other MDPs, may be exercise-sensitive myokines and further work is required to define inter- and intra-tissue targets in an exercise context.

Evidence of natural selection in the mitochondrial-derived peptides humanin and SHLP6.

James M Gruschus, Daniel L Morris, Nico Tjandra

Mitochondrial-derived peptides are encoded by mitochondrial DNA but have biological activity outside mitochondria. Eight of these are encoded by sequences within the mitochondrial 12S and 16S ribosomal genes: humanin, MOTS-c, and the six SHLP peptides, SHLP1-SHLP6. These peptides have various effects in cell culture and animal models, affecting neuroprotection, insulin sensitivity, and apoptosis, and some are secreted, potentially having extracellular signaling roles. However, except for humanin, their importance in normal cell function is unknown. To gauge their importance, their coding sequences in vertebrates have been analyzed for synonymous codon bias. Because they lie in RNA genes, such bias should only occur if their amino acids have been conserved to maintain biological function. Humanin and SHLP6 show strong synonymous codon bias and sequence conservation. In contrast, SHLP1, SHLP2, SHLP3, and SHLP5 show no significant bias and are poorly conserved. MOTS-c and SHLP4 also lack significant bias, but contain highly conserved N-terminal regions, and their biological importance cannot be ruled out. An additional potential mitochondrial-derived peptide sequence was discovered preceding SHLP2, named SHLP2b, which also contains a highly conserved N-terminal region with synonymous codon bias.

Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson's disease.

Kyung Hwa Kim

Rationale: Mitochondrial dysfunction is a key factor in the pathogenesis of Parkinson's disease (PD). Accordingly, many aspects of mitochondrial function have been studied as a putative therapeutic target. Here we present a novel strategy to promote mitochondrial function and protect against Parkinson's disease by the peptide encoded within mitochondrial genome, mitochondria-derived peptide (MDP) humanin (HN). Methods: To test humanin as a potential biomarker in PD, we measured protein levels of circulating humanin from the plasma of PD patients and transgenic or neurotoxic mouse models of PD. Next, we aimed to identify whether HN peptide treatment can regulate its activity or expression. Using mouse models of PD, we assessed HN delivery to the brain via the nasal route of administration. We further revealed a possible mechanism underlying the therapeutic effectiveness of HN peptide for PD using in vitro and ex vivo model of PD. Results: Although the expression of intracellular HN was not correlated with PD, HN treatment itself could induce intracellular HN expression and enhance mitochondrial biogenesis inducing mitochondrial gene expression. After intranasal administration, HN peptide resulted in neuroprotection and behavioral recovery in an animal model of PD. Interestingly, HN peptide following intranasal delivery was found within the brain, mainly via the trigeminal pathways. Mechanistically, HN treatment induced activation of phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway which led to enhanced mitochondrial biogenesis resulting in upregulation of mitochondrial gene including humanin. Conclusion: These data support a novel role of mitochondrial protein humanin in mitochondrial function and neuronal survival against Parkinson's disease, in which humanin treatment is sufficient for stimulating mitochondrial gene expression.

Evolution of Mitochondrially Derived Peptides Humanin and MOTSc, and Changes in Insulin Sensitivity during Early Gestation in Women with and without Gestational Diabetes.

David Ruiz, Miguel Santibañez, Bernardo Alio Lavín +3 more

Our purpose is to study the evolution of mitochondrially derived peptides (MDPs) and their relationship with changes in insulin sensitivity from the early stages of pregnancy in a cohort of pregnant women with and without gestational diabetes (GDM). MDPs (humanin and MOTSc) were assessed in the first and second trimesters of gestation in 28 pregnant women with gestational diabetes mellitus (GDM) and a subgroup of 45 pregnant women without GDM matched by BMI, age, previous gestations, and time of sampling. Insulin resistance (IR) was defined as a HOMA-IR index ≥70th percentile. We observed a significant reduction in both humanin and MOTSc levels from the first to the second trimesters of pregnancy. After adjusting for predefined variables, including BMI, statistically nonsignificant associations between lower levels of humanin and the occurrence of a high HOMA-IR index were obtained (adjusted OR = 2.63 and 3.14 for the first and second trimesters, linear p-trend 0.260 and 0.175, respectively). Regarding MOTSc, an association was found only for the second trimester: adjusted OR = 7.68 (95% CI 1.49-39.67), linear p-trend = 0.012. No significant associations were observed in humanin change with insulin resistance throughout pregnancy, but changes in MOTSc levels were significantly associated with HOMA-IR index: adjusted OR 3.73 (95% CI 1.03-13.50). In conclusion, MOTSc levels, especially a strong decrease from the first to second trimester of gestation, may be involved in increasing insulin resistance during early gestation.

