Carnosine

Not an ordinary peptide, Carnosine (β-alanyl-L-histidine) may be considered a multitasking molecule. It’s anantioxidant that also has anti-aging, anti-glycation, chelation, and anti-proliferation properties.Moreover, it has been demonstrated to play an anti-tumorigenic role in certain types of cancer.

Carnosine is not a drug and is available as an over-the-counter food supplement.

Supplementation with carnosine has its place in nutritional medicine. At this time, clinical studies in humans has shown carnosine supplementation to:

• Improve muscle function and recovery from muscle fatigue.
• Protect against degeneration of the brain as well as loss of cognitive function and memory associated with aging.
• Improve mental function and behavior in children with attention deficit disorder and autism.
• Heal peptic ulcers when it is combined with zinc.

A Closer Look at Carnosine Functions

In addition to being important in regulating the electrical charge in excitable tissue, research has shown carnosine to be important to cellular health for other reasons. In muscles, carnosine neutralizes the extensive formation of lactic acid during high intensity exercise, and promotes recovery from exercise. These effects accelerate the working capacity of muscle exhausted by preceding exercise, and explains carnosine’s popularity among bodybuilders and athletes for improving muscle function and recovery from muscle fatigue.

Carnosine is also an important intracellular antioxidant. Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as protect against peroxidation of cell membrane fatty acids during oxidative stress. It has also demonstrated significant anti-aging effects related in part to its antioxidant effects, but it also prevents glycation (the attachment of sugar molecules to proteins) associated with premature aging.

Carnosine is especially critical in protecting the brain against neurodegeneration, as well as loss of cognitive function and memory. Carnosine has also been shown to rejuvenate connective tissue cells, which may explain its beneficial effects on wound healing as well as its use in trying to fight off the effects of aging in the skin, causing wrinkles and loss of elasticity. Carnosine levels in the body decline with age. By the time a person is 70 years old, carnosine levels have decreased in their body by 63 percent. Because of all of these effects and others, carnosine is becoming well known as a longevity and anti-aging nutrient.

Clinical Research with Carnosine

The primary focus of the clinical research on carnosine has focused on its anti-aging effects, as well as its effects on brain function.

In regard to general anti-aging effects, several clinical studies have highlighted the potential of carnosine in slowing down the aging process by preventing oxidative damage, as well as glycation. In addition, carnosine has also been shown to directly and indirectly inhibits release of inflammatory mediators such as cytokines. Reducing silent inflammation is becoming another key target, not only for an anti-aging strategy, but also to help prevent the development of chronic degenerative diseases like heart disease, diabetes and neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease. Given the unique actions of carnitine within the brain, it may be an ideal agent for preventing age-related declines in cognitive function and memory as well.

In regard to boosting brain power, several double-blind, placebo-controlled studies have looked at the use of carnosine in patients with neurodegenerative conditions. In one study compared a daily dose of either 0.75g or 2g of carnosine to a placebo, for 21 days, in 42 patients with chronic encephalopathy a brain disorder that is a progressive degenerative disease most often seen in individuals with a history of multiple concussions and other forms of head injury. Significant improvements in cognitive function and reductions in oxidative stress were found in the carnosine group.

Another study examined the effect of 1.5g of carnosine daily for 30 days in Parkinson’s patients treated with L-Dopa. The addition of carnosine to the treatment regimen significantly improved neurological symptoms, with a 36 percent improvement in symptoms compared to a 16 percent improvement in the control group. Clinical signs of Parkinson’s disease, including decreased bodily movements, and rigidity of extremities, were also significantly improved. This improvement in the “everyday activity” of Parkinson’s patients allows them more independence and better quality of life, leading the authors of the study to conclude that carnosine is a reasonable way of improving the treatment of Parkinson’s disease and decreasing the possible toxic effects of standard drug therapy.

