PEPTIDES

Ipamorelin & Sermorelin

Sermorelin and ipamorelin peptides are very similar in many ways. Despite their similarities, however, these two peptides are different enough that their applications can be tailored for specific needs. Both peptides stimulate the natural secretion of growth hormone, but they do so via different receptors. As a result of their effects on growth hormone (GH) levels, Ipamorelin and Sermorelin both cause increased fat burning and muscle building, enhanced long bone growth, decreased inflammation, and improved wound healing. However, their actions via different receptors result in these two peptides having slightly different ancillary effects.

Sermorelin vs Ipamorelin: Receptor Science

Sermorelin is an analogue of growth hormone-releasing hormone (GHRH) and binds to the GHRH receptor (GHRH-R). Ipamorelin, however, is a ghrelin analogue and binds primarily to the growth hormone secretagogue receptor (GHS-R). While both peptides can be referred to under the umbrella category of growth hormone releasing peptides, their different receptor binding preferences mean they have different effects on GH levels.

At baseline, Sermorelin potentiates GH release and helps to extend GH highs. It is best thought of as extending GH peaks and prolonging the amount of time that GH levels are elevated while preserving the normal ebb and flow (pulsatile secretion) of GH throughout that day. Ipamorelin, on the other hand, is better thought of as dramatically raising GH levels, sometimes by as much as 13 times above baseline levels. Ipamorelin has dramatic, but short-lived effects on GH levels.

Sermorelin and Growth Hormone Potentiation

The GHRH-R is the primary receptor on the anterior pituitary gland for controlling growth hormone release. When stimulated, it causes the release of growth hormone. Research shows that Sermorelin binding to the GHRH-R is effective at concentrations as low as 0.4x10-15M. This makes Sermorelin an extremely potent GHRH agonist and approximately 50 times more potent than naturally occurring GHRH. This is the reason that it was originally referred to as a “super-active” analogue of growth hormone releasing hormone.

Interestingly, Sermorelin tends to not cause massive increases in GH levels when it is administered. It does, however, augment the duration of GH release. That is to say, while Sermorelin definitely increases GH levels, its primary effect is to extend the duration of GH release, helping to maintain peak levels for longer periods of time. By extending the release of GH, Sermorelin does, in fact, raise GH levels but it also smooths out the peaks of GH release and widens them a bit. This does not, however, obliterate the normal pulsatile secretion of GH, which is important for minimizing side effects. In fact, Sermorelin’s biggest benefit is the fact that it preservers the normal physiologic pattern of GH release, thus mitigating side effects like swelling, joint pain, and excessive long bone growth.

Ipamorelin and Growth Hormone Peaks

Ipamorelin (as well as ghrelin) is an amplifier of GH pulsatility and is speculated to play a role in creating a set point for insulin-like growth factor 1 levels. Research has shown that subcutaneous administration of Ipamorelin causes an intense spike in growth hormone levels just 5-15 minutes after injection followed by a relatively rapid decline. Thus, ipamorelin does not really potentiate GH secretion like Sermorelin does. Instead, ipamorelin is better thought of as boosting maximum levels of growth hormone output for a very short duration of time. Depending on when and how ipamorelin is administered, this could mean augmenting peak GH levels or raising trough levels. Thus, timing of ipamorelin administration can, to some extent, affect the peptide’s effects.

Ipamorelin, at its ED50 (50% of the maximum effective dose), causes plasma GH levels to increase to approximately 65 ng/mL in animal models. Normally, growth hormone levels in men are below 5 ng/mL while in women they are below 10 ng/mL. This means Ipamorelin administration raises GH levels by anywhere from 6.5 to 13 times the maximum level. In children, growth hormone levels range from 0-20 ng/mL based on age. Ipamorelin has a short half-life of two hours. When administered, it causes maximum GH release after about 40 minutes followed by an exponential decline.

This rapid on, rapid off property of Ipamorelin is a holdover from its natural counterpart, ghrelin. Recall that ghrelin and Ipamorelin can both stimulate appetite. This occurs via binding to the GHS-R and subsequent release of neuropeptide Y. Given that it takes time to eat and digest food, it makes sense that ipamorelin would have its maximum effects approximately 40 minutes after injection (or release in the case of ghrelin). This gives the peptide its best chance of making using of nutrients for building muscle, bone, connections between neurons, and more.

Sermorelin vs Ipamorelin: Structure and Route of Administration

Sermorelin is made up of the first 29 amino acids from the much larger, naturally occurring GHRH peptide. It is the smallest fraction of GHRH than retains all of the properties of the parent molecule. Weighing in at 3357.9 g/mol, Sermorelin is a relatively large, heavy peptide that must be injected sub-cutaneous to be absorbed. It is not orally bioavailable. As a result of its large size, Sermorelin has a more significant three-dimensional structure than Ipamorelin and is thus is a little less stable in terms of storage half-life.

Ipamorelin is substantially smaller than Sermorelin at just 5 amino acids and 711.868 g/mol. It is a derivative of GHRP-1, which is itself a derivative of met-enkephalin. Though the most common route of administration for Ipamorelin is via sub-cutaneous injection, the peptide is also orally active and can even be absorbed though the nasal mucosa.

Ipamorelin vs Sermorelin: Lean Body Mass

Both Sermorelin and Ipamorelin favor the development of lean body mass over fat mass, but Sermorelin is the more potent of the two. This arises from the fact that Sermorelin is both a growth stimulator and a fat burner while Ipamorelin is a more general growth stimulator. That is not to say that Ipamorelin isn’t effective, it is, but ipamorelin isn’t as strictly favorable of lean body mass deposition as Sermorelin. This difference arises from the fact that Ipamorelin is a ghrelin analogue and ghrelin favors food intake in general. Its growth hormone boosting properties shift the overall balance away from fat deposition and toward lean body mass deposition, but the Ipamorelin peptide is best thought of as a general weight boosting peptide while Sermorelin is best thought of as a more exclusive booster of lean body mass. In fact, Sermorelin is often referred to as a lipolytic or fat-burning peptide.

Both peptides stimulate the development of bone and other connective tissue, but Ipamorelin appears to have the advantage in this realm. In fact, ipamorelin is so effective in boosting bone density and mineralization that it has been investigated as a potential treatment for corticosteroid-induced bone loss as well as osteoporosis.

When it comes to muscle growth, Sermorelin is probably the big winner, though this can be debated endlessly. Sermorelin not only boosts muscle hypertrophy and hyperplasia, it reduces fat mass and thus causes a shift in body chemistry toward lean body weight. In other words, Sermorelin will always favor the production of lean body mass even if diet is not perfectly geared toward muscle development. Ipamorelin, on the other hand, is more of a mixed bag. It will always cause muscle growth, but ipamorelin may channel some of those calories into fat deposition as well.

Ipamorelin vs Sermorelin: Anti-Aging Properties

Both Ipamorelin and Sermorelin, via their GH releasing potential, have potent anti-aging properties. Sermorelin, however, is the clear front runner in this particular face off. Sermorelin has been shown to improve joint function, skin thickness, skin collagen structure, wound healing, cardiac fibrosis, strength, and metabolism. According to Dr. Richard Walker, Ph.D., of the International Society for Advanced Research in Aging, Sermorelin helps to preserve more of the growth hormone axis than most other GHRH analogues, resulting in a more youthful hormone profile. In other words, if you took profiles of GH biochemistry throughout an individual’s lifetime, you would find that Sermorelin tends to dial back that chemistry to a more youthful setting.

