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Life Extension Videos

Donate to the International Longevity Alliance’s Major Mouse Testing Program

Donate to the International Longevity Alliance’s Major Mouse Testing Program

According to modern science aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair systems. The good news is that the processes that constitute aging are amenable to medical intervention. We can slow down or even reverse some aspects of aging through the application of different therapies, which prevent or block some of these processes.

One of these processes of aging is cell senescence.

Senescent cells normally self destruct via a process called apoptosis, but unfortunately not all of them do. These “death resistant” senescent cells accumulate in the body with age and secrete toxic signals. This causes inflammation and damage to organs and tissues, increasing risks for cancer and other diseases of old age. This is why these cells are often called “good citizens but bad neighbors”. They remain partially functional, but their presence does more harm than good.

A new class of drugs known as Senolytics have recently demonstrated the ability to remove senescent cells to improve health. However, the potential of senolytics to increase health and lifespan beyond current maximums remains unknown. This is what we at Major Mouse Testing Program want to investigate – with your help!

Why is this study of particular interest?
It was discovered that senescent cells have increased expression of pro-survival genes, consistent with their resistance to natural cell death – apoptosis. Drugs targeting these pro-survival factors selectively killed senescent cells and improved health. Two such drugs were Dasatinib and Quercetin which were both able to remove senescent cells, albeit each in different tissue types. Even more excitingly it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types.

Venetoclax has also recently been discovered to be senolytic in nature and is a therapy we wish to explore as part of our combination testing. In cancer therapy Venetoclax has shown to work well with Dasatinib so we are interested in seeing if this can be applied to clearing senescent cells too.

Recent studies have shown removing senescent cells mitigates age related decline and improves healthy lifespan. Additional studies have shown that clearance of senescent cells is beneficial for cardiovascular health and lowers high cholesterol levels in the blood. This strongly suggests that Senolytics may be a viable therapeutic approach to combat aging.

In our study we have opted to treat already naturally aged mice. These mice will be 16-18 months old (equivalent to a human of approximately 60 years old). This has two advantages: we speed up research, and also demonstrate the feasibility of translating Senolytics to already middle aged or older humans.

Dasatinib and Venetoclax are already approved for use in humans to treat specific diseases, and Quercetin is a readily available supplement, so the application of these drugs or improved versions based upon them to prevent and postpone age-related damage to health could be developed relatively quickly.

Senolytics and Stem Cells
So far senolytics have only been shown to reduce the number of senescent somatic cells, but what effect do they have on stem cells? This has not been closely studied, and is a question we intend to fully answer in addition to the implications this presents for lifespan.

It is entirely possible that Senolytics taken alone may not extend maximum lifespan, but rather healthspan. Even if this is the case, it is no reason to be discouraged. What we learn in this first phase, paves the way for our next step – combining Senolytics with Stem Cell Therapy to encourage tissue regeneration.

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Life Extension

Metformin, A Breakthrough in Life Extension Research

As we already covered before, 2016 shows a lot of promise to be a great year for life extension research. One of the most interesting studies planned for this year is the TAME trial[1] (Targeting Aging with Metformin), a study that will test the use of aforementioned compound as a longevity drug in older adults who have cancer, heart disease, or cognitive impairment (or are at risk for these diseases).

What is it, exactly?

Metformin 3d skeleton
Metformin 3D structure

Metformin, also known as Glucophage ®, is an anti-diabetic drug that works by suppressing glucose production in the liver. Unlike the majority of diabetes drugs, however, it does not cause hypoglycemia (low blood sugar), even when given to non-diabetics.

Metformin is a drug of the biguanide class. As such, it resembles the compounds guanidine and galegine, found in the Galega officinalis plant (aka goat’s rue). Goat’s rue was known to have anti-diabetic activity since ancient times, but it proved too toxic to use.

The beginning of the history of metformin, however, has almost nothing to do with type 2 diabetes, but with an even worse disease: malaria.

History of Metformin

Cinchona officinalis bark
Harvested bark of Cinchona officinalis

Malaria is a disease caused by a parasitic microorganism of the Plasmodium species. The typical treatment for malaria before the advent of synthetic drugs was quinine, an alkaloid extracted from the bark of the South American tree Cinchona officinalis.

Quinine was expensive, and some parasites became resistant to it. Furthermore, the drug was imported from Java and the supply was unpredictable. In the 1930s, researchers began to discover and synthesize alternatives to quinine. A chemist named Francis H. S. Curd started investigating pyrimidine analogs at the ICI laboratories at Blackley, Manchester, after he noticed that some drugs with mild antimalarial activity had a pyrimidine ring in their structure.

