The epicenter of this media fuss is a publication in the prestigious scientific journal Nature.[4] The first author is molecular biologist Anissa Widjaja, affiliated with Duke-National University of Singapore Medical School.

At first glance, the publication is an animal study, as there are many in the field of anti-ageing research. Widjaja and her colleagues gave months-old mice – if the test animals had been humans, they would have been in their fifties – a substance that disables the interleukin-11 cytokine [spatial structure below]. As a result, they lived 23-25 ​​percent longer.

Interesting of course, but not unique. However, once you delve further into the details of this research, you come to understand why the highly regarded Nature wanted to publish this research. Then you will also understand that the fuss in the media might be completely justified.

Healthier

What is striking in this animal study is that the researchers do not report any adverse effects of their treatment, but they do report positive health effects. As lab mice age, they gain weight, lose muscle mass and their fur turns gray. They are less able to move, and their hearing and vision deteriorate. The treatment counteracts all these effects.

As the C57BL/6 J mice – the strain the researchers experimented with – age, they often develop cancer. In the mice in the control group, this happened to more than sixty percent of the test animals. However, the anti-aging remedy that the researchers studied reduced that chance to less than 16 percent.

Many anti-aging substances described in the literature have adverse health effects. At best they are neutral. This also applies to perhaps the most effective anti-aging drug at this moment, rapamycin. “Rapamycin is good for lifespan, but not healthspan,” said research leader Stuart Cook in an interview with Nature.[5]

Pharmacokinetics

For their experiments, the researchers used genetically modified lab mice in which interleukin-11 no longer functioned. They lived longer than comparable and unmanipulated laboratory animals. However, the effects of the genetic intervention on the life span were less significant than the effects of administration of a pharmacological substance. We described this above.

This substance is an antibody that attaches to interleukin-11 in the body and thereby neutralizes it. The dosage the researchers needed was remarkably low. If the mice had been adult humans, that dose would have been about 120-180 milligrams.

The researchers did not administer the antibodies daily, but only once a month. They injected the antibodies into the small intestines of the mice. Many substances that are effective with that method of administration are also orally active. We dare not say whether this also applies to these antibodies.

Effective in humans?

In an interview with the Spanish daily El Pais, co-author and biochemist Jesús Gil said that he expects the proven antibodies to be effective in humans as well. “There is no reason to think that what we have seen in mice will not work in people,” Gil said.[6]

Gil’s statement conflicts with the biomedical rule of thumb that only one percent of substances that work well in animal studies also show good results in human research. But in this case, there may be reason for some optimism.

The antibody that Anissa Widjaja, Stuart Cook, Jesús Gil and their colleagues are studying is an antibody that should eliminate human interleukin-11. At amino acid level, human interleukin-11 is 88 percent identical to murine interleukin-11.[7] If this human antibody already shows hopeful effects in mice, there is a chance that it will do so in humans as well.

X203

The life-extending antibody is called X203. It was developed by Stuart Cooke’s research group by injecting laboratory animals with human interleukin-11, harvesting the antibodies from their blood, selecting the very best ones, and then reproducing them.

In 2019, Cooke’s group published an animal study in which X203 was effective against idiopathic pulmonary fibrosis.[8] In 2022, an animal study followed in which X203, in combination with an ACE inhibitor, extended the life span in laboratory animals with congenital kidney disease.[9]

Blocking interleukin-11

Cooke and his colleagues build on the accepted insight that runaway inflammation plays an important role in the aging process. As cells age, they release increasing amounts of inflammatory factors that accelerate the aging of healthy cells and can damage healthy tissues.[10]

Many strategies that reduce the signs of aging inhibit inflammation. This includes reducing psychological stress,[11] supplementing with probiotics such as Lactobacillus pentosus var. plantarum C29[12] or fish oil,[13] eliminating senescent cells with the combination of quercetin and dasatinib,[14] and administering metformin.[15]

Cooke’s research focused on eliminating one specific inflammatory factor, interleukin-11. Inflammatory factors and inflammation help to clean up damaged cells and therefore have a function, but according to Cooke, this is less true for interleukin-11. “This is something we have inherited in an evolution from fish, and it does good things in the fish,” the British newspaper Daily Mail quoted Cooke saying.[16] “’Unfortunately for us, it is an evolutionary hangover that causes harm, and it causes disease.”