Ipamorelin as Pain Reliever

One of the biggest differences between Ipamorelin and Sermorelin lies in the fact that Ipamorelin triggers the release of neuropeptide Y. This peptide is an important neurotransmitter in the control of appetite and food preference, but it also plays an important role in how we perceive pain. In fact, the connection between food and good feelings is likely due, in part, to the effects of neuropeptide Y.

Research in rats indicates that Ipamorelin may help to reduce pain perception by has much as 2-fold. This is particularly true of visceral pain, which is to say “stomach” pain. Visceral pain is difficult to treat, so ipamorelin offers a potential starting point for understanding how to better control the pain associated with conditions like irritable bowel syndrome, Crohn’s disease, ulcerative colitis, and more. There are also potential applications in neuropathic pain syndromes like diabetic neuropathy and degenerative disk disease.

Sermorelin and Sleep

Research in rats shows that Sermorelin is an effective regulator of the sleep cycle. Sleep and aging go hand int hand, with one affecting the other such that older people often have less adequate less restful sleep. Sermorelin appears to achieve its sleep benefits by regulating orexin release from specialized neurons in the brain. Orexin is an important neurotransmitter in sleep regulation and Sermorelin appears to boost orexin secretion. This leads to an increase in non-REM slow-wave sleep, which is associated with more restful sleep, improved immune function, better wound healing, and happier mood. Its effects on sleep may be one of the reasons that Sermorelin is a potent anti-aging peptide.

Sermorelin vs Ipamorelin: Summary

Sermorelin peptides and Ipamorelin peptides are more similar than they are different, but that doesn’t mean there aren’t distinctions between these two growth-promoting peptides. Practically speaking, Sermorelin is the “all-around” peptide. It promotes lean body mass gains, boosts fat burning, and fights the effects of aging. It is also a more holistic simulator of the GH axis and, as such, helps the body to maintain “youth-like” patterns of GH secretion.

Ipamorelin is the more potent of the two peptides. Its effects are large, but relatively short-lived. Ipamorelin is a “gainer” peptide. It builds lean body mass, but also builds overall body mass. It is a potent stimulator of bone growth and has some pain fighting properties as well.

There has been some research investigating the effects of combining Sermorelin and Ipamorelin. Because these peptides affect two different receptors, their actions when combined tend to be synergistic. Unfortunately, the research in this area is limited, so there isn’t a great deal of data on how the combination of these two peptides can help to improve appetite, alter body composition, fight off cardiovascular disease, slow the progression of aging, and promote general good health. In the end, both Ipamorelin and Sermorelin have been studied extensively, but individually, for their significant impacts on GH. Both peptides are effective, but have slightly different ancillary effects that have driven researchers in different directions as they explore potential applications for ipamorelin peptides and sermorelin peptides.

Dihexa

Dihexa was developed by Joe Harding and Jay Wright, Professors of Neurology at Washington State University in the United States. Harding and Wright have spent 20 years researching angIV-related peptides for their procognitive effects in order to find out how they affect the hippocampus and how they can be used to restore the mental decline associated with dementia.Animal trials note that the nootropic drug effectively improved the cognitive functions in the rats it was given to. More studies are needed to validate these results. Still, Harding and Wright are hopeful that with extensive testing and FDA approval, the nootropic drug will be beneficial in treating central nervous system trauma and other cognitive diseases.

Benefits

Dihexa requires more testing and clinical trials to prove both its safety and the benefits that it can provide. As only animal testing has currently been done on the nootropic, the potential benefits of the drug are not guaranteed. The possible benefits of the nootropic drug include:

An improvement in critical thinking- Restoration of the synapses between neurons in the nervous system
Improved production of dopamine and noradrenaline
Increased mental stamina
Enhanced articulation
Improved circulation
Accelerated wound healing
An increase in muscle growth
Reduction of cognitive decline in patients with Alzheimer’s disease or other degenerative cognitive diseases
Enhanced creative thinking
Improvement of problem-solving abilities
Improved cardiovascular health
Increased motivation

Gonadorelin

Gonadorelin is a gonadotropin releasing hormone agonist that has shown benefit in the treatment of infertility and hypogonadism. Recent research suggests that gonadorelin may be useful in slowing the growth of breast and prostate cancer. Studies also show promise in the treatment of Alzheimer’s disease.

Overall Health Benefits of Gonadorelin

Treats testicular atrophy
Improves fertility by increasing testosterone production
Increases sexual desire
Prevents cancer
Increases muscle mass
Promotes healthier bones
Improves mood
Treats amenorrhea

What is Gonadorelin?

Gonadorelin, also known as Gonadotropin-releasing hormone (GnRH), is produced in the brain region called hypothalamus. This hormone stimulates the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. Gonadorelin is mainly used for treating infertility, delayed puberty, and amenorrhea (absence of menstruation).

How Gonadorelin Works

Gonadorelin stimulates the pituitary gland to increase the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In women, gonadorelin is used to stimulate the release of an egg from the ovary. This in turn results in regular ovulation and higher chances of pregnancy. In men, gonadorelin is used to stimulate spermatogenesis or sperm production. It also boosts the production of testosterone by the testes. Gonadorelin is used in conjunction with testosterone to minimize testicular atrophy (shrinking of the testicles).

Chemical Structure of Gonadorelin

Research on Gonadorelin

A. Treats Testicular Atrophy

There are also studies supporting the beneficial effects of gonadorelin on testicular atrophy, a condition characterized by shrinking of the testicles:

In infants with undescended testes, gonadorelin therapy through nasal spray significantly increased the testicular volume after 5 years.
In adolescents who had left varicocelectomy (removal of enlarged veins in the scrotum), gonadorelin treatment increased testicular volume.

B. Improves Fertility by Increasing Testosterone Production

A number of convincing studies suggest that gonadorelin can help improve fertility in both men and women:

In men with steroid-induced azoospermia (absence of sperm), gonadorelin therapy resulted in increased sperm production.
In boys and girls with delayed puberty, long-term administration with gonadorelin improved reproductive health.
In men with testosterone deficiency, gonadorelin was found to be helpful in restoring sperm production.
In male goats, a single dose of gonadorelin exhibited beneficial effects on testicular blood flow which in turn improved sperm production.
In men testosterone deficiency, long-term gonadorelin therapy was successful in stimulating sexual maturation.
In goats, gonadorelin administration promoted ovulation and resulted in a higher number of embryos.
In dairy cattles, gonadorelin administration after insemination resulted in increased pregnancy rate.
In cows with low sexual cycles, gonadorelin injections were found to be effective in increasing the number of the subjects’ pregnancies.
In women, pulsatile administration of gonadorelin was successful in improving the pregnancy rate of the subjects with lesser risks than the conventional gonadotropin treatment.
In breeder cows, conception rates became significantly high after gonadorelin injection.
A study showed that gonadorelin treatment was effective in restoring sperm production in infertile men.
In infertile men, gonadorelin treatment increased testosterone and sperm production.
In patients with Kallman’s syndrome (delayed or absent puberty) who failed traditional treatment, gonadorelin treatment restored sperm production.
In adolescent boys, low-dose administration of gonadorelin induced testicular growth and sperm production.
A study showed that gonadorelin therapy could be used to trigger testosterone and sperm production in men with sex hormone deficiency.
In cows, gonadorelin treatment resulted in a higher ovulatory period rate.

C. Increases Sexual Desire

Gonadorelin has also been found to increase sexual desire:

In camel bulls, gonadorelin administration resulted in improved sperm concentration and libido.
In female monkeys, gonadorelin injection resulted in improved sexual behavior.