Because of carnosine’s beneficial effects in improving both muscle and brain function, researchers at Georgetown University recently assessed its effects in Gulf War illness (GWI) or chronic multisymptom illness (CMI); terms used to describe the disabling fatigue, widespread pain and cognitive dysfunction experienced by about 25 percent of 1990-1991 Persian Gulf War veterans.

A leading theory proposes that GWI/CMI is the result of wartime exposure to a variety of factors including vaccinations, various chemicals and stress. These factors initiate prolonged production of inflammation, free radicals, and the resulting injury to the brain, nervous system and muscle tissue. Since carnosine has been shown to protect the brain and muscle cells from the sort of damage underlying GWI/CMI, a double-blind, placebo-controlled study was designed to determine if nutritional supplementation with L-carnosine would significantly improve pain, cognition and fatigue in GWI. The 12-week study involved 25 GWI subjects who were given L-carnosine at 500, 1000 and 1500mg increasing at four-week intervals or a placebo. Primary outcomes included measures assessing cognitive function; feelings of fatigue and pain; and activity levels. The only measure that showed consistent benefit was the influence of carnosine supplementation on improving mental function.

While researchers had hoped to see improvement in all areas of GWI/CMI, the ability of carnosine supplementation to improve mental function in these patients was significant and adds additional clinical support for carnosine in this application.

Carnosine may also be helpful in improving brain function in autism. In one double-blind, placebo-controlled trial in 31 children with autism carnosine was shown to improve expressive and receptive vocabulary and subjective improvement on an autism rating scale over an eight-week trial at a dosage of 800mg/day.

Zinc Carnosine to Relieve Peptic Ulcers

Zinc increases mucin production in cell culture studies and has been shown to have a protective effect on peptic ulcers in animal studies. In human studies, zinc supplementation appears to be helpful for healing peptic ulcers with zinc bound to carnosine being the most beneficial. Clinical studies in humans using zinc carnosine demonstrate not only an ability to heal peptic ulcers, but also antagonize the bacteria (Helicobacter pylori or H. pylori) linked to indigestion (dyspepsia), peptic ulcer disease, and stomach cancer. When 60 patients suffering from dyspepsia with H. pylori infection were given either antibiotics alone (lansoprazole, amoxycillin and clarithromycin) or antibiotics plus zinc carnosine for seven days, better results were seen with the group getting zinc carnosine (94 percent success rate vs. 77 percent).

In one double-blind trial, 248 patients with confirmed gastric ulcers were randomly assigned to one of four groups receiving 150mg daily of zinc-carnosine extract or its respective placebo, or 800mg of cetraxate hydrochloride (a mucosal protective agent) or its respective placebo. Study medications were started within one week of endoscopy-diagnosed gastric ulcer and were continued for eight weeks. At eight weeks, 75 percent of the zinc-carnosine group experienced markedly improved symptoms compared to 72 percent for the cetraxate group. The endoscopic cure rate was 60.4 percent in the zinc-carnosine group and 46.2 percent in the cetraxate group at eight weeks.

Dosage Recommendations

The typical dosage recommendation for taking advantage of the anti-aging effects of carnosine is 1,500 to 2,000 mg per day. For children with autism, the dosage is 800 to 1,000mg per day. For peptic ulcers and indigestion, the dosage for zinc carnosine is usually 75mg twice daily.

L-Carnosine is found throughout the body, but it is particularly abundant in those cells that are long-lived, such as nerve cells (neurons) and muscle cells (myocytes). Chemically, it is a dipeptide (a molecule consisting of two amino acids) constructed from beta-alanine and L-histidine, hence its chemical name – beta-alanyl-L-histidine. L-carnosine, as is true of the antioxidant enzyme superoxide dismutase (SOD), is one of a handful of compounds that are present in tissues at levels that correlate strongly with the life spans of animal species. Muscle levels of L-carnosine decline approximately 63% between the ages of 10 and 70. However, brain levels of L-carnosine remain high in comparison with the levels found in most other tissues. Scientists have speculated that this may be one reason that brain function remains stable into old age despite the brain’s dependence upon glucose for energy metabolism and the unusually high ratio of fructose to glucose in the brain.