Humanin attenuates palmitate-induced hepatic lipid accumulation and insulin resistance via AMPK-mediated suppression of the mTOR pathway.

ChangHyuk Kwon, Jaw Long Sun, Ji Hoon Jeong +1 more

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains unclear. Humanin (HN), a cytoprotective polypeptide, reportedly exhibits neuroprotective effects via suppression of inflammation and improvement of insulin resistance in neurons. This study aim was to investigate effects of HN on lipid accumulation in the hepatocytes and insulin signaling, and explore the underlying mechanisms. Protein expression levels were analyzed by Western blotting. Hepatic lipid accumulation was confirmed by Oil red-O staining. We found that HN-treatment ameliorated palmitate-induced lipid accumulation, expression of lipogenesis-associated genes (processed SREBP1, FAS, and SCD1), cell death, and caspase 3 activity in hepatocytes in a dose-dependent manner. Additionally, HN attenuated palmitate-induced impairment of insulin signaling. HN enhanced AMPK phosphorylation, whereas it suppressed palmitate-induced phosphorylation of mTOR. AMPK knockdown by siRNA neutralized the effects of HN on palmitic acid-treated hepatocytes. Collectively, HN prevents palmitate-induced hepatic lipid accumulation, apoptosis, and insulin resistance via AMPK-mediated suppression of the mTOR/SREBP1 pathway, suggesting that it may serve as a potential therapeutic agent in NAFLD treatment.

Humanin and diabetes mellitus: A review of in vitro and in vivo studies.

Chrysoula Boutari, Panagiotis D Pappas, Theodoros D Theodoridis +1 more

Humanin (HN) is a 24-amino acid mitochondrial-derived polypeptide with cyto-protective and anti-apoptotic effects that regulates the mitochondrial functions under stress conditions. Accumulating evidence suggests the role of HN against age-related diseases, such as Alzheimer's disease. The decline in insulin action is a metabolic feature of aging and thus, type 2 diabetes mellitus is considered an age-related disease, as well. It has been suggested that HN increases insulin sensitivity, improves the survival of pancreatic beta cells, and delays the onset of diabetes, actions that could be deployed in the treatment of diabetes. The aim of this review is to present the in vitro and in vivo studies that examined the role of HN in insulin resistance and diabetes and to discuss its newly emerging role as a therapeutic option against those conditions.

Mitochondrial-Derived Peptides in Diabetes and Its Complications.

Ying Wu, Liankun Sun, Zhoudao Zhuang +2 more

The changes of mitochondrial function are closely related to diabetes and its complications. Here we describe the effects of mitochondrial-derived peptides (MDPs), short peptides formed by transcription and translation of the open reading frame site in human mitochondrial DNA (mtDNA), on diabetes and its complications. We mainly focus on MDPs that have been discovered so far, such as Humanin (HN), mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) and Small humanin-like peptides (SHLP 1-6), and elucidated the role of MDPs in diabetes and its major complications stroke and myocardial infarction by improving insulin resistance, inhibiting inflammatory response and anti-apoptosis. It provides more possibilities for the clinical application of mitochondrial derived peptides.

The role of humanin in the regulation of reproduction.

Hui Lei, Meng Rao

Humanin, a mitochondria-derived peptide, has been found to exert variously protective function in many tissues, especially in the nervous tissues. However, relatively limited studies have focused on the role of humanin in the regulation of reproduction. Current observations indicate that humanin plays an important role in regulating the response of the cell to oxidative stress and apoptosis in ovaries and testes via the modulation of several signaling pathways, especially when the body is in an abnormal state. Even so, the detailed mechanism of humanin function needs to be explored urgently. In this passage, we demonstrate how humanin exerts its protective role in female and male reproduction and raise several questions that need further investigations. Given humanin's new frontier for the design of novel therapeutic approaches for male infertility, male contraception, female infertility, and glucose metabolism in polycystic ovary syndrome, it is worthy of further study on its protective effects and clinical applications in reproductive function.

Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study.

Yingying Wang, Zhengyan Zeng, Shuhua Zhao +10 more

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism and insulin resistance (IR); however, the pathogenesis of local ovarian IR in PCOS remains largely unclear. Humanin, a mitochondria-derived peptide, has been reported to be associated with IR. Our previous study confirmed that humanin is expressed in multiple cell types in the ovary and is present in follicular fluid. However, it remains unknown whether humanin participates in the pathogenesis of local ovarian IR or whether humanin supplementation can improve IR in PCOS patients. In this study, we compared humanin concentrations in follicular fluid from PCOS patients with and without IR. We further investigated the effect of humanin analogue (HNG) supplementation on IR in a rat model of dehydroepiandrosterone-induced PCOS. Humanin concentrations in the follicular fluid were found to be significantly lower in PCOS patients with IR than in those without IR. HNG supplementation attenuated both the increases in the levels of fasting plasma glucose and fasting insulin in rats with PCOS and the decreases in phosphorylation of IRS1, PI3K, AKT, and GLUT4 proteins in the granulosa cells of these rats. Combined supplementation with HNG and insulin significantly improved glucose consumption in normal and humanin-siRNA-transfected COV434 cells. In conclusion, downregulated humanin in the ovaries may be involved in the pathogenesis of IR in PCOS, and exogenous supplementation with HNG improved local ovarian IR through modulation of the IRS1/PI3K/Akt signaling pathway in a rat model. This finding supports the potential future use of HNG as a therapeutic drug for PCOS.

Humanin: A Potential Treatment for PCOS?

Valentina Rodriguez Paris, Kirsty A Walters

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets.

Siarhei A Dabravolski, Nikita G Nikiforov, Antonina V Starodubova +2 more

Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets.

[Role of endocrinological factors and metabolic processes in regulating life-span].