D. Prevents Cancer

Evidence suggests that gonadorelin has potent anti-cancer properties:

In mice, gonadorelin injection resulted in the suppression of intestinal and colonic tumor growth.
In pre-menopausal women with early and advanced breast cancer, gonadorelin therapy prevented the growth of breast cancer cells.
A study suggested that gonadorelin can help suppress the growth of prostate cancer.
A study showed that gonadorelin may play an important role in modulating several malignant human tumors.
Research found that gonadorelin is safe and cost-effective and that using it for 15 years could reduce the risk of breast cancer by 70%.
Gonadorelin has been found to reduce the growth of estrogen-sensitive cancer and boost the efficacy of receptor blocking medications.
In postmenopausal women with high levels of estrogen, long-term GnRH treatment was associated with a reduced risk of breast cancer.
In men with aggressive prostate cancer, gonadorelin administration has been found to produce similar efficacy to surgical removal of the testicles in preventing the spread of cancer.
Research suggests that gonadorelin may help treat castration-resistant prostate cancer.
When used effectively and combined with early detection, the addition of gonadorelin to chemotherapeutic drugs may help cure 99% of all prostate cancer.

E. Increases Muscle Mass

Studies suggest that gonadorelin is essential for muscle health:

In healthy young men, administration of gonadorelin significantly improved muscle mass and strength.
In healthy older men, monthly treatment with gonadorelin increased muscle mass and leg strength.
A study showed that gonadorelin treatment among male subjects resulted in increased muscle mass strength.
In healthy older men, the increase in testosterone caused by gonadorelin administration induced muscle improvements.

F. Promotes Healthier Bones

Gonadorelin is also important for maintaining a healthy skeletal frame according to studies:

In young men with sex hormone deficiency, gonadorelin treatment resulted in increased bone mineral density.
In patients with bone disorders caused by ovarian cysts, gonadorelin treatment increased bone mineral density.
In women with endometriosis, a condition where the womb tissue starts to grow in other places, gonadorelin treatment combined with physical training resulted in bone formation.
A study found that surgically-castrated men with prostate cancer who received gonadorelin treatment had lower rate of bone loss compared to the untreated group.

G. Improves Mood

Studies suggest that gonadorelin can help improve mood through its antidepressant effects:

In women with severe premenstrual syndrome, daily intranasal administration of low-dose gonadorelin greatly reduced depression and irritability.
In men with central hypogonadism, gonadorelin administration produced positive effects on mood by treating sexual dysfunction.

H. Treats Amenorrhea

Gonadorelin can also help restore normal menstrual cycle according to clinical studies:

In women with amenorrhea, administration of gonadorelin produced menstruation without any side effects.
In women with primary and secondary amenorrhea, gonadorelin treatment was extremely effective in inducing ovulation and menstruation.

Associated Side Effects of Gonadorelin

Gonadorelin side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on gonadorelin. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of gonadorelin. Despite this, it was listed as a side effect associated with gonadorelin even though these associated side effects are very uncommon.

Side effects associated with gonadorelin may include the following:

Abdominal discomfort
Dizziness
Flushing
Headache
Lightheadedness
Nausea
Skin rash

Kisspeptin

Kisspeptin acts to control hormone secretion as it relates to reproduction. Kisspeptin can influence testosterone levels and sex-related behaviors like drive and motivation. Research also suggests it may help to reverse some of the effects of aging.

Ibutamoren Mesylate (MK-677)

Ibutamoren mesylate, also known as MK-677, is an orally active non peptide growth hormone (GH) secretagogue, which stimulates growth hormone (GH) release through a pituitary and hypothalamic receptor that is different from the GH-releasing hormone receptor. Clinically, it has been demonstrated to increase the endogenous release of growth hormone (GH) as well as insulin-like growth factor 1 (IGF-1) without the adverse increase of prolactin or cortisol often seen with GHRPs. Additionally, increases in lean body mass can be achieved while lowering LDL cholesterol.

Research Behind Ibutamoren

Studies have shown Ibutamoren stimulates brain regions involved with metabolic action, such as the hypothalamus and the pituitary. Ibutamoren may be effective in increasing both muscle mass and bone mineral density, making it a promising therapy for the treatment of frailty and osteoporosis in the elderly. Ibutamoren also aids in wound healing, tissue regeneration and improves sleep.

An affiliated study with Merck Research Laboratories stated growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin-like growth factor I (IGF-I). The research determined that once daily dosing with ibutamoren, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.

Ibutamoren Benefits

1. Helps Build Muscle

Ibutamoren is frequently used as an anabolic substance, to increase lean body mass. It is orally active and can be taken once a day. Ibutamoren stimulates Growth Hormone and IGF-1 which each factor in significantly to maintaining lean body mass. Growth Hormone is believed by many to stimulate an increase in muscle size and strength and the ability of ibutamoren to increase Growth Hormone production make it a popular choice.

One study using 60-year-old men indicated that injections to stimulate Growth Hormones led to increased strength in thigh muscles. In another study of 24 obese men, a two-month treatment with ibutamoren increased lean mass, and transiently increased basal metabolic rate (BMR).

2. Reduces Muscle Wasting

Ibutamoren has shown in recent studies to alleviate muscle wasting that can be caused by a decline in protein within an individual’s diet. In one study a group of healthy young adults were tested to determine if ibutamoren could reverse protein catabolism. The study determined that ibutamoren is theorized to be an effective treatment for individuals who suffer from catabolic conditions.

3. Increases Bone Density

Several studies have indicated that long-term use of ibutamoren can have tremendous results to increase bone mineral density. An affiliated study with Merck Research Laboratories stated growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin-like growth factor I (IGF-I). The research determined that once daily dosing with ibutamoren, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.

4. Improves Sleep

Since Growth Hormone is known to help improve sleep quality, it is commonly thought that Ibutamoren Mesylate can assist with sleep quality since it stimulates production of Growth Hormone. A study showed that in both younger and elderly subjects, ibutamoren improved sleep quality, REM (rapid eye movement) and improved sleep duration.

Apart from scientific studies, there have been many reports of subjective improvements in sleep quality from patients at Aspire Rejuvenation Clinic.

5. Combats Aging and May Increase Longevity

Aging patients taking ibutamoren can benefit greatly since Growth Hormone and IGF-1 can significantly elevate. As we age, our body stops producing as much human growth hormone (HGH) and therefore IGF-1. Human growth hormone is responsible for the development of muscle and bone mass. In fact, the natural production of HGH decreases by around 15% each decade from the age of twenty-five.

Ibutamoren therapy can counteract this decline by stimulating the body to release more HGH, which can lead to an increase in lean muscle mass, a reduction in body fat, increased energy and stamina and a reduction in musculoskeletal inflammation.

6. Nootropic Effects

Since ibutamoren shares a lot of similar qualities to Ghrelin and binds to its receptors, it is believed that ibutamoren can have the same effects on the brain that Ghrelin has.

There are no studies that confirm ibutamoren has direct nootropic effects on the brain. Scientists theorize ibutamoren may indirectly improve cognitive function through IGF-1 elevation. The ability of Ibutamoren to stimulate IGF-1 production can indirectly improve cognitive function based on IGF-1’s role in cognitive function. One study indicated that IGF-1 positively affected patients’ ability to perform well on cognitive tests.