Carnosine Is an mTOR inhibitor

Both the cause and outcome of aging are usually regarded as multifactorial.Accordingly, more effective control might be achieved by intervention at multiple sites.

The endogenous dipeptide carnosine may have anti-aging properties due to its reputed pluripotency. The pluripotency of biological compounds refers to the ability of these substances to produce several distinct biological responses. There are three anti-aging mechanisms of carnosine (see Figure 1).8

  1. Inhibition of the mTOR pathway(see“Resveratrol’s Second Life Extension Mechanism” in the May 2010 issue of Life Extension)
  2. Inhibition of the TGF-β (Transforming growth factor-β)/Smad3 pathway (Aging and aging related chronic diseases are associated with an increase of TGF-β/Smad3 signaling and expression)
  3. Suppression of the effects of reactive carbonyl compounds

Aging is a Multifactorial in its Causality and Final Outcome

It is generally assumed that aging is not a single process, but is the result of various persistent deleterious effects which eventually compromise cellular and organism homeostasis. Physiologically, homeostatic dysfunction characterizes cellular and whole animal aging, ultimately resulting in reproductive failure. When analyzed from a biochemical perspective, aging is usually regarded as multifactorial in both its causality and ultimate outcome. Macromolecular dysfunction, in particular deleterious changes in nucleic acids, proteins and lipids appear to accumulate in aged tissues. For example, aging is associated with increased somatic mutation, progressive homeostatic dysfunction, accompanied by protein modification and lipid peroxidation, which may be attributed to the effects of either exogenous agents or/and interaction with endogenous but potentially deleterious metabolites.

Justly, it can be argued that any effective anti-aging agent should be pluripotent in order to counteract the various molecular changes, which underlie age-related cellular dysfunction.

The endogenous dipeptide carnosine is synthesized in muscle and by astrocytes in the brain. In muscle, carnosine is found in higher concentrations in glycolytic (fast- twitch) fibers than in mitochondria-enriched aerobic muscle; it is degraded back to its constituent amino acids by carnosinases present in a variety of tissues, including plasma and kidney.

Several pieces of evidence suggest a high correlation between life expectancies of mammalian species and muscle carnosine concentration. For example, carnosine content in human muscle (20–30 mM) was twenty times higher than found in mice, ten times than in rabbits and three times than in cows—such differences approximately consistent with their different lifespans. In humans, lower levels of muscle carnosine were found in elderly individuals compared to younger adults.

To repeat, supplementation with carnosine has anti-inflammatory, antioxidant, antiglycation and chelating roles, and may act as a buffering agent in skeletal muscle and improve calcium handling. Although circulating carnosine levels are affected by the presence of plasma carnosinase in humans, long-term supplementation of carnosine results in improved health and/or behavioral outcomes.

Consequently, we suggest that chronic supplementation maintains a more constant plasma level of carnosine mainly due to saturation of carnosinase. Carnosine is considered to possess anti-aging properties because of its pluripotency, although the exact route or routes whereby carnosine achieves this remain(s) to be defined.

While few studies have investigated the effect of carnosine on aging, administration of carnosine to senescence-accelerated mice increased the mean lifespan by 20%, and 50% survival rate by 20%.

In humans, lower levels of
muscle carnosine were found in
elderly individuals compared to
younger adults.

Possible areas in which carnosine could exert beneficial effects include suppression of telomere shortening, along with the already-mentioned anti-oxidant activity, anti-AGE activity (carbonyl scavenging), suppression of glycolysis, upregulation of mitochondrial activity, activation of proteolysis, inhibition of tumor cell growth, apoptosis, extension of Hayflick limit, rejuvenation of senescent cells, effects on phosphorylation of translation initiation factors, and effects. Carnosine has no known side effects.