Safety profile

Cooke is convinced that turning off interleukin-11 can take the sting out of a wide range of chronic diseases or aging-related conditions.[17] In animal studies, Cooke and his team were able to show that turning off interleukin-11 prevents the formation of connective tissue in overworked heart muscle,[18] a fatty liver,[19] and disease-damaged kidneys.[20]

Based on these animal studies, adverse effects are unlikely to occur. Inspired by this ‘reassuring safety profile’ and the impressively broad spectrum of positive effects, Cooke founded Enlofeon, a research company focused on the development of interleukin-11 blockers. Enlofeon has acquired patents for the use of these agents in diabetes, eye disease, kidney disease and a variety of other pro-inflammatory diseases.

In 2020, Cooke sold Enlofeon to the pharmaceutical company Boehringer Ingelheim.[21] Enlofeon was one of three research companies exploring the possibilities of disabling interleukin-11.

One of them, the American Lassen, has already conducted a phase 1 trial.[22] Lassen’s interleukin-11 blocker is an antibody. It is called LASN01. Unlike X203, LASN01 neutralizes the receptor for interleukin-11, and not the inflammatory factor itself. However, in its trial, Lassen found no adverse effects either.

However, anti-aging researcher Ilaria Bellantuono from the University of Sheffield suspects that X203, LASN01 or another interleukin-11 inhibitor that will receive attention from the longevity scene in the near future may indeed appear to have adverse effects. “Every drug has side effects,” he says.[23]

Speculating about the nature of these possible side effects is difficult, not least because science has never been able to determine the precise function of interleukin-11. Cooke assumes this means interleukin-11 has no important functions, but a more cautious stance is that science simply hasn’t looked closely enough.

We do know that interleukin-11 plays a role in skeletal health[24] and perhaps also in the production of platelets. Oncologists know oprelvekin, a recombinant version of interleukin-11, as a drug that stimulates platelet production.[25] In a few years, when the current trials are completed, we may know more.

Market availability

X203 is not yet available on the gray or black market. This may change. There are sufficient starting points in the literature that allow chemical manufacturers in countries with liberal views on intellectual property to produce their own versions of X203. But as far as we know, this is not yet the case.

Speculations are already circulating on social media about supplements that naturally suppress the activity of interleukin-11. One of these is curcumin, which, according to in vitro research, indeed reduces the release of interleukin-11.[26]

However, the concentration required for this effect is not achievable with regular curcumin supplementation. We found a study in which Indian researchers who gave nano supplements with curcumin to test subjects were able to approach the necessary concentration for three minutes.[27] For this they needed a dose of several grams of nanocurcumin per day. This implies that, just like regular curcumin, nano-curcumin is not suitable for lowering the concentration of interleukin-11. Life extensionists who want to experiment with interleukin-11 inhibitors such as X203 will have to wait until they appear somewhere on the web as a research chemical.

References

[1] Gallagher J. ‘Supermodel granny’ drug extends life in animals. BBC News, 17 July 2024.

[2] Geissler H. Anti-ageing breakthrough with miracle drug that could ‘extend life’. Express, Jul 17, 2024.

[3] Buvailo A. Accidental Breakthrough in Aging Research. BioPharmaTrend, July 19, 2024.

[4] Widjaja AA, Lim WW, Viswanathan S, Chothani S, Corden B, Dasan CM, Goh JWT, Lim R, Singh BK, Tan J, Pua CJ, Lim SY, Adami E, Schafer S, George BL, Sweeney M, Xie C, Tripathi M, Sims NA, Hübner N, Petretto E, Withers DJ, Ho L, Gil J, Carling D, Cook SA. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature. 2024 Jul 17. doi: 10.1038/s41586-024-07701-9. Online ahead of print.