Tamás Halmos, Ilona Suba

Összefoglaló. Az emberek a lehető leghosszabb ideig akarnak élni, jó egészségben. Ha kiküszöbölnénk a kedvezőtlen külső körülményeket, a várható élettartam meghaladhatná a 100 évet. A 20. és 21. században a jóléti társadalmakban a várható élettartam jelentősen megnőtt, így Magyarországon is. Az áttekintett irodalom alapján megvizsgáltuk, hogy a genetika és az öröklődés mellett milyen endokrinológiai és metabolikus tényezők játszanak szerepet az élet meghosszabbításában. Megvizsgáltunk minden endogén tényezőt, amely pozitívan vagy negatívan befolyásolhatja az életkorral összefüggő betegségeket (Alzheimer-kór, szív- és érrendszeri betegségek, rák) és az élettartamot. Kiemeltük a hyperinsulinaemia, az inzulinrezisztencia, a metabolikus szindróma öregedést gyorsító hatását, az inzulinszerű növekedési hormon-1 ellentmondásos szerepét, valamint az élet meghosszabbításában részt vevő, újabban felfedezett peptideket, mint a klotho és a humanin. Ismertettük a mitochondriumok szerepét az élettartam meghatározásában, bemutattuk a mitohormesis folyamatát és annak stresszvédő funkcióját. Bemutattuk a rapamicin célszervét, az mTOR-t, amelynek gátlása meghosszabbítja az élettartamot, valamint a szirtuinokat. Kitértünk az autophagia folyamatára, és ismertettük a szenolitikumok szerepét az öregedésben. Az időskori autoimmunitás csökkenése hozzájárul az élettartam rövidüléséhez, utaltunk a thymus koordináló szerepére. Kiemeltük a bélmikrobiom fontos szerepét az élettartam szabályozásában. Hivatkoztunk a "centenáriusok" megfigyeléséből nyert humánadatokra. Megvizsgáltuk, milyen beavatkozási lehetőségek állnak rendelkezésre az egészségben tölthető élettartam meghosszabbításához. Az életmódbeli lehetőségek közül kiemeltük a kalóriabevitel-csökkentés és a testmozgás jótékony szerepét. Megvizsgáltuk egyes gyógyszerek feltételezett hatásait. Ezek közé tartozik a metformin, az akarbóz, a rezveratrol. E gyógyszerek mindegyikének hatása hasonló a kalóriamegszorításéhoz. Nincs olyan "csodaszer", amely igazoltan meghosszabbítja az élettartamot emberben. Egyes géneknek és génmutációknak jótékony hatásuk van, de ezt környezeti tényezők, betegségek, balesetek és más külső ártalmak módosíthatják. Kiemeljük az elhízás, az alacsony fokozatú gyulladás és az inzulinrezisztencia öregedésre gyakorolt gyorsító hatását. A metabolikus szindróma elterjedtsége miatt ez jelentős népegészségügyi kockázatot jelent. Az inzulin, a növekedési hormon és az inzulinszerű növekedési faktorok hatásainak értékelése továbbra is ellentmondásos. Az egészséges, szellemileg és fizikailag aktív életmód, a kalóriacsökkentés mindenképpen előnyös. Az életet meghosszabbító szerek értékelése még vitatott. Orv Hetil. 2021; 162(33): 1318-1327. Summary. People want to live as long as possible in good health. If we eliminate the unfavorable external conditions, the life expectancy could exceed 100 years. In the 20th and 21th centuries, life expectancy in welfare societies increased significantly, including in Hungary. Based on the reviewed literature, we examined what endocrinological and metabolic factors play a role in prolonging life in addition to genetics and inheritance. We examined all endogenous factors that can positively or negatively affect age-related diseases (Alzheimer's disease, cardiovascular disease, cancer) and longevity. We highlighted the aging effects of hyperinsulinemia, insulin resistance, metabolic syndrome, the controversial role of insulin-like growth factor-1, and more recently discovered peptides involved in prolonging lifespan, such as klotho and humanin. We described the role of mitochondria in determining longevity, we demonstrated the process of mitohormesis and its stress-protective function. We presented the target organ of rapamycin, mTOR, the inhibition of which prolongs lifespan, as well as sirtuins. We covered the process of autophagy and described the role of senolytics in aging. The decrease in autoimmunity in old age contributes to the shortening of life expectancy, we referred to the coordinating role of the thymus. We highlighted the important role of intestinal microbiome in the regulation of longevity. We referred to human data obtained from observations on "centenarians". We examined what intervention options are available to prolong healthy life expectancy. Among the lifestyle options, we highlighted the beneficial role of calorie reduction and exercise. We examined the putative beneficial effects of some drugs. These include metformin, acarbose, resveratrol. The effect of each of these drugs is similar to calorie restriction. There is no "miracle cure" that has been shown to prolong life-span in humans. Some genes and gene mutations have beneficial effects, but this can be modified by environmental factors, diseases, accidents, and other external harms. We highlight the accelerating effects of obesity, low-grade inflammation, and insulin resistance on aging. Due to the prevalence of metabolic syndrome, this poses a significant risk to public health. The assessment of the effects of insulin, growth hormone, and insulin-like growth factors remains controversial. A healthy, mentally and physically active lifestyle, calorie reduction is definitely beneficial. The evaluation of life-prolonging agents is still controversial. Orv Hetil. 2021; 162(33): 1318-1327.

Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment.

Hemal H Mehta, Jialin Xiao, Ricardo Ramirez +4 more

The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both humanin and small-humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism.

Effects of prolonged type 2 diabetes on mitochondrial function in cerebral blood vessels.

