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The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

aging mitochondria peptides humanin

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#1 Engadin

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Posted 26 June 2020 - 08:28 PM


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S O U R C E :   AgING

 

 

 

 

 

 

Abstract
 
Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer’s disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.
 
 
Introduction
 
Mitochondria are central to several theories of aging as they are the major producer of both energy and free radicals, they regulate cell apoptosis, and their dysfunction is central to the observed physiological declines that occur during the aging process [1–5]. Similarly, mitochondrial dysfunction is found in many age-related diseases, although whether this is causal or simply correlative has yet to be established [6–9]. Furthermore, in addition to their role in energy utilization and cell survival, alterations in mitochondrial genes can increase lifespan in several model organisms and mitohormesis has been implicated in lifespan [10–16]. Interestingly, although the vast majority of the proteins found within the mitochondria are encoded by the nuclear genome, mitochondria have their own unique translational machinery and genome, which was previously believed to only code for 13 proteins [17, 18].
 
In the past decade the number of identified mitochondrial derived peptides (MDPs) and micropeptides have grown exponentially [19, 20]. Micropeptides are an emerging group of small (<100 amino acids) proteins that are often encoded within long-noncoding RNAs, introns, or 5’ and 3’ untranslated regions [21–26]. Perhaps because of the compact nature of the mitochondria and absence of introns, MDPs are encoded in alternative open reading frames within known genes. These MDPs are a novel group of micropeptides encoded within the mitochondrial genome and have been shown to have a large number of biological effects [27–32].
 
Humanin is the first member of this new class of mitochondrial-derived signaling peptides that now includes MOTS-c and SHLP1-6 [19, 20]. The humanin gene is found as a small open reading frame within the 16s rRNA gene of the mitochondrial genome. It is highly conserved in chordates but can also be found in species as distant as the nematode [33], suggesting that humanin is an ancient mitochondrial signal used to communicate to the rest of the organism. It was initially discovered in a screen for proteins that protected against Alzheimer's disease (AD), but was also independently found to bind IGFBP3 and Bax [33–35]. Since its initial discovery, humanin’s role in protecting against many other age-related diseases such as atherosclerosis and stroke has expanded with numerous beneficial effects now evident [36–38]. Circulating levels of humanin correlate with lifespan in different mouse models of aging and bi-weekly injections of the humanin analogue HN-S14G delays the cognitive decline in mice [39–42]. Another MDP, MOTS-c, has already been associated with longevity in centenarians [43], although association studies of humanin levels in humans have been equivocal [44–46]. In this study we further investigated the relationship between humanin, longevity, and healthspan using transgenic worms, multiple mammalian species with divergent lifespans, and also the children of centenarians compared to age-matched controls.
 
 
Results
 
Humanin overexpression is sufficient to increase lifespan in worms
 
Humanin has been shown to protect against many toxic insults. For example, we found that humanin treatment protected against lethal doses of heat shock in yeast (Supplementary Figure 1). To test if humanin is sufficient for an increase in lifespan, we generated a transgenic worm overexpressing humanin using a ubiquitous promoter (ife-1) and MoscI technology (Knudra, Murray, UT). After backcrossing the worms to wild-type/N2 worms six times, we examined their lifespan and found that the transgenic worms had a small but consistent and significant (p<.05) increase in lifespan compared to wildtype/N2, indicating that humanin is sufficient to increase lifespan in worms (Figure 1A). Using epistatic analysis, we found that the increase in lifespan was dependent on the daf-16/FOXO gene as humanin overexpression does not increase lifespan in a daf-16(mu86) deficient strain (Figure 1B). Humanin's interaction with the insulin/IGF signaling pathway has been previously shown in mice, suggesting that this is a conserved mechanism of action for humanin [39, 47]. Phenotypic analysis of these transgenic worms also found them to have a decrease in body size, body fat, and reproductive output (Figure 1C–1E).
 