Potential Side Effects

Reported side effects of ibutamoren are typically the result of unnaturally high levels of growth hormone in the body from taking too much too often, which include increased appetite, lethargy, potential joint pain, insulin resistance and possible increase in prolactin levels. When dosed properly, the side effects of ibutamoren are minimal to none.

The Insulin-like Growth Factor: IGF-1 LR3

The Insulin-like Growth Factor (IGF-1) is one of the endocrine hormones that is produced in the liver. The release of this hormone increases in the presence of Human Growth Hormone. Numerous cells throughout the muscles of the human body are equipped with cell receptors that have a high affinity for Insulin-like Growth Factor. This makes this hormone one of the best growth hormones and a facilitator of general cell growth which it does by targeting different specific tissues and in more autocrine cell communication processes, it facilitates cell division.

Some Benefits of the Insulin-like Growth Factor 1 and some of the reasons why it has substantial advantages include:

It facilitates protein synthesis in the body.
It regulates the storage of fat and channels it to be used for the production of energy. This results in a noticeable fat loss.
Promotes positive effects on metabolism; increasing lean body mass and decreases fat
It increases the regenerative properties of the body’s nerve tissues.
Upregulates anti-oxidant benefit and ligament strength
It boosts hyperplasia in muscle cells, which leads to fuller muscle tissues.

Optimal IGF-1 and growth hormone levels are crucial to bone development during childhood and throughout adult life.

The half-life of IGF-1 LR3 is about 20 – 30 hours. It is more potent than the regular base IGF-1. Because it can be sustained in the body for more than a day, it efficiently binds to cell receptors in the muscle cells and activates cell communication which subsequently improves the growth rate of muscles all day long.

IGF-1 LR3 inhibits the movement of glucose into the body cells which facilitates fat burning and the use of fat in the body for the production of energy. Its long life of close to a day has made it a preferred variant by a majority of patients and physicians because site injections are never necessary. IGF-1 LR3 cycles the whole body and binds to the receptors on muscle cells then acts for about a day, so a daily administration of this dosage is strongly supported.

KPV

KPV is a peptide that is naturally produced in the body. This particular peptide is naturally found in our body in form known as hormone alpha-MSH. It is used for inflammation, gut health and conditions such as Inflammatory Bowel Disease (IBD) and colon cancer.

What are the Uses, Benefits & Applications of KPV?

Anti-inflammatory
Anti-microbial
Used in healing wounds & injuries
Helps with Inflammatory Bowel Diseases (IBD) and colitis
Some benefits with cancer

Anti-Inflammatory -KPV is an anti-inflammatory peptide that has potential to treat a wide range of inflammatory diseases.

How Does KPV Work as an Anti-inflammatory Peptide?

KPV exerts its anti-inflammatory function inside cells, where it inactivates inflammatory pathways. KPV enters the cell and interacts directly with inflammatory signalling molecules inside the cell. It enters the nucleus of the cell and, once there, can inhibit the interaction of inflammatory substances and molecules.

It suppresses inflammatory signaling in a type of lung cell known as the bronchial epithelial cell. KPV causes a dose-dependent inhibition of NFκB, IL8 and other inflammatory molecules. KPV can target airway inflammation in lung disease. It also suppresses both local and systemic immune responses which commonly cause airway damage and remodelling in inflammatory lung disease.

Anti-Microbial

In addition to its anti‐inflammatory effect, KPV also has antimicrobial effects against pathogens. Its antimicrobial effects were demonstrated on two major pathogens called S. aureus and C. albicans. S. aureus is a bacterium frequently found in the upper respiratory tract and on the skin. Usually, it does not cause any harm but sometimes S. aureus can cause infections. C. albicans is an opportunistic pathogenic yeast. In one study, KPV significantly inhibited S. aureus from forming colonies.

Wound Healing

Research in wound healing shows KPV can speed wound healing, reduce infection, fight inflammation, and lead to better cosmetic results. Often with wounds, various microbes enter the wound. This must be controlled by the innate immune system to avoid infection. Skin is well equipped to do this with a number of antimicrobial peptides. KPV, with its anti-inflammatory and anti-microbial properties, can be very helpful for combatting these microbes and healing wounds.

Gut Issues: Ulcerative Colitis & Inflammatory Bowel Diseases (IBDs)

A lot of research on KPV is in the treatment of inflammatory bowel disease and it might be a new and helpful therapy for IBD.

Inflammatory bowel disease (IBD) is chronic inflammation of all or part of the digestive tract. The two most common types of IBD are Crohn’s disease and Ulcerative Colitis. They manifest as chronic inflammation of the gastrointestinal (GI) tract and this inflammation results in damage to the GI tract.

Colitis is inflammation of the lining of the colon, caused by infection, Inflammatory Bowel Disease (IBD) and other issues.

KPV significantly decreased inflammation in colitis. It decreases the inflammatory response by inhibiting proinflammatory cytokine (molecule) synthesis and secretion. KPV can stop the proinflammatory mechanisms in both intestinal epithelial cells and immune cells. It can interact directly with immune cells which can reduce inflammation. KPV may help in the case of IBDs through inhibited immune responses.

Taken orally, KPV reduces the incidence of colitis, as shown by a decrease in proinflammatory cytokines. In the case of colitis, KPV reduced weight loss, colonic activity and decreased inflammation and proinflammatory cytokine levels. KPV calms the response of colonic epithelial and immune cells and reduces the incidence of colitis in vivo.

KPV also supports healing of the mucosal lining of the gut. This helps with the condition Ulcerative Colitis. In one study KPV was given to mice with Ulcerative Colitis, in combination with other therapeutic substances. These mice experienced significant improvements in body weight, colon length and disease symptoms.

Cancer

KPV treatment is able to decrease tumorigenesis. Tumorigenesis, or carcinogenesis, is the formation of cancer, where normal cells are transformed into cancer cells. KPV was sufficient to decrease the inflammation of carcinogenesis. Using KPV before the development of colon cancer might be a preventive way to stop colonic carcinogenesis before it begins. The precise mechanism by which KPV decreases tumorigenesis is not yet fully understood.

Method of Delivery for KPV

Iontophoresis is method of taking medications. KPV is often taken via this method. It uses low-level current to drive charged compounds across the skin barrier. Iontophoresis is very useful because it increases the absorption of drugs and is a way of driving KPV, or another drug, deeper into the skin.

The benefits of using transdermal drug delivery, via the skin, include improved systemic bioavailability because it bypasses the first metabolism in the gut. Variables in taking drugs orally include pH, the presence of food or enzymes and transit times. These can all be eliminated with iontophoresis.

Side Effects

KPV is a naturally derived peptide without any notable side effects. KPV has been shown in animal studies to be safe and effective when administered orally, intravenously, subcutaneously and transdermally.

There is always the chance of potential interactions with other medications a person may be taking. It is very important to work with an experienced Functional Medicine practitioner when taking KPV or any other peptides. Our clinic has extensive experience with peptides and can help you with KPV or other peptides.

LL-37

Antimicrobial peptide LL-37, belongs to the cathelicidin family of peptides, and this peptide corresponds to the sequence of the first amphipathic alpha-helical peptide isolated from humans. They are small, cationic peptides found in humans and other species. Specifically, they are stored in neutrophil granules as inactive precursors and are released as mature peptides when required and cleaved by neutrophil elastase.

LL-37 is expressed in various cells and tissues such as circulating neutrophils and myeloid bone marrow cells, epithelial cells of the skin, and is also expressed in the gastrointestinal tract, as well as in the epididymis and lungs. Expression was also detected in squamous epithelium of the mouth, tongue, esophagus and in the colonic and bronchial mucosal epithelium.