[5] Ledford H. Mice live longer when inflammation-boosting protein is blocked. Nature, 17 July 2024.

[6] Ansede M. A simple monthly injection allows mice to live 25% longer and free from diseases. El Pais, July 17, 2024.

[7] Biotechne R&D Systems. Recombinant Human IL-11 (CHO-expressed) Protein, CF. Catalog #: 10836-IL. Via rndsystems.com.

[8] Ng B, Dong J, D’Agostino G, Viswanathan S, Widjaja AA, Lim WW, Ko NSJ, Tan J, Chothani SP, Huang B, Xie C, Pua CJ, Chacko AM, Guimarães-Camboa N, Evans SM, Byrne AJ, Maher TM, Liang J, Jiang D, Noble PW, Schafer S, Cook SA. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci Transl Med. 2019 Sep 25;11(511):eaaw1237.

[9] Widjaja AA, Shekeran SG, Adami E, Ting JGW, Tan J, Viswanathan S, Lim SY, Tan PH, Hübner N, Coffman T, Cook SA. A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome. J Am Soc Nephrol. 2022 Apr;33(4):718-30.

[10] Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023 Jun 8;8(1):239.

[11] Casaletto KB, Staffaroni AM, Elahi F, Fox E, Crittenden PA, You M, Neuhaus J, Glymour M, Bettcher BM, Yaffe K, Kramer JH. Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults. Am J Geriatr Psychiatry. 2018 Sep;26(9):952-63.

[12] Jeong JJ, Kim KA, Jang SE, Woo JY, Han MJ, Kim DH. Orally administrated Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent colitis by inhibiting the nuclear factor-kappa B signaling pathway via the regulation of lipopolysaccharide production by gut microbiota. PLoS One. 2015 Feb 17;10(2):e0116533.

[13] Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Hwang BS, Glaser R. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial. Brain Behav Immun. 2012 Aug;26(6):988-95.

[14] Saccon TD, Nagpal R, Yadav H, Cavalcante MB, Nunes ADC, Schneider A, Gesing A, Hughes B, Yousefzadeh M, Tchkonia T, Kirkland JL, Niedernhofer LJ, Robbins PD, Masternak MM. Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice. J Gerontol A Biol Sci Med Sci. 2021 Oct 13;76(11):1895-905.

[15] Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, Bourdeau V, Pollak MN, Ferbeyre G. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013 Jun;12(3):489-98.

[16] Hunter W. Is this the anti-ageing elixir we’ve all been waiting for? Daily Mail, 18 July 2024.

[17] Cook SA. Understanding interleukin 11 as a disease gene and therapeutic target. Biochem J. 2023 Dec 13;480(23):1987-2008.

[18] Corden B, Lim WW, Song W, Chen X, Ko NSJ, Su L, Tee NGZ, Adami E, Schafer S, Cook SA. Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice. J Cardiovasc Transl Res. 2021 Apr;14(2):222-8.

[19] Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D’Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, Tripathi M, Lim SY, Shekeran SG, Chothani SP, Rabes A, Sombetzki M, Bruinstroop E, Min LP, Sinha RA, Albani S, Yen PM, Schafer S, Cook SA. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. Gastroenterology. 2019 Sep;157(3):777-792.e14.

[20] Widjaja AA, Viswanathan S, Shekeran SG, Adami E, Lim WW, Chothani S, Tan J, Goh JWT, Chen HM, Lim SY, Boustany-Kari CM, Hawkins J, Petretto E, Hübner N, Schafer S, Coffman TM, Cook SA. Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease. Nat Commun. 2022 Dec 5;13(1):7497.