Carnosine Inhibits mTOR

Carnosine is traditionally used to increase athletic and exercise performance, and has preventive and therapeutic benefits in obesity, insulin resistance, type 2 diabetes, and diabetic microvascular and macrovascular conditions (cardiovascular disease and stroke) as well as number of neurological and mental health conditions.

Life Extension by Inhibiting Growth

When cells become senescent, they no longer proliferate, but that doesn’t mean they don’t grow. In fact, a very interesting recent review2 explains how cellular senescence involves both blocked cell cycling (discontinuation of replication) as well as excessive growth-promoting pathways. (See Durk Pearson & Sandy Shaw’s Life Extension News, Volume 13 No. 1 • February 2010 in the April 2010 issue of Life Enhancement.)

When the cell cycle is arrested, a continuation of cellular-mass growth results in senescent morphology. In fact, in another paper3 it is noted that older cells are indeed larger. An increase in cell size is a hallmark of senescent fibroblasts. Their cell volume is several-fold greater compared with proliferating cells. Cell size is progressively increased in cell culture as cells progress toward senescence. In other words, when the cell cycle is blocked in the presence of growth-promoting signaling, then cells increase in size.

mTOR

A major growth-promoting pathway includes TOR (target of rapamycin) along with its upstream regulators and downstream effectors. The TOR gene is structurally and functionally conserved from yeast to humans (including worms, flies, plants, and mice), acting as a cell growth regulator. Excessive growth is a driving force for aging.2 Indeed, inhibition of TOR signaling increases lifespan in worms, flies, yeast, and possibly mammals. In mice, decreased signaling through the insulin/insulin-like growth factor (IGF-1) pathway in adipose tissue results in less mTOR (mammalian TOR) signaling and increases lifespan.3 Reduced caloric intake (as in dietary restriction) also reduces signaling through mTOR and is a well-known method of increasing lifespan in many species, including monkeys.

TOR (target of rapamycin) is inhibited by rapamycin, a natural metabolite produced by soil bacteria to inhibit growth of fungal competitors. Interestingly, rapamycin is a prescription drug in clinical practice; it is administered to renal (kidney) transplant patients to prevent organ rejection.3 Results in these patients include the prevention of cancer and even cures of some pre-existing cancers. Moreover, two years after renal transplantation, the body-mass index of patients treated with rapamycin was significantly lower than the patients treated with cyclosporine,3 another immunosuppressant. In a study of 11 healthy men treated with 6 mg of rapamycin, (insulin resistance that accompanies the large increase of nutrients that ordinarily induce mTOR signaling) was prevented.3 At present, rapamycin is being investigated in clinical trials as a treatment for cancer.

Pharmaceutical companies are seeking to develop rapamycin derivatives to inhibit mTOR for possible treatment of cancer, autoimmune disorders, type 1 and type 2 diabetes, and obesity. For example, in relation to type 2 diabetes, chronic hyperglycemia can lead to chronic activation of mTOR in pancreatic beta cells.4Rapamycin (which reduces the activity of mTOR) induces autophagy, a process of programmed self-digestion which, for example, helps to clear aggregated proteins in neurodegenerative diseases such as Alzheimer’s disease.

The mTOR Pathway is Sensitive to Redox State

A complex containing mTOR and the regulatory protein raptor is a key component of a nutrient-sensitive signaling pathway that regulates cell size by controlling the accumulation of cellular mass. HEK293T cells treated with potent oxidants activated the raptor-mTOR [regulatory-associated protein of mTOR] pathway even under nutrient-deprived conditions, when this pathway is ordinarily suppressed (see Figure 1).