Moreover, production of LL-37 in macrophages is stimulated by vitamin D released by sunlight through the skin. LL-37 plays an important role in the first line of defense against infection and systemic invasion of pathogens at sites of inflammation and wound. It is cytotoxic to both bacterial and normal eukaryotic cells and is significantly resistant to proteolytic degradation in solution. They show a broad spectrum of antimicrobial activity against bacteria, enveloped viruses, and fungi. Along with exerting direct antimicrobial effects, they are also critical in triggering specific defense responses in the host.

Mechanism of Action

In its direct antibacterial role, it is believed that LL-37 acts via disrupting the bacterial Membrane. Generally, membrane disrupting AMPs are assumed to act via one of three mechanisms of action: (i) formation of a pore with a barrel-stave conformation, where a tight bundle of amphiphilic peptides forms a hydrophilic pore across the membrane, (ii) toroidal pore formation, where a loose bundle of peptides modulates the membrane into a lipid headgroup lined pore, and (iii) the carpet mode, where peptides remain on the surface of the membrane until a threshold is reached to facilitate a breakdown in membrane integrity. However, the mechanism of action of LL-37 does not fit into any of these categories; it remains parallel to the surface throughout its action and does not insert into the membrane, and its orientation is unaffected by peptide concentration, membrane charge, presence of ions, or temperature.

Furthermore, LL-37 is not as selective as other α-helical, amphipathic AMPs; it does not exhibit a clear preference for charged membranes and while its minimum inhibitory concentration (MIC) ranges from 1 to 10μM for a variety of Gram positive and Gram-negative bacteria, it exhibits eukaryotic cytotoxicity at 13–25μM concentrations. Hence, it was proposed that LL-37 is a nonspecific, albeit highly effective, cell killer that acts via the carpet mechanism.

However, it was shown that LL-37 disrupts the lipid bilayer without breaking the membrane into small fragments, and fluorescence measurements also suggested a pore forming mechanism. The activity against mammalian cell membranes is also ambiguous: it was proposed that LL-37 could act, at least in part, by decreasing the fluidity and hence lowering the permeability of epithelial cell membranes, making it harder for certain bacteria to attack. Hence, there are many uncertainties around the mechanism of LL-37 action and attention has shifted to developing more active variants of LL-37 using systematic mutation while the study of the actual mechanism of action has been largely neglected.

LL-37 also has an indirect role in the immune response to foreign antigens. It displays an ability to activate various immune cells thus possessing functional dualism in the human body. Following stimulation by proinflammatory signals hCAP18 is released into the extracellular environment and cleaved by proteinase 3 in neutrophils and kallikrein. Exposure to LL-37 results in recruitment of inflammatory cells, induction of M1 macrophages, and stimulation of inflammatory responses such as inflammasome activation and type 1 IFN production. LL-37 has strong anti-inflammatory effects such as neutralization of TLR4 activation by LPS, downmodulation of inflammatory cytokine responses, and preventing invasion and inflammatory responses to pathogenic bacteria.

What have Research Studies Shown?

-Scientific research has revealed that LL-37 can do the following:

-Immune Defense Against Bacterial Invasion

-Antiviral and Antifungal Activity

-Increases Epithelial Stiffness and Decreases Permeability to Bacterial Invasion

-Treatment of Respiratory Syncytial Virus (RSV)

-Potential Contraceptive Therapy

LL-37 in Research (Expanded)

Immune Defense Against Bacterial Invasion

A number of studies have been performed to determine the immune activity of LL-37 against a wide array of bacterial species and have been proven effective in the treatment of such pathogens. Many patients with indwelling devices obtain chronic infections which are refractory to antibiotic treatment and most of the time caused by staphylococcus epidermidis. A study was performed which indicated that the use of LL-37 is a potential candidate in prevention and treatment strategies of staph epidermidis. Specifically, the study indicated that LL37 significantly decreased both the attachment of bacteria to the surface while also inhibiting biofilm production. Thus, its potential indications for the prevention of bacterial infections post-medical device implantation is significant.

Due to the increasing resistance of bacteria to conventional antibiotics, the effectiveness of LL-37, along with other medications, have been tested to determine how well elimination of both extra- and intracellular pathogens can be done. In a recent study done, LL-37 was compared to conventional antibiotics such as lactoferricin B and doxycycline; and, it was found to be superior at killing both intra- and extracellular staph aureus in that it was more potent, faster, and concretely more effective quantitatively. Thus, LL-37 could potentially be used to treat chronic and recurrent infections due to its effectiveness in eliminating pathogens.

Antiviral and Antifungal Activity

LL-37 not only contains antibacterial characteristics, but it can affect viruses and fungi as well. Specifically, it has been shown to be a potent contributor to the defense against Influenza A Virus. A recent study was done to determine how it affects viral membranes under electron Microscopy. Unlike collectins and defensins, LL-37 did not induce viral aggregation, rather it appeared to cause disruption of viral membranes. Thus, confirming that is acts differently from surfactant protein D or defensins in the defense against viral infections such as influenza A. LL-37 has also shown significant antifungal properties.

Candida albicans is one of the most common fungal pathogens against humans, and at times can be difficult to treat due to the presence of moisture and warmth throughout the human body. There have been numerous studies that indicate that LL-37 has the ability to kill Candida albicans fungal species. Altogether it was shown that LL-37 can affect fungal species in a variety of ways. It has the ability to change the integrity and architecture of the cell wall, along with being able to modulate the expression of genes with a variety of functions for the development and replication of the fungi.

Respiratory Syncytial Virus

The leading cause of respiratory tract infections in infants is Respiratory Syncytial Virus (RSV), and it causes significant morbidity and mortality. There have been many studies done to determine the effect LL-37 has on the virus and the results have been significant. Multiple studies suggest that LL-37 significantly impacts the ability of the virus to survive and replicate. It damages the viral envelope, disrupts viral particles, and inhibits binding to epithelial cells.

Further, exogenously applied LL-37 is protective against RSV-mediated disease in pulmonary RSV infection in vivo. In a healthy human adult RSV infection model, nasal levels of LL-37 were significantly increased. These studies indicate LL-37 is crucial in first line of defense against pulmonary infection with RSV and are an inducible target for the prevention of severe infections by the virus.

Contraceptive Therapy

The demand for oral contraceptives with antimicrobial is increasing with the vast increase in global sexually transmitted disease. LL-37 is naturally found in the reproductive tract, specifically, the vagina, in the female. LL-37 is produced in the vagina and has been shown to have bacteriostatic effects against HIV-1 infections.

One study indicated that binding of LL-37 to the sperm head dose-dependently inhibited fertilizing ability in vitro. This same study showed how LL-37 can have a significant impact on the perforation of the sperm cell membrane while not causing toxicity to the human vaginal and ecto- and endocervical cell lines. Thus, there is potential therapeutic benefit for LL-37 as a vaginal contraceptive as well as prevention of reproductive infections.

Respiratory

LL-37 has been indicated in a variety of medical problems within the respiratory system. Chronic obstructive pulmonary disease (COPD) increases risk for decline in lung function, health status problems, and even death. One of the most common things that can lead to exacerbations of problems associated with COPD is lung infection. LL-37 plays an important role in fighting lung infections, and it has been shown that in patients with COPD, the risk of infection was higher due to lower levels of circulating LL-37.