[21] Boehringer Ingelheim. Boehringer Ingelheim Partners with Enleofen to Develop First-in-Class Anti-IL-11 Therapies for a Range of Fibrotic Diseases. Press release, 01/09/2020.

[22] Lassen Therapeutics. Lassen Therapeutics Commences Dosing in Phase 1 Clinical Study of LASN01, a First-in-Class Interleukin-11 Receptor-Blocking Antibody. Press release, 28 September 2022.

[23] Science Media Centre. Expert reaction to study on the ageing effects of a pro-inflammatory protein, IL11, in mice. Via sciencemediacentre.org, July 17, 2024.

[24] Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ. Interleukin-11 receptor signaling is required for normal bone remodeling. J Bone Miner Res. 2005 Jul;20(7):1093-102.

[25] Sitaraman SV, Gewirtz AT. Oprelvekin. Genetics Institute. Curr Opin Investig Drugs. 2001 Oct;2(10):1395-400.

[26] Kondo A, Mogi M, Koshihara Y, Togari A. Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. Biochem Pharmacol. 2001 Feb 1;61(3):319-26.

[27] Mohanty C, Sahoo SK. The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials. 2010 Sep;31(25):6597-611.

The post X203 | Living longer by blocking interleukin-11 appeared first on Increase Lifespan.

By Willem Koert

Is urolithin A actually present in foods? When we researched this wonderful substance, we were unable to find the answer to that question. It could be that urolithin A is only being synthesized in the human body, thanks to probiotic bacteria such as Bifidobacterium and Eubacterium. When these organisms convert a group of polyphenols that biochemists call ellagitannins, found in foods such as tea, red grapes, walnuts, berries, raspberries, and pomegranate, urolithin A is formed.[1]

Of these foods, pomegranate is probably the best source. The polyphenols found in a glass of pomegranate juice consist mainly of ellagitannins.[2] These ellagitannins – better formulated: the metabolites of these ellagitannins – probably cause the increase in blood flow to the brain.[3] This improves the memory of forgetful people over sixty who drink a glass of pomegranate every day.

The basic chemical building block of ellagitannins is the polyphenol ellagic acid. When people ingest ellagitannins, bacteria in the intestines cut the molecules into pieces so that ellagic acid can be released. Ellagic acid is poorly absorbed.[4] After consuming ellagitannins, ellagic acid does appear in the blood, but only in negligible amounts. What does appear in blood are urolithins. These are biosynthesized by bacteria in the intestines that convert ellagic acid. Substances that are created in this way are called ‘postbiotics’.

Urolithins were discovered in the early 1980s when British scientists gave ellagic acid to laboratory animals.[5] Even then it became clear that urolithins not only circulated in relatively high concentrations but were also present for a considerably longer time than you would expect from polyphenols.

In humans the situation is somewhat more complicated.[6] In approximately 55 percent of people, after taking ellagitannins or ellagic acid, you will mainly find urolithin A in the blood. In 30 percent of people, the intestinal flora produces multiple urolithins. In this group, after ingestion of ellagitannins or ellagic acid, in addition to urolithin A, urolithin B and C also appear in the bloodstream. In the remaining 15 percent of people, the microflora is unable to produce any urolithins.

Biological effects

Because urolithins, unlike for example quercetin or resveratrol, are present in the body in relatively high concentrations for a long time, life scientists are studying their possible health effects with growing interest. For example, cancer researchers have discovered through in vitro research that urolithins can inhibit the effect of estradiol.[7] In petri dishes, but in animal studies as well, urolithin A and B appear to be able to inhibit muscle breakdown.[8] In vitro research suggests that urolithin A protects muscle from breakdown by switching on rejuvenating molecules such as SIRT1 and AMPK, increasing the activity of metabolites such as NAD+ and simultaneously stimulating the formation of capillaries that supply muscle cells with oxygen and nutrients.[9]

This is of course interesting, but in 2016 Swiss scientists at Swiss Federal Institute of Technology de Lausanne published a few animal studies that made urolithins – and especially urolithin A – even more interesting.[10] The researchers exposed nematodes to urolithin A for life and saw that their life span increased by 45 percent. When the researchers gave elderly mice a supplement with urolithin A every day for 6 weeks, their endurance increased by 40 percent. Moreover, they became more active. Old mice don’t move much. They prefer to spend their days sitting. However, when the animals were given urolithin A, they became more active.