 
 
Clipboard01.jpg
 
Figure 1. Humanin overexpression is sufficient to increase lifespan in C. elegans. HN overexpression significantly increased lifespan in worms (average lifespan of 19.0 days) compared to wild-type/N2 (average lifespan 17.7 days) (A). This increase in lifespan was dependent on daf-16 as daf-16(mu86) mutants did not have any increase in lifespan when crossed with the humanin-tg strain (average lifespan 15.5 days vs 16.1 days respectively) (p < 0.2) (B). Hn-tg worms also had a significant decrease in body length, body fat, and reproductive output (CE). *indicates p<.05.
 
 
 
Humanin mice are protected from toxic insult and phenocopy the transgenic worms
 
Having created transgenic worms, we next developed a transgenic mouse model using a construct that included the humanin-ORF driven by a CMV promoter to test the effects of long-term exposure to humanin. Mice harboring the humanin transgene were both viable and fertile. We have previously published that there is a 16% increase in circulating humanin levels in these mice [48]. With this model, the effects of long-term exposure to humanin were assessed. Phenocopying the worms, the mice had a decrease in body length, body weight, and litter size (Figure 2A–2C). To further assess the HN-tg mice and because humanin has been shown to be cytoprotective by many different labs, we utilized the well-established cyclophosphamide toxicity model. Cyclophosphamide (CP) is a chemotherapeutic agent that causes many side effects, but humanin administration has been shown to prevent many of these [49]. Similar to previous studies that administered humanin exogenously, humanin transgenic mice were also protected from many of the side effects of CP such as the decrease in lymphocytes and increase in apoptosis in germ cells (Figure 2D, 2E). Under control conditions, there were no differences in germ cell apoptosis between control and HN-tg mice, suggesting that germ cell apoptosis was not the cause of the decreased fertility in these mice (Figure 2E).
 
 
 
Clipboard02.jpg
 
Figure 2. HN-tg mice phenocopy the transgenic worms and are protected from toxic insult. Humanin transgenic mice have a significant decrease in body length by 12% at 28 days of age (n= 5 for control and n=3 for the hn-tg mice) (A). Body weight at the same age was also decreased by 10.4% (n=26 and n=16 for control and hn-tg mice respectively) (B), while litter size decreased by 46.5% (n=10 and n=15 for control and hn-tg mice respectively) (C). When administered cyclophosphamide, mice have a decreased lymphocyte count and transgenic mice are protected from this toxin (n=6 or 7 per group) (D). Similarly, when examining germ cell apoptosis organized by spermatogenic stages in the same cyclophosphamide treated mice, humanin transgenic mice are significantly protected from CP induced apoptosis (E). * indicates p<.05.
 
 
 
Humanin treatment in middle-aged mice improves metabolic health
 
To examine if humanin treatment can increase the lifespan and healthspan in a mammalian model, 18-month-old, female C57BL/6N mice were obtained from the NIA and administered bi-weekly HNG (4 mg/kg, IP), a potent humanin analogue. Body weight was significantly reduced compared to control/vehicle injected until older ages (Figure 3A), but food intake did not significantly differ between HNG-treated and control mice during this same time period (Figure 3B), suggesting a possible metabolic effect as opposed to the treatment causing illness. At 28-months of age, body composition was determined by micro-CT [50] and even without a significant difference in body weight at this time point, the HNG-treated mice had a decrease in visceral fat (Figure 3C), an increase in lean body mass (Figure 3D), and no change in subcutaneous fat (Figure 3E) (N=5/group). After 14-months of treatment, there was no significant difference in lifespans between the groups (Figure 3F). However, the HNG-treated group showed improvements in healthspan related parameters such as a significant decrease in IGF-I and trend for a decrease in leptin (Figure 3G, 3H).
 
 
 
 
 
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#2 adamh

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Posted 27 June 2020 - 01:03 AM

Well damn, if it helps middle aged mice how about some for humans? Where can we get this or is it something super hard to get and $1000 a daily dose? I think a lot of us would be willing to try it. 



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#3 adamh

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Posted 27 June 2020 - 01:22 AM

I looked around and its expensive but depends on how much a dose may be. I saw it at $300 a mg but did find it at $155 for 10mg at this site https://www.peptides...om/humanin-10mg

 

Is 1 mg 1 dose, perhaps several doses? In which case its not too bad cost wise. 