Goat's rue
Goat’s rue

A number of compounds were synthesized and tested on malaria-infected chicks. Some of them were also tested on humans, but they proved too toxic for clinical use. Nonetheless, Curd persisted on in his research, and he figured out that using only a portion of the pyrimidine structure could potentially minimize toxicity while maximizing antimalarial effects. Paludrine, the fruit of Curd’s successful hypothesis, was synthesized in 1945. It is also interesting to note that part of Paludrine’s structure closely resembled galegine, the active component in goat’s rue mentioned above. Animal studies conducted two years after Paludrine’s discovery established that it was able to cause a small decrease in blood glucose. At the same time, in the Philippines, molecules of the same biguanide class were used by Dr. Eusebio Garcia, a local expert in infectious diseases. He noticed that flumamine, a guanidine analog, cured malaria in addition to lowering blood sugar levels.

The real breakthrough came with the work of French diabetologist Jean Sterne. While working at Aron Laboratories in Paris, he was prompted to action by Garcia’s report on flumamine. In collaboration with Denise Duval and others, he evaluated the anti-diabetic effect of flumamine in animals. It showed a powerful glucose-lowering effect which led him to coin the name Glucophage ®, meaning “glucose eater”. He published his results in 1957.[2]

Flumamine eventually became metformin and, in 1962, the first major clinical trial that tested metformin’s efficacy in type 2 diabetes was published.[3] 39 subjects were involved in the study, with almost all of them being over 30 years old. The study came to the following conclusions:

  • of the 39 patients, 14 showed satisfactory control of the disease with metformin
  • another 6 showed some improvement if the metformin was combined with low-dose insulin or another oral anti-diabetic agent
  • ‘pancreatic’ diabetics (now known as type 1 diabetes) did not respond to the treatment
  • treatment was with 1–3 grams of metformin per day, given as three divided doses, titrating up slowly and limited by the emergence of certain side effects.

Metformin was not the only biguanide anti-diabetic discovered in the 1930s. Phenformin and Buformin, used respectively in America and Europe, were actually stronger in anti-diabetic activity and had been the drugs of choice for type 2 diabetes up until the 70s, when they were banned after an ever-increasing number of deaths by lactic acidosis. Because metformin was seen as closely related to these two drugs, metformin’s public image was damaged. Although metformin hardly ever causes lactic acidosis, its damaged reputation meant it would take longer to catch on.

The next few decades saw a steady accumulation of data concerning metformin’s effectiveness and safety. One study, in particular, helped establish Glucophage ® as a safe and effective treatment for diabetes. The United Kingdom Prospective Diabetes Study, conducted from 1977 through 1997, effectively gave scientific evidence that metformin increases the lifespan of patients with obesity and type 2 diabetes.[4] Patients treated with metformin also had less incidence of heart attacks when compared to those treated with insulin or other diabetes drugs.

The Food and Drug Administration (FDA) of the United States approved metformin in 1994, which prompted its ascent as a popular diabetes drug in America. The patents covering metformin expired in 2002, which allowed it to be produced and sold inexpensively as a generic drug.[5]

New uses for an old drug

Cancer

fight cancer with metforminEven though the research on Metformin as a cancer prevention tool is still in its infancy, it appears to be very promising. Metformin and other biguanide medications have been increasingly investigated for their chemopreventive (cancer-preventive) and antineoplastic (tumor growth-inhibiting) properties. There have been various studies conducted on lab animals that investigate metformin’s ability to reverse or prevent tumor growth. One meta-analysis on the subject reported that metformin’s effects on cancer have been tested on 17 different organs in various strains of rats, mice, and hamsters. Some studies investigated its effects on naturally-occurring cancer while others investigated how it affected cancer induced in the lab by 16 different chemical classes of carcinogens. In other words, metformin’s anticancer effects were studied under a wide variety of unique and nuanced cases of tumor growth. Many different dosing regimens and routes of administration were also tested.[6] In the majority of cases (86%) the treatment with metformin and other biguanides led to inhibition of carcinogenesis. No cases of stimulation of carcinogenesis by the antidiabetic biguanides were ever detected.