If the oxidizing compounds are mimicking an endogenous oxidant that normally activates the raptor-mTOR pathway, the reducing reagent should inhibit pathway activation caused by nutrients. Indeed, the authors found this to be the case; incubating cells with a reducing agent called BAL (2,3-dimercapto-1-propanol) significantly reduced the phosphorylation of S6K1 (an effector of the raptor-mTOR pathway) and was associated with an increase in the amount of raptor recovered with mTOR as is seen in cells in nutrient-deprived conditions.

This is an exciting finding as it suggests that it might be possible to suppress mTOR activation even under conditions of full feeding by using appropriate safe and effective doses of certain powerful reducing agents. We haven’t seen any further work on this (though it may be that such research is being done but is being kept proprietary).

Two natural products that have been
reported to be possible inhibitors of
mTOR are curcumin and resveratrol.

Natural Products That Inhibit mTOR

Two natural products that have been reported to be possible inhibitors of mTOR are curcumin and resveratrol. Curcumin disrupts the mTOR-raptor complex (mTORC1) that results from the activation of the mTOR pathway, and thus may represent a new class of mTOR inhibitor.5 Curcumin, along with possibly active (in inhibiting mTOR) molecularly related curcuminoids, can be obtained by supplementing with turmeric root powder.

Resveratrol inhibits the mitogenic signaling (growth promoting) by mTOR that causes smooth muscle cells to proliferate in response to oxidized LDL.6 This could be a very important protective effect of resveratrol since the proliferation of smooth muscle cells is a major part of atherosclerotic development. Rapamycin dose-dependently inhibited the DNA synthesis (marker of cellular proliferation) and cell proliferation of smooth muscle cells in culture, with complete inhibition taking place at 10-100 nM, indicating that the smooth muscle cell proliferation was under the control of mTOR.

This effect was not due to cytotoxicity of rapamycin because in cells treated with oxidized LDL (50μg apoB/ml), rapamycin was not toxic up to 100 nM. Since resveratrol has been reported to have inhibitory effects on smooth muscle cell (SMC) proliferation, the authors tested it for its effects on mTOR and SMC proliferation. Dose-response experiments showed that DNA synthesis and cell proliferation were significantly inhibited by 25 μM resveratrol without any significant apoptotic effects [indicative of toxicity] at this concentration. It should be noted that 50 μM resveratrol exhibited a slight toxic effect in the presence of oxLDL [oxidized LDL]. This strongly suggests that resveratrol acts on an upstream target in the PI3K/Akt/mTOR signaling pathway.. ­­­­

Resveratrol Dose Limited by Toxicity

Although resveratrol can inhibit mTOR and thus suppress cellular senescence, the concentration required is close to the high dose at which resveratrol is toxic to cells.7 At lower doses, 8-25 μM, resveratrol was reported to “slightly but detectably” prevent the loss of proliferative activity (e.g., senescence) of the cells in which it was tested. Still, 6.25 – 12.5 μM resveratrol was shown to block the cell cycle and 25 μM caused apoptosis in vascular smooth cells in another study (cited in paper #7).

A “low dose” of dietary resveratrol (4.9 mg/kg) partially mimics caloric restriction and retards aging parameters in mice on a non-calorically restricted diet.

Rats fed a standard diet plus 6 mg of resveratrol/liter of drinking water had a reduced ratio of GSH/GSSG (reduced glutathione/oxidized glutathione) and enhanced GSSG, indicative of increased oxidative stress, in liver cells; in the same study, rats on a high fat diet receiving the same amount of resveratrol in their drinking water had reduced GSSG with GSH/GSSG not significantly different from controls on a standard diet, indicative of less oxidative stress. Though this dose of resveratrol (6 mg/liter of water) is, the authors say, below the maximal tolerated dose, the study suggests that the dose ingested by the standard diet fed rats (an average of a total of 48.2 mg/kg of body weight of resveratrol over 45 days or about 1 mg of resveratrol/kg body weight/day) had toxic effects, particularly (as noted above) increased oxidative stress in the liver. Meanwhile, the total amount of resveratrol, 14.8 mg/kg, ingested over 15 days (about 1 mg/kg body weight per day) by the high fat diet fed rats had protective effects.