If the mice had been adult humans, they would have been given about 400 milligrams of urolithin A daily. If those adult people had preferred not to use a supplement but a regular food, they could also have drunk one and a half liters of pomegranate juice every day. At least if they belong to the group that is able to convert ellagitannins into urolithin A.[11]

Mechanism

The most extraordinary discovery that the Swiss made concerned the mechanism of action of urolithin A. The researchers discovered that urolithin A forced cells to break down outdated and poorly functioning mitochondria and replace them with new ones.

Mitochondria convert nutrients into energy. They can be seen as separate small cells, with their own hereditary material, that are part of our cells and provide them with energy. During the aging process, mitochondria function less well due to an accumulation of genetic abnormalities. The mitochondria start to emit more and more potentially aggressive molecules that damage the cells and still have less energy available to them.[12] This has negative consequences for the cells, the tissues that make up the cells and of course for health in general.

Damaged mitochondria are a contributor to aging-related conditions and diseases,[13] clearing and replacing them is a strategy to slow aging. Cells act on their own to some extent and that process is called mitophagy.[14] Urolithin A was the first natural substance that stimulated mitophagy, according to the Swiss.

Amazentis

The Swiss found urolothin A so promising that they founded a company to finance further research into urolothin A and to market the substance themselves. This company is called Amazentis and now markets a supplement line of products with high concentrations of urolithin A. Amazentis uses the trade name Mitopure.

Amazentis has already acquired a respectable number of patents in a short time. They relate to the use of urolithin A against neurodegenerative diseases and cognitive disorders, neuromuscular diseases, and obesity, but also to the use of urolithin A in longevity supplements. In addition, Amazentis patented a process for producing limited amounts of urolithin A from ellagitannins.

More preclinical data

Time will tell to what extent urolithin A will be a success. However, recent animal studies are promising. They even suggest that urolithin A might be an interesting weight-loss drug. For example, Chinese researchers published in PLoS Biology an animal study in which fattened mice lost as much as 60 percent of their body fat after administration of urolithin A.[15] The human equivalent of the dose used was approximately 250 milligrams of urolithin A per day. As far as the Chinese could tell, urolithin A enhanced the effect of thyroid hormone on fat cells that could ‘brown’. Brown fat cells can burn their contents and convert them into heat. You must keep in mind that adult humans have significantly fewer of these types of fat cells than mice.

In other animal studies, urolithin A inhibits the early stages of Alzheimer’s disease,[16] improves muscle function in Duchenne’s disease[17] and urolithin A maintains the immune system of old laboratory animals.[18] In addition, in vitro studies suggest that urolithin A may inhibit the metastasis of colon cancer cells[19] and protect against hearing loss.[20]

Safety

Researchers affiliated with Amazentis have also published human research in recent years. Remarkable in these studies are the doses, which are always above the human equivalent of the doses given to laboratory animals. In the Amazentis trials, test subjects receive 500 or 1000 milligrams of urolithin A per day. In 2019, Amazentis published a trial in which inactive but healthy elderly people used these doses for 4 weeks, without any harmful side effects. Scientists have since assumed that urolithin A is safe in these doses.[21]

Rejuvenating muscles

In the Amazentis trials, test subjects do not respond as convincingly as laboratory animals. However, the trials do suggest that urolithin A can reverse aging symptoms in humans. This was, for example, the case with the trial that Amazentis published in 2022 and in which 88 test subjects participated. The subjects were middle-aged, healthy, had a sedentary lifestyle and were overweight or obese.[22]

The researchers divided their study subjects into 3 groups. One group took a placebo every day for 4 months. The other group took capsules every day in the morning, before breakfast, that provided a total of 500 milligrams of urolithin A. Yet another group took 1,000 milligrams of urolithin A every day.