While the mechanism of action for the chemopreventive activity of Metformin is not entirely clear, it is likely caused by the activation of AMPK-dependent and AMPK-independent pathways, in addition to energy metabolism aberration, cell cycle arrest, apoptosis or autophagy induction,[7] as well as mTOR signaling inhibition.[8]

Life Extension

In April of 2003, researchers at Biomarker Pharmaceuticals in California studied the effects of metformin on aging processes and longevity. The researchers found that metformin actually mimics the anti-aging effects of caloric restriction. Caloric restriction is a type of dietary method that involves consuming a significantly reduced amount of calories while still consuming proper amounts of essential vitamins and nutrients. This method has been touted by some to slow the aging process and extend lifespan. When tested on mice, metformin appears to induce a change in gene expression that is identical to that caused by a CR diet. This change in gene expression has the potential to extend animal life spans by 20 percent. Metformin is the first medication that has been discovered to mimic the effects of a CR-induced lifespan extension.[9]

Another study published in the AGING Journal showed that female mice treated with metformin from an early age lived longer and had fewer tumors. These effects were not seen in aged mice[10]

Contraindications and Side effects

Metformin is a relatively safe drug. As said before, it can be taken by non-diabetics as long as the dose does not exceed 1500-1700 mg. A good idea is to check blood glucose levels. It’s not advised to take Glucophage ® should the blood glucose levels be equal or lower than 80mg/dL.

Metformin should not be used in those with liver disease, kidney problems or lung disease, and any other condition that could increase the risk of lactic acidosis.

Long-term use of high doses of Metformin may cause Vitamin B12 deficiency[11], especially in those who do not consume animal products (vegetarians and vegans). The amount of B12 in a multivitamin is generally not enough to correct the deficiency[12]. It is therefore a good idea to supplement Vitamin B12 when taking Metformin.

Even though it doesn’t have serious interactions, be sure to check the Metformin page on Drugs.com or the patient information leaflet.

The most common adverse effect are related to the gastrointestinal system, and may include diarrhea, cramps, nausea, vomiting, and increased flatulence. To avoid these side effects Metformin should be started at the lowest dose (500 mg) and slowly increased to the desired dose.

Conclusion

Metformin has been a revolutionary drug for diabetes, and new research on biguanides shows that these drugs may enhance lifespan as well as prevent cancer. While it’s still a bit early to recommend metformin to every >50 years old, (or subjects in high-risk populations, like smokers), we’re finally getting closer to a real breakthrough in life extension research.

More research is needed in order to understand the correct dosage and efficacy of Metformin in humans.

References   [ + ]

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Life Extension

Epitalon: The Fountain of Youth

For centuries mankind has searched for the “Fountain of Youth”; that proverbial source of everlasting life. Herodotus wrote of a spring that gave the water of youth to all who bathed in it. Juan Ponce de Leon looked for it in south Florida centuries later but didn’t find it. Man’s quest for such a fountain failed until Dr. Vladimir Khavinson discovered Epitalon in the 1980’s. The fountain turned out to be a peptide produced by the pineal gland [1].

Telomeres
Telomeres resemble the plastic tips on the ends of the shoelace that prevent it from fraying.

There are many theories of aging, one of which is the shortening of telomeres in our DNA. A telomere is like the plastic tip on the end of your shoe lace. It protects the DNA from unraveling during each cell division. Each cell division results in a slightly shorter telomere length, and eventually, the cell can no longer divide. This is called the Hayflick Limit, after Dr. Leonard Hayflick’s discovery that cells have a limited number of times that they can divide.[2] In mammals, the telomeres are protected from shortening until the onset of sexual maturity. After that, they begin to shorten with each cell division, eventually leading to an inability to divide any more in order to replace worn out, damaged or diseased cells. There is an enzyme called telomerase that is produced in the cells which stimulates the lengthening of the telomeres. The pineal gland produces a hormone called epithalamin that tells the cells to produce telomerase which in turn results in longer telomeres in our DNA. The functionality of the pineal gland declines with age, and is partly responsible for age related diseases. [3]

Dr. Vladimir Khavinson
Dr. Vladimir Khavinson
Khavinson V.” by Nikolay bilakOwn work. Licensed under CC BY-SA 3.0 via Commons.

What Dr. Khavinson found was that introducing epithalamin into mammals resulted in a reversal of age related diseases, and a reversal of the signs of aging. He was able to take geriatric female mice, who were no longer fertile, give them epithalamin, and after about two weeks of treatment, the mice became fertile again, got pregnant and had pups.[4] He showed that Epitalon induces telomerase activity in human somatic cells, proving that telomeres were lengthened by the peptide.[5] The synthetic version of epithalamin was patented by Dr. Khavinson and called “Epitalon” (also sometimes called epithalon since the original word is in Russian). It was approved for general use in the Soviet Union in 1990 and has been used in gerontology there ever since. No adverse side effects have ever been reported, according to Dr. Khavinson.