Further research is needed to understand the effects of different doses of resveratrol in rats (and, indeed, in humans) fed different diets to determine optimal doses. It has already been found that dietary composition may affect the degree of life extension resulting from caloric restriction in fruit flies.

The amount of resveratrol in red wine is reportedly about 90 µg of resveratrol/fluid ounce of red wine.

The authors of paper #7 speculate that “even transient inhibition of mTOR is already sufficient to slightly suppress senescence.” They also suggest that “a combination of non-toxic doses of resveratrol with rapamycin would also extend life span in animals on a standard diet.” Resveratrol has already been shown to extend the lifespan of mice on a high-fat diet. They, of course, would like to see a test of non-toxic doses of resveratrol along with curcumin for its effects on mTOR and on life extension in animals on a standard diet. They would also be interested in the effects on mTOR of the curcumin-related curcuminoids found in turmeric root powder.

Durk & Sandy take their turmeric root powder (2 capsules four times a day) rather than taking only curcumin due to the possible additional benefits of the curcuminoids. They do not know what the optimal amount of resveratrol is for the purpose of decreasing cellular senescence and inhibiting mTOR, though they do drink moderate amounts of red wine and also take resveratrol supplements.

Beware Rapamycin

Long term use of rapamycin, approved for use in several disease indications, has had side effects such as canker sores, impaired wound healing, weight gain and glucose insensitivity (which could lead to diabetes)—raising questions about its use to prevent the chronic diseases of aging. That said, it’s notable that researchers at the Buck Institute for Research on Aging have discovered new insights into how rapamycin inhibits the nutrient signaling pathway mTOR, a finding that could provide a way to avoid or eliminate side effects of the drug.

References

  1. Zhang Z, Miao L, Wu X, Liu G, Peng Y, Xin X, Jiao B, Kong X. Carnosine inhibits the proliferation of human gastric carcinoma cells by retarding Akt/mTOR/p70S6K signaling. J Cancer. 2014 Apr 24;5(5):382-9.
  2. Blagosklonny MV. Aging-suppressants. Aging-suppressants: cellular senescence (hyperactivation) and its pharmacologic deceleration. Cell Cycle. 2009; 8(12):1883-7.
  3. Blagosklonny MV, Hall MN. Growth and aging: a common molecular mechanism. Aging (Albany NY). 2009 Apr 20;1(4):357-62.
  4. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today. 2007 Feb;12(3-4):112-24. Epub 2006 Dec 15. Review. Erratum in: Drug Discov Today. 2008 Sep;13(17-18):824.
  5. Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res. 2009 Feb 1;69(3):1000-8. doi: 10.1158/0008-5472.CAN-08-2367. Epub 2009 Jan 27. PubMed PMID: 19176385; PubMed Central PMCID: PMC4307947.
  6. Brito PM, Devillard R, Nègre-Salvayre A, Almeida LM, Dinis TC, Salvayre R, Augé N. Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells. Atherosclerosis. 2009 Jul;205(1):126-34.
  7. Barger JL, Kayo T, Vann JM, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008 Jun 4;3(6):e2264. doi:10.1371/journal.pone.0002264. Erratum in: PLoS One.2008;3(6). doi: 10.1371/annotation/c54ef754-1962-4125-bf19-76d3ec6f19e5. PLoS One. 2008;3(6). doi: 10.1371/annotation/8333176c-b08c-4dfb-a829-6331c0fc6064. PLoS One. 2008;3(6). doi: 10.1371/annotation/7d56e94e-3582-413d-b987-fccd0da79081. PubMed PMID: 18523577; PubMed Central PMCID: PMC2386967.
  8. Hipkiss AR, Baye E, de Courten B. Carnosine and the processes of ageing. Maturitas. 2016 Jun 22. pii: S0378-5122(16)30134-7.

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