Before the supplementation period started and at the end of it, the researchers determined the endurance and muscle strength of the test subjects. They saw that the 500 mg dose had increased muscle strength by 12 percent and that the 1000 mg dose had increased endurance capacity by 15 percent. The highest dose of utolithin A had improved the body’s ability to absorb oxygen by 10 percent. In a human study in which test subjects were not subjected to a challenging training schedule with strict supervision, this is a remarkable result.

In the blood of the test subjects, the researchers found indications that urolithin A supplementation had indeed improved the functioning of the mitochondria. Markers indicative of less complete conversion of fatty acids into energy were reduced.

Ongoing trials

Amazentis has conducted trials in which highly trained athletes were given urolithin A.[23] Although this trial has been completed, at the time of writing this blog we were unable to find any results. However, we did find anecdotes from older but passionate athletes who have experimented with urolithin A. For example, the Ageist website published the experiences of a 59-year-old well-trained fitness fanatic who used urolithin A. The man found that the time he needed to recover from his workouts drastically reduced.[24]

There is also interest in urolithin A outside Amazentis, as shown by the databases that register trials. The US government has set up a trial in which people over 55 with diabetes are given urolithin-A,[25] the University of Oklahoma in the US is studying the cardiovascular effects of urolithin A in obesity[26] and Canadian sports scientists from McMaster University are investigating whether the addition of urolithin A to protein shakes can prevent muscle breakdown during prolonged inactivity.[27] In yet other trials, oncologists give urolithin A to men with prostate cancer in the hope that it will slow their disease[28] and German researchers are studying the effects of urolithin A on the immune system.[29]

If a natural substance has such potential, it stands to reason that pharmaceutical companies will investigate whether they can synthesize a substance in their laboratories that does the same – and which they can then market lucratively as a drug. A group of pharmacologists from India and the United States have already created such a substance, studied it in preclinical research and patented it.[30] The researchers are provisionally calling the compound UAS03 and hope that the compound has an anti-inflammatory effect in acute inflammation in the intestinal tract.

No final verdict

Despite the high expectations, we cannot say much with certainty about how urolithin A performs as an anti-aging supplement. Perhaps urolithin A, when formulated and used properly, is as effective a longevity supplement as reveratrol, AKG, and NMN. Perhaps there will turn out to be some pitfalls with urolithin A. Or perhaps – and this is not at all impossible – urolithin A will exceed even the wildest expectations.

References

[1] Amakura Y, Okada M, Tsuji S, Tonogai Y. High-performance liquid chromatographic determination with photodiode array detection of ellagic acid in fresh and processed fruits. J Chromatogr A. 2000 Oct 27;896(1-2):87-93.

[2] Gil MI, Tomás-Barberán FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem. 2000 Oct;48(10):4581-9.

[3] Bookheimer SY, Renner BA, Ekstrom A, Li Z, Henning SM, Brown JA, Jones M, Moody T, Small GW. Pomegranate juice augments memory and FMRI activity in middle-aged and older adults with mild memory complaints. Evid Based Complement Alternat Med. 2013;2013:946298.

[4] Garcia-Muñoz C, Vaillant F. Metabolic fate of ellagitannins: implications for health, and research perspectives for innovative functional foods. Crit Rev Food Sci Nutr. 2014;54(12):1584-98.

[5] Doyle B, Griffiths LA. The metabolism of ellagic acid in the rat. Xenobiotica. 1980 Apr;10(4):247-56.

[6] Tomás-Barberán FA, García-Villalba R, González-Sarrías A, Selma MV, Espín JC. Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric Food Chem. 2014 Jul 16;62(28):6535-8.