Since Epitalon is patented and trademarked, no drug company will research it. Since drug companies pay for almost all of the research on new medicines, no human clinical trials have been done in the West on it. Almost all of the research has been done by Dr. Khavinson and his associates. The results of his research are startling: for example, the application of Epithalamin diminished mortality in aged humans by 1.8 times over a 6 year period of observation. [6] Here in the West, Epitalon is sold as a research chemical, not approved by the FDA for any purpose, but unregulated for research purposes. Anyone who uses it is considered a “researcher,” in other words.

Epitalon chemical structure

Epitalon is a small peptide of 4 amino acids: Ala-Glu-Asp-Gly and can be administered via injection, as a nasal spray, or through the skin. The most effective route of administering it is via injection, either subcutaneously or intramuscularly. The peptide is typically given 2-3 times a day for 10-20 days in doses of 5-10 mg each. This cycle is repeated once every six to twelve months, but Epitalon can be given as often as desired. There are no negative side effects from the drug ever reported in over 100 studies on the peptide and from clinical use in Russia since 1990. Epitalon works mainly on the endocrine system but has effects on the entire body.[7]


 
When I first started taking it, my sense of smell returned, my digestion improved and I slept better. I have also noted positive changes in my vision and hearing. All of these functions are related to the autonomic nervous system and the endocrine system. Epitalon has been shown to restore normal melatonin production in aging monkeys, as well as restore the normal circadian rhythm for cortisol production, both of which result in better sleep at night.[8]

Epitalon is certainly one of the most interesting anti-aging substance on the market, but further studies are needed to assess the efficacy and safety of telomerase activators.

Epitalon is not approved by the FDA and should not be used to treat or cure any disease.

For more in-depth information about Epitalon check out Epitalon, Part II: Mechanism of Action and the Epitalon’s Facebook group.

References   [ + ]

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Life Extension

Epitalon, Part II: Mechanism of Action

Peptide bioregulators, like Epitalon, Cortexin or Thymalin work via pleiotropic mechanisms, providing support to diverse areas of day-to-day cellular and tissue-related functions. The culmination of these small supportive mechanisms is believed to produce the purported anti-ageing effect of peptide bioregulators and, in particular, Epitalon. In this article, a few central mechanisms contributing to this preserving effect will be highlighted.

Physiology

To begin, peptides are small chains of amino acids (the basic units of organic matter) linked by amide bonds, & can be thought of as «small proteins». Proteins are larger macromolecules comprised of many more amino acids linked together. Despite their size, however, peptides play many important roles in the normal functioning of the human body. Some examples include insulin, which is responsible for controlling levels of glucose within the blood, and substance P, a peptide playing a major role in the perception of pain.

Telomere Elongation

With each cellular replication, the telomeres (in green) are shortened. The maximum number of times that DNA can be replicated is called the Hayflick Limit. Once this number is reached, the cell undergoes apoptosis or programmed cell death. Telomerase is an enzyme which restores telomere length.

Epitalon is a synthetic peptide which were originally developed based upon the action of epithalamin, a hormone produced by the pineal gland. This hormone was found to stimulate the production of telomerase, an enzyme which plays a role in maintaining telomere length. Telomeres are non-coding terminal regions of DNA strands which preserve the integrity of the strand. With each revision, telomeres are shortened until the DNA strand cannot be further replicated. This process is highly implicated in the ageing process. Elongating telomeres theoretically extend the lifespan of a copy of DNA and allows it to replicate more times than usual. This was the theory behind the development of Epitalon®, a synthetic version of epithalamin which also stimulates the production of telomerase. Indeed, this theory has been confirmed in vitro in human cell cultures[1].

Neutralisation of Harmful Free Radicals

The role of antioxidants in mitigating damage from free radicals.

Cytotoxicity secondary to free radical damage has been implicated in the ageing process[2]. Administration of epithalon has also been shown to exert an antioxidant effect[3]. The presence of toxic compounds within the body can lead to the formation of reactive oxygen species (ROS) which can damage DNA, leading to cellular death &/or mutations leading to the formation of cancerous cells.

Inhibition of Cancer Formation & Growth

Maintaining the integrity of the genetic information stored in DNA is one of the mechanisms in which peptide bioregulators work to prevent cancer.

The anti-carcinogenic effect of Epitalon has also been explored in several animal studies. Epitalon has shown beneficial effects in animal models of breast[4] & colorectal cancer[5] without significant rates of adverse effects. Purported mechanisms include inhibition of carcinogenic receptor expression (Human Epithelial growth factor Receptor 2, also known as HER2, which is over-expressed in breast cancer) & retardation of metastasis[6],[7].