 

I have not seen any studies using it for humans which seems odd. Either the cost is astronomical or there is some problem. Maybe it takes many mg per day? I would think, since this has been known about for some time, there must be a problem. Its been shown to help so many diseases in animals but no trials on people. 


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#4 Engadin

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Posted 27 June 2020 - 08:23 PM

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Josh Mitteldorf has some fairly interesting comments, dating 2017, about humanin peptide:

 

 

 

Humanin and her sisters

 
Mitochondria have ringlets of their own DNA, encoding just 37 genes.  (That doesn’t mean that the mitochondria only need 37 proteins; the great majority of proteins needed by mitochondria are coded in chromosomes of the cell nucleus, and transported to the mitochondria as needed.)  Just 16 years ago, the first mitochondrial-coded protein to be discovered was named Humanin, because it was found to improve cognitive function to dementia patients, restoring some of their “humanity”.  In addition to being neuroprotective, humanin promotes insulin sensitivity.  Humannin’s action is not confined to the mitochondrion in which it was produced, but in fact it  circulates in the blood as a signal molecule.  Blood levels of humanin decline with age.
 
In experiments with mice, humanin injections have been shown to protect against disease.  Lifespan assays with humanin are not yet available.
 
 

To date, HN and its analogs have been demonstrated to play a role in multiple diseases including type 2 diabetes (2543), cardiovascular disease (CVD) (2347), memory loss (48), amyotrophic lateral sclerosis (ALS) (49), stroke (50), and inflammation (2251). The mechanisms that are common to many of these age-related diseases are oxidative stress (52) and mitochondrial dysfunction (53). Mitochondria are major source of ROS, excess of which can cause oxidative damage of cellular lipids, proteins, and DNA. The accumulation of oxidative damage will result in decline of mitochondrial function, which in turn leads to enhanced ROS production (53). This vicious cycle can play a role in cellular damage, apoptosis, and cellular senescence – contributing to aging and age-related diseases. Indeed, oxidative stress is tightly linked to multiple human diseases such as Parkinson’s disease (PD) (54), AD (55), atherosclerosis (56), heart failure (57), myocardial infarction (58), chronic inflammation (59), kidney disease (60), stroke (61), cancers (6263), and many types of metabolic disorders (6465). We and others have shown that HN plays critical roles in reducing oxidative stress (6668). [2014 review]

Pinchas Cohen, MD (Dean, School of Gerontology, University of Southern California Davis, Los Angeles, California) is an expert in humanin, a protein (peptide) produced in mitochondria. Mitochondria are energy-generating organelles in cells, which have their own DNA separate from the DNA in the nucleus. The amount of DNA found in the mitochondria is much less than that found in the nucleus. As such, mitochondrial DNA contains codes for only a few proteins, humanin being one of them. Humanin was discovered by a search for factors helping to keep neurons alive in undiseased portions of the brains of Alzheimer’s disease patients. Humanin protects neurons against cell death in Alzheimer’s disease, as well as protecting against toxic chemicals and prions (toxic proteins)[ref].  Dr. Cohen’s team has shown that humanin also protects cells lining blood vessel walls, preventing atherosclerosis. In particular, they have shown that low levels of humanin in the bloodstream are associated with endothelial dysfunction of the coronary arteries (arteries of the heart).[ref] Humanin has also been shown to promote insulin sensitivity, the responsiveness of tissues to insulin. Because humanin levels decline with age, it is believed that reduced humanin contributes to the development of aging-associated diseases, including Alzheimer’s disease and type II diabetes. [Ben Best]

 

Personal notes: This lab near where I am visiting in Beijing is taking leadership in characterizing a group of short peptides similar in origin to humanin, and this company across the street from us is selling mitochondrial peptides.
 
If humanin were a patentable drug, there would be much excitement and multiple clinical trials for AD, probably leading to expansion into general anti-aging effects.
 
 
 
 
 
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#5 motorcitykid

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Posted 27 June 2020 - 09:34 PM

This is one of the most reputable peptide companies out there:https://www.canlab.n...humanin-hng-5mg



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#6 johnross47

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Posted 28 June 2020 - 03:49 PM

Have there been any studies of varying levels with age?



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