Ivan Merdzo, Ibolya Rutkai, Venkata N L R Sure +2 more

One of the major characteristics of hyperglycemic states such as type 2 diabetes is increased reactive oxygen species (ROS) generation. Since mitochondria are a major source of ROS, it is vital to understand the involvement of these organelles in the pathogenesis of ROS-mediated conditions. Therefore, we investigated mitochondrial function and ROS production in cerebral blood vessels of 21-wk-old Zucker diabetic fatty obese rats and their lean controls. We have previously shown that in the early stages of insulin resistance, and short periods of type 2 diabetes mellitus, only mild differences exist in mitochondrial function. In the present study, we examined mitochondrial respiration, mitochondrial protein expression, and ROS production in large-surface cerebral arteries. We used 21-wk-old animals exposed to peak glucose levels for 7 wk and compared them with our previous studies on younger diabetic animals. We found that the same segments of mitochondrial respiration (basal respiration and proton leak) were diminished in diabetic groups as they were in younger diabetic animals. Levels of rattin, a rat humanin analog, tended to decrease in the diabetic group but did not reach statistical significance (P = 0.08). Other mitochondrial proteins were unaffected, which might indicate the existence of compensatory mechanisms with extension of this relatively mild form of diabetes. Superoxide levels were significantly higher in large cerebral vessels of diabetic animals compared with the control group. In conclusion, prolonged dietary diabetes leads to stabilization, rather than deterioration, of metabolic status in the cerebral circulation, despite continued overproduction of ROS.NEW & NOTEWORTHY We have characterized for the first time the dynamics of mitochondrial function during the progression of type 2 diabetes mellitus with regard to mitochondrial respiration, protein expression, and reactive oxygen species production. In addition, this is the first measurement of rattin levels in the cerebral vasculature, which could potentially lead to novel treatment options.

Human Aging and Longevity Are Characterized by High Levels of Mitokines.

Maria Conte, Rita Ostan, Cristina Fabbri +10 more

Mitochondrial stress elicits the production of stress response molecules indicated as mitokines, including fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), and humanin (HN). Many diseases are characterized by progressive mitochondrial dysfunction with alterations of mitokine secretion. It is still controversial whether healthy aging and extreme longevity are accompanied by an altered production of mitokines. We analyzed FGF21, HN, and GDF15 plasma levels in 693 subjects aged from 21 to 113 years, and the association of these mitokines with parameters of health status. FGF21, HN, and GDF15 resulted increased in old age, with the highest levels found in centenarians. These molecules are associated with worsened parameters (such as handgrip strength, insulin sensitivity, triglycerides), particularly in 70-year-old persons, and their levels are inversely correlated with survival in the oldest subjects. Considering the positive biological effect of these molecules, our results can be interpreted in the framework of the hormetic paradigm as an attempt of the cells/tissues to cope with a stress that can have beneficial or detrimental effects depending on its intensity. Finally, persons with Down Syndrome (characterized by accelerated aging) have higher levels of GDF15 and HN with respect to their siblings, suggesting that these molecules, especially GDF15, could be considered markers of biological age.

Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects.

Manjunath Ramanjaneya, Ilham Bettahi, Jayakumar Jerobin +5 more

Background: Mitochondrial dysfunction is implicated in the pathogenesis of Type 2 diabetes (T2D) and the development of diabetes related complications such as cardiovascular disease and stroke. Mitochondria produce several small polypeptides that may influence mitochondrial function and may impact on insulin sensitivity, such as humanin (HN) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) that are mitochondrial derived proteins (MDP). The aim of this study was to determine MDP in normal, prediabetes and diabetes subjects. Subjects and Measurements: In this cross-sectional study, we analyzed the serum concentrations of MDP and adiponectin (ADP) in 225 subjects: normal (n = 68), pre-diabetes (n = 33), T2D less than (good control; n = 31), and greater than HbA1c 7% (poor control; n = 93) subjects. The relationship of serum MDP and ADP concentrations with biochemical and anthropometric measurements were performed and assessed by multilinear regression. Results: Serum HN concentrations were lower in T2D (p < 0.0001) and negatively correlated with age (p < 0.0001), HbA1c (p < 0.0001), glucose (p < 0.0001), triglycerides (p < 0.003), ALT (p < 0.004), and TG/HDL ratio (p < 0.001). Circulating HN levels were positively correlated to cholesterol (p < 0.017), LDL (p < 0.001), and HDL (p < 0.001). Linear regression analysis showed that HbA1c and ALT were two independent predictors of circulating HN. Similarly, serum MOTS-c was significantly lower in T2D subjects compared to controls (p < 0.007). Circulating MOTS-c positively correlated with BMI (p < 0.035), total cholesterol (p < 0.0001), and LDL (p < 0.001) and negatively correlated with age (p < 0.002), HbA1c (p < 0.001), and glucose (p < 0.002). Serum ADP concentrations were lower in T2D (p < 0.002) and negatively correlated with HbA1c (p < 0.001), weight (p < 0.032) TG (p < 0.0001), and ALT (p < 0.0001); and positively correlated with HDL (p < 0.0001) and HN (p < 0.003). Linear regression analysis showed that HbA1c and weight were two independent predictors of circulating ADP. Multilinear regression showed that HN and MOT-c correlated with each other, and only HN correlated with HbA1c. Conclusion: The MDPs HN and MOT-c, similar to ADP, are decreased in T2D and correlate with HbA1c. The data provide an additional evidence that mitochondrial dysfunction contributes to glycemic dysregulation and metabolic defects in T2D.