On the flip side of that coin, LL-37 can itself play a role in the progression of COPD due to its inflammatory response in mucosal production. It has been shown that LL-37 is associated with MUC5AC production involving the TACE-EGFR-ERK1/2 pathway. Further, the increase collage matrix formed leads to an increase in fibroblast. Thus, it enhances airway mucus production which leads to the progression of COPD as more of the lung is obstructed and subsequent problems arise from that. So, although it seems that LL-37 is essential for the innate immune response to infection and exacerbations of problems with COPD, LL-37’s innate role in the progression of COPD due to mucus overgrowth must be considered.

Gastrointestinal

LL-37 has also been shown to play a significant role in many diseases associated with the Gastrointestinal (GI) tract. It has been shown that in the inflamed mucosa of ulcerative colitis and Crohn’s disease has significantly elevated expression of LL-37. This increase in expression was elicited by TLR-3 stimulation and upregulation, and through the TLR9-ERK pathway, leads to fibrosis.

LL-37 has an anti-fibrotic effect. And, its antimicrobial action in the mucosa was shown due to its action against LPS. It has also been shown that low levels of circulating LL-37 lead to progressively worse outcomes in patients with irritable bowel disease.

Skin/Wound Healing

Psoriasis is a common skin disease and is largely mediated by a T cell auto-response. It occurs in a largely unknown fashion, but it is known that it is an autoimmune disease regulated by T cells. It has been found, however, that a majority of patients contain T cells specific for LL-37 which is overexpressed in the skin of patients with psoriasis, and can trigger activation of innate immune cells. Further, pro-inflammatory signaling is triggered by T cells specific to LL-37. They act on a pathway to induce IFN-gamma and Th17 cytokines. It has been shown that circulating LL-37 significantly correlates with disease activity and contributes to pathology behind psoriasis.

On the flip side, it has been shown that topical vitamin D enhances the upregulation of LL-37 after acute skin injury. This is an indication that vitamin D(3) is a key factor in the regulation of LL-37 in the skin and is fundamental in the process of protecting the integrity of the skin upon injury. So, again, LL-37 shows its double-sided properties of being fundamental for protection of the skin acting as an innate immune system member, but it can further act on the adaptive immune system to enhance inflammatory diseases such as psoriasis.

Cancer

LL-37 has also been shown to play in cancer pathophysiology in the gut. Specifically, colorectal and gastric adenomas play a role in the down regulation of cathelicidins. Thus, the effects of LL-37 tumor suppression have been investigated. One study showed that LL-37 activates a GPCRp53- Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells. Exposure of these colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation which was independent of caspase activation.

Further, LL-37 was shown to inhibit gastric cancer cell proliferation through activation of bone morphogenetic protein (BMP) signaling via proteasome-dependent mechanism which subsequently phosphorylates Smad1/5 and induces p21. Thus, there is potential for an antitumor therapy using LL-37 in the GI tract.

In Conclusion

Understanding that LL-37 could be an excellent tool to improve the innate immune system we must be respectful of the potential where the overproduction of AMPs can lead to up regulating the adaptive immune system where AMP’s are up regulated in Psoriasis, rheumatoid arthritis and SLE. Autoimmune disease may be the AMP’s are dysregulating the innate system leading to changes in the adaptive immunity. Further investigation of pro inflammatory and anti-inflammatory effects are underway.

Summary

LL-37 is an antimicrobial peptide. It has been shown to have antimicrobial activity against multiple Gram-positive and Gram-negative human pathogens. Antimicrobial peptides (AMPs) have the potential to serve as an alternative to antibiotics. It's simple, AMPs kill the microbial pathogens (the bugs).

AMPs can possibly regulate bacteria/virus invasion and may control infection. It has been reported that AMPs could be used to activate the innate mucosal immune response in order to get rid of the infections. (Mucosal refers to the immune response at mucosal membranes of the intestines, the urogenital tract and the respiratory system, i.e., surfaces that are in contact with the external environment).

MOTS-C

MOTS-C (mitochondrial open-reading-frame of the twelve S rRNA-C) is a peptide made of up 16 amino acids that helps promote and increase metabolism. It can supercharge metabolism and increase the ability to exercise, build muscle and lose weight.

In general, the peptide is located in many different organs such as the liver, brain, and muscle tissues.

Mitochondria themselves, have their own DNA and within the “mitochondrial DNA” (mtDNA) are short open reading frames (sORFs) that can be used to encode and produce peptides.

MOTS-C is a peptide that helps regulate mitochondrial energy to optimize your metabolic balance. This is an important peptide for continuing to build muscle and also reversing or lowering the ageing process.

WHAT ARE THE BENEFITS OF MOTS-C

The Mitochondrial-Derived Peptide MOTS-C increases metabolic homeostasis and lowers obesity and insulin resistance.

Mitochondria also play a crucial role in determining metabolic flexibility. We know that mitochondria are the main building blocks devoted to ATP (energy) production and fatty acid oxidation.

Benefits may include:

weight loss by promoting fatty acid metabolism in the liver
muscle gain
osteoporosis prevention by promoting osteoblast activity
strengthened immunity
improves endurance
increased energy by upregulating mitochondria
promotes metabolic flexibility and homeostasis
protects against age and diet-dependent insulin resistance and obesity
promotes resistance to metabolic stress
improves glucose regulation

HOW DOES MOTS-C WORK

MOTS-C helps regulate metabolic functions in the body, including turning glucose into usable energy. MOTS-C targets muscle tissue primarily.

When taken, MOTS-C mimics exercise in the body by increasing insulin sensitivity and increasing glucose uptake in myocytes (muscle cells). This process occurs through the AMPK pathway. It is a mimic because traditional exercise increases muscle glucose uptake without stimulating insulin.

AMPK (AMP‐activated protein kinase), was found to be the master switch for metabolism and the central regulator of both glucose and lipid (fat) metabolism. Since the same process has been a target for therapeutic intervention against metabolic conditions such as type‐2 diabetes.

MOTS-c treatment leads to a decrease in the systemic and tissue-specific levels of myostatin, which may block the weakening of muscle strength.

This potential double side effect of MOTS-c in skeletal muscle and WAT could be an important target in ageing-related diseases. The enhancement of energy expenditure via increasing muscle mass and browning of WAT by MOTS-c may be essential in the protection against common diseases in the elderly.

HOW DOES MOTS-C WORK

MOTS-C helps regulate metabolic functions in the body, including turning glucose into usable energy. MOTS-C targets muscle tissue primarily.

MOTS-c treatment leads to a decrease in the systemic and tissue-specific levels of myostatin, which may block the weakening of muscle strength.

WHAT IS THE DOSAGE OF MOTS-C

MOTS-C is supplied in a 10 mm per ml in a 10 ml vial

The standard dosage is to inject 10 mg subcutaneously once a week. This can be repeated in 6 months and or once every year.

WHAT ARE THE SIDE EFFECTS OF MOTS-C

MOTS-C has no reported side effects.Common side effects of MOTS-C include:injection site reactions (such as pain, swelling, or redness)

NAD+

NAD+ is necessary for mitochondrial viability and genetic control in aged organisms. In addition, the amount of NAD+ in the body decreases as it ages, making it more difficult for the body to produce energy. As we age, our bodys supply of NAD+ diminishes. Its common knowledge that by the time youre 50, youve lost around half of the muscular mass you had as a teenager. Reducing levels of this peptide in the blood have been linked to various age-related conditions, including accelerated aging and metabolic and cardiovascular illness. NAD+ deficiency is linked to aging-related disorders because of a sluggish metabolic process. There are promising outcomes in the therapy of aging-related diseases, the extension of human life span, and a longer lifetime when NAD+ levels are restored in experimental animals.