[7] Adams LS, Zhang Y, Seeram NP, Heber D, Chen S. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila). 2010 Jan;3(1):108-13.

[8] Rodriguez J, Pierre N, Naslain D, Bontemps F, Ferreira D, Priem F, Deldicque L, Francaux M. Urolithin B, a newly identified regulator of skeletal muscle mass. J Cachexia Sarcopenia Muscle. 2017 Aug;8(4):583-97.

[9] Ghosh N, Das A, Biswas N, Gnyawali S, Singh K, Gorain M, Polcyn C, Khanna S, Roy S, Sen CK. Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1. Sci Rep. 2020 Nov 19;10(1):20184.

[10] Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016 Aug;22(8):879-88.

[11] Singh A, D’Amico D, Andreux PA, Dunngalvin G, Kern T, Blanco-Bose W, Auwerx J, Aebischer P, Rinsch C. Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. Eur J Clin Nutr. 2022 Feb;76(2):297-308.

[12] Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, Sinclair DA. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol. 2022 Apr;18(4):243-58.

[13] Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013 Mar;123(3):951-7.

[14] Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14.

[15] Xia B, Shi XC, Xie BC, Zhu MQ, Chen Y, Chu XY, Cai GH, Liu M, Yang SZ, Mitchell GA, Pang WJ, Wu JW. Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice. PLoS Biol. 2020 Mar 27;18(3):e3000688.

[16] Esselun C, Theyssen E, Eckert GP. Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease. Int J Mol Sci. 2021 Aug 3;22(15):8333.

[17] Luan P, D’Amico D, Andreux PA, Laurila PP, Wohlwend M, Li H, Imamura de Lima T, Place N, Rinsch C, Zanou N, Auwerx J. Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy. Sci Transl Med. 2021 Apr 7;13(588):eabb0319.

[18] Girotra M, Chiang YH, Charmoy M, Ginefra P, Hope HC, Bataclan C, Yu YR, Schyrr F, Franco F, Geiger H, Cherix S, Ho PC, Naveiras O, Auwerx J, Held W, Vannini N. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems. Nat Aging. 2023 Sep;3(9):1057-66.

[19] Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2018 Feb;57(2):193-200.

[20] Cho SI, Jo ER, Song H. Urolithin A attenuates auditory cell senescence by activating mitophagy. Sci Rep. 2022 May 11;12(1):7704.

[21] Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019 Jun;1(6):595-603.

[22] Singh A, D’Amico D, Andreux PA, Fouassier AM, Blanco-Bose W, Evans M, Aebischer P, Auwerx J, Rinsch C. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Rep Med. 2022 May 17;3(5):100633.

[23] NCT04783207.

[24] Stewart D. How Mitopure Improved My 59-Year-Old Endurance, Recovery, and Athletic Performance. Ageist. February 21, 2023.

[25] NCT06274749.

[26] NCT05921266.

[27] NCT05814705.

[28] NCT06022822.

[29] NCT05735886.

[30] Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, Langille MGI, Douglas GM, Cheng X, Rouchka EC, Waigel SJ, Dryden GW, Alatassi H, Zhang HG, Haribabu B, Vemula PK, Jala VR. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019 Jan 9;10(1):89.

The post A postbiotic mitochondrial rejuvenator | Urolithin A appeared first on Increase Lifespan.

By Willem Koert

In December 2023, the scientific journal Geroscience published an animal study that received a lot of attention in the life extension movement. American aging researchers reported how they gave middle-aged mice astaxanthin and saw that the male animals lived an average of 12 percent longer as a result.[1]

The average age that the test animals in the control group could reach was 817 days. However, if the mice were given animal food enriched with astaxanthin, their average life span increased to 911 days.

Nevertheless, the study was a disappointment. The amount of astaxanthin the animals received was astronomical. Had the mice been adult men, they would have consumed 1200-1800 milligrams of astaxanthin per day. That is significantly more than the 0.2 milligrams per kilo of body weight per day that the European EFSA still considers acceptable.[2] For an adult man weighing 80 kilos, this amounts to 16 milligrams of astaxanthin per day.