[The underestimated coding potential of mitochondrial DNA].

Annie Angers, Philip Ouimet, Assia Tsyvian-Dzyabko +2 more

Mitochondria are ancient organelles that emerged from the endosymbiosis of free-living proto-bacteria. They still retain a semi-autonomous genetic system with a small genome. Mitochondrial DNA (mtDNA) codes for 13 essential proteins for the production of ATP, the sequences of which are relatively conserved across Metazoans. The discovery of additional mitochondria-derived peptides (MDPs) indicates an underestimated coding potential. Humanin, an anti-apoptotic peptide, is likely independently transcribed from within the 16S rRNA gene, as are recently described SHLPs. MOTS-c, discovered in silico, has been demonstrated to be involved in metabolism and insulin sensitivity. Gau, is a positionally conserved open reading frame (ORF) sequence found in the antisense strand of the COX1 gene and its corresponding peptide is strictly colocalized with mitochondrial markers. In bivalves with doubly uniparental inheritance of mtDNA, male and female mtDNAs each carry a separate additional gene possibly involved in sex determination. Other MDPs likely exist and their investigation will shed light on the underestimated functional repertoire of mitochondria.

Mitochondrial-Derived Peptides Exacerbate Senescence.

Andrew R Mendelsohn, James W Larrick

Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA, play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions. Humanin and its homologs and MOTS-c are two of several MDPs hypothesized to have antiaging activity based on correlative studies. For example, humanin plasma levels are inversely correlated with growth hormone and insulin-like growth factor 1 expression, which may promote accelerated aging. Humanin has been shown to protect cells from beta amyloid toxicity and preserve endothelial cell function in a mouse model of atherosclerosis. Furthermore, both humanin and MOTS-c improve insulin sensitivity in mouse models of type 2 diabetes. Recently it was reported that a potent analogue of humanin blocks cardiac fibrosis in aging mice. Although it has been hypothesized that MDPs might have senolytic activity, in a recent report humanin and MOTS-c both exacerbate the senescence-associated-secretory-phenotype (SASP) in senescent cells by stimulating the secretion of IL-6, IL-1β, IL-8, IL-10 and tumor necrosis factor α. It appears that the cytoprotective activity of the MDPs may be permissive for increased expression of a set of proinflammatory cytokines. Given the potential benefits of MDPs in many of the same diseases associated with the presence of senescent cells, a combination of senolytic and MDP-based treatments may be additive or synergistic. The MDPs would protect normal cells, whereas senescent cells would be eliminated by the senolytic therapy. It is even possible that MDPs by increasing the SASP phenotype would make the senescent cells more apt to be cleared by the immune system or more sensitive to senolytics. In contrast, if the MDPs actually cytoprotect the senescent cells, then the treatment can be performed serially with the senolytic used first.

Humanin promotes mitochondrial biogenesis in pancreatic MIN6 β-cells.

Qingqing Qin, Jieqiong Jin, Fang He +4 more

Mitochondrial dysfunction is associated with β-cell failure and insulin resistance in diabetes. Humanin is an endogenous cytoprotective peptide. In the current study, we aimed to define the effects of Humanin on mitochondrial biogenesis in pancreatic β-cells. Our findings demonstrated that Humanin treatment significantly increased the expression of PGC-1α and its downstream target genes NRF1 and TFAM in MIN6 β-cells. Notably, Humanin treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial mass, elevating mtDNA/nDNA ratio, and stimulating the expression of cytochrome B, which were suppressed by the specific AMPK inhibitor compound C. Indeed, Humanin treatment caused the phosphorylation of AMPK, which was involved in the induction of PGC-1α, NRF1, and TFAM by Humanin. Importantly, our findings indicate that Humanin treatment led to a possible functional gain of the mitochondria by increasing ATP levels and respiratory rate. Our findings provided a new insight into the molecular mechanisms of action by which Humanin improves pancreatic β-cell function via enhanced mitochondrial mass and performance.