NAD+ peptide

Do you know what NAD means? In humans, animals, yeast, and just about everything else that can live, nicotinamide adenine dinucleotide (NAD) is a kind of coenzyme.

For subsequent enzymes to work effectively, the body needs coenzymes. A simple definition of nicotinamide is provided here. According to Wikipedia, Adenine dinucleotide is a cofactor that may be present in all live cells. It plays a role in energy metabolism and several other biological processes essential to the existence of life. Two nucleotides make NAD+, representing the building blocks of nucleic acids and DNA.

Benefits Aging

From flora to primates, many creatures have a genetic component known as keepers of genomes that prevents degeneration and illness. As a result, when the body is put under physical strain or a lack of food, these genes mobilize troops to protect the body. According to a study, DNA synthesis is facilitated by sirtuins, and they have anti-aging effects, such as the ability to extend lifespans in research species. The genomes are powered by NAD+, the energy source. On the other hand, Sirtuins are powerless without NAD+, much as a car would be if it didnt have gas. According to the research, an increase in the bloods NAD+ balance boosts sirtuins and extends the lives of several organisms, including cerevisiae, nematodes, and rats.

There’s a lot of movement going on.

Since the bodys natural energy reserve is mitochondrial activity, it is critical to exercise efficiency that it has healthy mitochondrial activity. NAD+ is one of the most crucial components when it comes to mitochondrial health. Increasing the concentration of NAD+ in the muscles of rats improves the activity of the mitochondria and the animals endurance. Using NAD+ enhancers, scientists observed that mice were slimmer and could sprint further on a circuit, indicating that the mice had superior total exercise performance than previously thought. Those older animals with a larger concentration of NAD+ perform better than their younger peers. A researcher may purchase NAD+ peptides from a medical supply store or an internet retailer of medical supplies. You can easily get NAD+ peptide for sale on the internet at relatively affordable rates relative to the benefits it gives, but for research purposes only.

An unbalanced metabolic process

Obesity has been declared a pandemic by the World Health Organization, making it one of the most widespread health issues in human history. 1.6 million individuals died globally in 2010 from diabetes, linked to obesity and other chronic illnesses. Dietary high-fat intake and age are associated with a decrease in NAD+ levels in the blood. Weight growth in rats is inhibited by NAD+ supplementation in studies, which also increases overall exercise capacity in older animals.

NAD+ and sirtuins in aging and disease

Abstract

Nicotinamide adenine dinucleotide (NAD(+)) is a classical coenzyme mediating many redox reactions. NAD(+) also plays an important role in the regulation of NAD(+)-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD(+) biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD(+) levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD(+) by supplementing NAD(+) intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Abstract

Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.

Interacting NAD+ and Cell Senescence Pathways Complicate Antiaging Therapies

Abstract

During human aging, decrease of NAD+ levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells, and neurons. At the same time, the number of senescent cells, associated with damage or stress that secretes proinflammatory factors (SASP or senescence-associated secretory phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models, including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis. A recent report links these processes, such that decreased NAD+ levels associated with aging may attenuate the SASP potentially reducing its pathological effect. Conversely, increasing NAD+ levels by supplementation or genetic manipulation, which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together, these findings suggest a fundamental trade-off in treating aging-related diseases with drugs or supplements that increase NAD+. Even more interesting is a report that senescent cells can induce CD38 on macrophages and endothelial cells. In turn, increased CD38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals. So, accumulation of senescent cells may itself be a root cause of decreased NAD+, which in turn could promote dysfunction. On the contrary, the lower NAD+ levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD+ therapies may be beneficial and increase safety, and in the best-case scenario reduce the need for NAD+ supplementation.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

Abstract

NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

Background: Aging is a natural part of human life. However, recent discoveries indicate that pharmacological approaches used for the improvement and possibly, for the delay of the aging process, might shed a new light on this topic. This might obviously contribute to the extension of the active life of older people and maintenance of their quality of life, which could consequently reduce both social and economic burden of each country, especially the developed ones.

Objective: The purpose of this study is to explore pharmacological discoveries which may help to the delay or improvement of the aging process. More specifically, the authors focus on three anti-aging drugs candidates: metformin, rapamycin and resveratrol and one anti-aging component NAD+ precursors whose randomized control trials on animals have appeared to provide some efficacy in this respect and they seem to be promising in the aging process of human beings.

Methods: This was done by conducting a literature review of available sources describing the issue of aging process with special focus on those anti-aging drug candidates.

Results: The results of this study indicate that promising anti-aging candidates seem to be metformin, especially as far as cardiovascular or cancer mortality is concerned, and NAD+ precursors since they appear to promote better organ function, increased physical resistance, disease resistance and prolonged life expectancy.

Conclusion: There is a call for more longitudinal clinical trials, which would prove the efficacy of the promising anti-aging drugs candidates in humans.

PEG-MGF

Aging is a natural, continuous process where the body undergoes a natural change, and the rate of bodily functions begins to decline. The normal levels of hormones and proteins also decrease resulting in slower functioning of the body.

During younger age, the phenomenon of muscle mass development and strength occurs at a normal rate. However, as people age, there is a loss of muscle growth, repair, and strength.

MGF is a naturally occurring protein that helps to build muscle mass in the body. MGF is found to be both age and exercise dependent and with increased age and increased exercise rate, the levels of MGF fluctuate in the body.

What is MGF

MGF is an acronym for Mechano Growth Factor and belongs to the class of IGF-1 (insulin like growth factor) family.

An isoform of IGF-1, MGF is also known as IGF-1Ec and is mainly produced in the liver.

IGF-1 gene undergoes transcription and generates the three mRNA isoforms, that’s IGF-1Ea, IGF-1Eb and IGF-1Ec. This fact means that MGF (or IGF-1Ec) is identical to IGF-1 but with a different E domain. Each isoform is synthesized by the body in response to different stimuli and possesses specific functions in different tissues.

What is the Difference Between MGF and PEG-MGF?

In few words, PEG-MGF, or polyethylene glycol (PEG)ylated MGF, is a synthetic form of MGF.

Pegylation is a phenomenon of connecting the polyethylene glycol (PEG) to another compound and altering its structure. In this case, MGF by itself has a very short half-life, however, once bound with PEG, the half-life is extended to a few days.

Studies have demonstrated that PEG IGF-1 is more effective than recombinant human IGF-1 for muscle regeneration and improving muscle function. The main reason was attributed to the fact that PEG does not easily bind with any other compounds and hence leads to the delayed clearance. In addition to this, the modification to the C terminus of IGF-1 with the addition of PEG increases the peptide efficacy at the tissue levels.

MGF Discovery Timelines

Upon research, it was known that there were three IGF-1 precursor proteins formed upon the splicing of the mature IGF-1. Each precursor is composed of 70 amino acids residue from the mature IGF-1, and only differs in the amino acid sequence attached to the COOH terminal, which also determines its function.

During the late 1990s and early 2000s, it was discovered that the levels of one of the three precursors, IGF-1EC (MGF), increased significantly upon muscle injury.

Several studies have been carried out thereafter to isolate and synthesize the (PEG)ylated MGF to modify and improve the efficacy and bioavailability of the peptide.