Attenuation of Inflammation

fire

Inflammation is a normal immune response that can become dysregulated and potentiated in a broad spectrum of disorders from rheumatoid arthritis to ulcerative colitis and even has been implicated in psychiatric disorders. The inflammatory process is dependent upon intercellular communication mediated by biomolecules such as cytokines, C-reactive protein, and other acute phase reactants[8]. Epithalamin has been observed to play a role in the regulation of these molecules[9] & thus attenuate the inflammatory response[10].

Endocrine Regulation

Hormones released by endocrine glands play signalling roles that coordinate different organs of the body.

Epitalon has been shown to help regulate endocrine activity in the body. Hormones are responsible for many key signalling circuits between cells which on a larger scale comprise the functions of large organs. For example, melatonin is a hormone which regulates the circadian rhythm, an internal biological clock. Endogenous melatonin production has been observed to decrease with ageing. A 2007 study of Epitalon administration in elderly patients found that the compound helped to restore pineal gland function & increased release of melatonin[11], which is purported to be the mechanism behind the restoration of sleep. Other studies have found that Epitalon exerts regulatory effects on gonadotropic hormones (FSG, LG, prolactin), which are involved in sexual & reproductive functions[12].

Summary

These are but a few of the many mechanisms by which Epitalon support normal functioning of the human body, and ultimately produce their anti-ageing effect. Telomerase activation, neutralisation of free radicals, oncostasis, modulation of inflammatory mediators, and endocrine regulation are all ways in which peptide bioregulators can help to ultimately prolong life. Peptide bioregulators as a class are still relatively uncharacterised, and most of the available clinical data are from Russian studies. As interest in this class of drugs grows, more mechanisms of action may be discovered, and the true treatment effects of Epitalon and peptide bioregulators may begin to be better understood.

References   [ + ]

1. Khavinson VK, Bondarev IE, Butyugov AA. Epithalon peptide induces telomerase activity & telomere elongation in human somatic cells. Bull Exp Biol Med. 2003 Jun;135(6):590-2.
2. Hekimi S, Lapointe J, Wen Y. Taking a “good” look at free radicals in the aging process. Trends In Cell Biology. 2011;21(10) 569-76.
3. Anisimov VN, Arutjunyan AV, Khavinson VK. Effects of pineal peptide preparation Epithalamin on free-radical processes in humans and animals. Neuro Endocrinol Lett. 2001;22(1):9-18.
4. Anisimov VN, Khavinson VK, Provinciali M, Alimova IN, Baturin DA, Popovich IG, et al. Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumours in HER-2/neu transgenic mice. Int J Cancer. 2002 Sep 1;101(1):7-10.
5. Anisimov VN, Khavinson VK, Popovich IG, Zabezhinski MA. Inhibitory effect of peptide Epitalon on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats. Cancer Lett. 2002 Sep 8;183(1):1-8.
6. Kossoy G, Zandbank J, Tendler E, Anisimov V, Khavinson V, Popovich I, et al. Epitalon and colon carcinogenesis in rats: proliferative activity & apoptosis in colon tumors & mucosa. Int J Mol Med. 2003 Oct;12(4):473-7.
7. Kossoy G, Anisimov VN, Ben-Hur H, Kossoy N, Zusman I. Effect of the synthetic pineal peptide epitalon on spontaneous carcinogenesis in female C3H/He mice. In Vivo. 2006 Mar-Apr;20(2):253-7.
8. Owen JA, Punt J, Stranford SA. Immunology. 7th ed. New York: W.H. Freeman & Company; (c) 2013.
9. Labunets IF, Butenko GM, Korkushko OV, Shatilo VB. Effect of epithalamin on the rhythm of immune and endocrine systems functioning in patients with chronic coronary disease. Bull Exp Biol Med. 2007 Apr;143(4):472-5.
10. Khavinson VKh. Peptide regulation of aging. Proceedings of the 17th World Congress of the International Association of Gerontology; Jul 1–6 2001; Vancouver, Canada. Gerontology: 2001; 47(1).
11. Korkushko OV, Lapin BA, Goncharova ND, Khavinson VK, Shatilo VB, Vengerin AA, et al. Normalizing effect of the pineal gland peptides on the daily melatonin rhythm in old monkeys & elderly people. Adv Gerontol. 2007;20(1):74-85.
12. Slepushkin VD, Mordovin VF, Zoloev GK, Iakovleva RA, Khavinson VK. Effect of the epiphysial preparation epithalamin on the gonadotropic function of the hypophysis. Probl Endokrinol (Mosk). 1983 Nov-Dec;29(6):51-4.