Functioning of MGF

The studies have shown that under muscle stress, especially during exercise, the mature IGF-1 gets spliced as a response towards stress, and hence produces and releases one of the isoforms called IGF-1EC, also known as Mechano growth factor (MGF).

One of the hypotheses is that once the levels of the MGF increases, the amino acid sequence attached to the COOH terminal of MGF gets activated and promotes cell proliferation in muscle stem cells.

Further studies demonstrated that upon administering the PEG-MGF, it stimulates the proliferation of C2C12 muscle cells and human myoblasts. Based on these results, it was determined that the exogenously administered MGF peptide is biologically active and inert by nature.

What does PEG-MGF Help With?

PEG-MGF induces stronger, durable effects of normal MGF that includes below therapeutic advantages:

Capacity to rebuild muscles
Potential to grow new muscle cells
Possesses neuroprotective effects, i.e. protection of nervous system, including brain
Demonstrates cardioprotective effects
Promotes tissue repair and wound healing
Promotes bone injury repair

Research and Clinical Studies With PEG-MGF

Below listed research studies were conducted on MGF, and since PEG-MGF is similar, in fact the ‘better’ version of MGF, there is reasonable evidence to believe that these studies are also representative of PEG-MGF effects.

Effects on Skeletal Muscles

Effects on Muscles In Animals

The main goal of this study was to examine the effects of MGF on muscle repair and wound healing.

Experimental mice that were induced with muscle contusion and muscular macrophage depletion were selected as study subjects. These mice were then administered with MGF directly into the damaged muscles.

Based on comprehensive analyses, it was determined that MGF induced muscular repair in the wounded tissues. MGF administration declined the rate of fibrosis in the contused muscles and reduced the expressions of inflammatory cytokines, chemokines, and stress factors.

These results demonstrate that MGF induces muscle regeneration and potentially decreases wound effects such as inflammation and oxidative stress.

Effects on Muscles In Humans

In this 2009 study, the effects of both natural MGF (i.e., IGF-1 isoforms) and synthetic MGF were evaluated on the exercise induced damaged muscle cells.

Ten healthy male volunteers were selected for this study and their muscle biopsy samples were collected before exercise. These volunteers were then subject to excessive exercise and the muscle biopsy samples were again collected 6 hours, 2, 5 and 16 days after exercise.

It was determined that this muscular damage stimulated increased secretion of IGF-1 isoforms, especially IGF-1Ea and IGF-1Eb, both of which are predominant forms of MGF. Similarly, synthetic MGF also promoted proliferative effects to heal muscular damage.

Synthetic MGF had an added benefit as their effects were not inhibited by the IGF-1 receptor antagonist.

These studies demonstrated that both natural IGF-1 isoform, MGF, and synthetic MGF exerted muscular regeneration and repair post injury.

MGF Cardioprotective Effects

The main goal of this study was to evaluate the effects of MGF on cardiac muscles undergoing programmed cell death following hypoxia, which is a condition characterized by limited supply of oxygen.

Rats were experimentally induced with hypoxia with only 1% oxygen supply leading to cellular apoptosis.

A microrod delivery device was fabricated with PEGDMA hydrogel chemical which was loaded with MGF peptide and then administered into the experimental rats. These injectable microrods possessed 30kPa stiffness, same as heart, and were the same size of myocyte cells.

Once administered, these rods induced successful release and delivery of MGF into the body within 2 weeks. It also induced increased migration of human stem cells to the heart which led to inhibition of apoptosis.

These results demonstrated that the 2-week MGF biological activity reduced cellular damage and increased stem cells, thereby potentially helping in cardiac muscle regeneration.

MGF Healing Effects on Bone Injury

The main goal of this study was to evaluate the healing effects of MGF on bone injury.

27 rabbits were experimentally induced with a 5-mm bone defect and were then divided into three groups that were treated with one of the two different doses of MGF namely 28 microg/kg bodyweight and 57 microg/kg bodyweight, or with a placebo for 5 consecutive days.

Post treatment, when the bone tissues were histologically examined, it was seen that the placebo treated tissue was the least healed, whereas the bone tissue treated with the highest MGF dose was the most healed tissue. This outcome suggested that MGF induced bone proliferation effects that promoted bone defect healing.

These results represented the potential use of MGF in the healing of fractures in humans.

MGF Effects on Brain Cells

Several studies were conducted on mice who were experimentally treated in order to increase the levels of MGF in their body and thereby study the effects of increased MGF concentration on their brain cells.

One study included breeding of mice in order to constitutively overproduce MGF in the hippocampus area of the brain. Hippocampus is primarily responsible for regulating the neurogenesis phenomenon in the body. This overproduction of MGF resulted in high concentrations of BrdU, which is a biological marker representative of proliferative actions in the body. This result demonstrated that MGF led to increased cell proliferation and brain development.

Another study was conducted where mice were bred to conditional MGF production at 1, 3 and 12 months old. Behavioral analysis and biological responses were examined after 2 years. These mice also showed elevated levels of BrdU and neurogenesis. It was determined that the enhanced levels of neurogenesis led to improved cognitive functions.

These studies demonstrate that MGF has potency to promote neurogenesis in brain cells and thereby be potentially used to treat cognitive disorders in humans.

PEG-MGF Potential Use in Dental Applications

Research studies were carried out on mice to determine the effects of MGF on chondrocytes. Chondrocytes are responsible for regulating cartilage health and deposition. These studies showed that MGF enhanced the migration of chondrocytes from bone cells into the cartilage where chondrocytes then exert their biological effects.

Similar to this, when PEG-MGF was administered in human periodontal ligament cell culture (in vitro human studies), it elevated the process of bone differentiation. This was suggestive that MGF promotes improvisation in the repair of ligaments that primarily attach the tooth to the bone.

As a result of this, it is possible the PEG-MGF may be used in dental applications as an alternative implant, and potentially even be used to treat and maintain surgically re-implanted teeth.

Side Effects of PEG-MGF

While studies are still ongoing for PEG-MGF to fully understand their biological effects and any adverse effects in humans, there is reasonable data online to suspect that there may be some potential side effects of PEG-MGF, including:

Hypoglycemia
Decreased blood pressure
Swelling, redness and itchiness at the site of injection administration
Nausea
Headache, dizziness

PEG-MGF Use as a Doping Agent

Scientists argue that very little is known about PEG-MGF and its effects on humans, however MGF has been widely welcomed in the bodybuilding industry. PEG-MGF administration is highly common amongst fitness enthusiasts either as solo administration or in combination with other anabolic compounds. While there are details about peptide administration, it should be noted that these are a mixture of both scientific research and hear-say about self-administration.

Given that it’s currently being misused as a doping agent by some athletes and fitness enthusiasts, PEG-MGF has been banned by World Anti-Doping Agency (WADA) in sports.

Summary

Mechano Growth Factor, MGF, is a potent isoform of IGF-1 family, which promotes tissue, bone and muscle recovery post injury.

Polyethylene glycol (PEG)ylated MGF, or simply PEG-MGF, is a synthetic version of MGF which is a combination of both PEG chemical and MGF protein. Due to the presence of PEG, it makes the MGF protein highly sustainable in the body and leads to longer lasting effects.

Several research studies have shown that exogenous administration of MGF helps to recover damaged tissues, muscles and bone cells and repair them at a significantly high rate.

Additionally, MGF also possesses cardioprotective and neuroprotective effects and have shown potential to be used as therapeutic agent in the medical field to treat human ailments. Research continues to date to fully explore the effects of PEG-MGF in humans and establish a safe peptide profile for its use in therapeutic fields.