The dose studied in Geroscience is also more than what consumers of supplements ingest during normal use. In most cases, these products provide 4-12 milligrams of astaxanthin per recommended daily intake.

On the other hand, the animal study confirmed what we already knew about astaxanthin: astaxanthin is safe, even in particularly high doses. And what we also already knew is that astaxanthin has a host of positive effects at much lower doses than the high dose studied in the Geroscience publication.

What is astaxanthin?

Astaxanthin, [structure shown above] like beta-carotene, lutein, and zeaxanthin, is a carotenoid. Like these other carotenoids, astaxanthin is a fat-soluble substance. For this reason, the supplement industry sometimes puts astaxanthin, dissolved in oleic acid or MCTs, in gel capsules, and supplement users can further increase astaxanthin absorption if they take their capsules with foods containing fat, such as nuts.

The best natural source of astaxanthin is the micro-algae Haematococcus pluvialis, but yeasts such as Pfaffia rhodozyma and bacteria such as Paracoccus carotinifaciens also produce astaxanthin. Salmon, shrimp, and lobster owe their purple color to astaxanthin. Although biotechnologists are looking with increasing interest at yeasts and molds to produce astaxanthin, there is much to be said for choosing Haematococcus pluvialis as a source of astaxanthin for the time being. One reason for this is that extracts from this alga contain not only astaxanthin, but also peptides with an anti-aging effect.[3] In this blog, we will not take this aspect into consideration.

In the body, astaxanthin molecules spread to all organs. Physiologists find them in the eyes, muscles, heart, blood vessel walls, joints, brain, and skin. There the molecules accumulate in the membranes of cells and mitochondria and, in combination with vitamins C and E, protect the cell against aggressive molecules in the cell and outside. The antioxidant effect of astaxanthin exceeds that of vitamins C and E by a factor of several hundred.

Anti-aging

Thanks to its protective effect, astaxanthin extends the lifespan of yeast cells[4] and the nematode Caenorhabditis elegans.[5] Astaxanthin not only neutralizes aggressive molecules before they damage the cell, but also stimulates the cell to carry out repair processes and clean up poorly functioning mitochondria.

In nematodes, astaxanthin mimics the effect of caloric restriction by activating the gene daf-16, Chinese researchers reported in 2021.[6] Humans have an equivalent of that gene. It’s called FOXO3.

FOXO3 becomes active when the influence of hormones such as insulin and IGF-1 decreases while the activity of longevity genes such as SIRT1 increases. FOXO activates protective enzymes, shifts growth processes down a notch and repair processes up a notch.[7] FOXO3, together with APOE, is one of the two most important genetic factors that can slow down aging. Based on animal studies, researchers suspect that astaxanthin works by inhibiting FOXO3[8] and activating SIRT1[9] [10] [11] enhances the immune system,[12] helps clear cancer cells,[13] and protects against Parkinson’s disease,[14] and dementia.[15]

Human studies

We do not know to what extent astaxanthin as a supplement will fulfill all the above promises. There are no human studies yet that can tell us. On the other hand, a respectable number of trials have already been published that collectively show that astaxanthin in doses of 4-16 milligrams per day has a remarkably broad spectrum of positive health effects.

4 milligrams per day | protects the skin against UV light

Astaxanthin is a popular supplement among endurance athletes. Runners and cyclists use it not only because astaxanthin improves endurance performance (more about that later), but also because astaxanthin in a relatively small dose makes the skin more resistant to sunlight.[16] During long running or cycling sessions, the supplement reduces the chance of the skin burning. Occasionally, athletes even notice that they no longer need sunscreen when supplementing with astaxanthin.

6 milligrams per day | reduces wrinkles

Non-athletes can also benefit from the cosmetic effects of astaxanthin. That is not surprising, because exposure to UV light is an important factor in skin aging. According to a 2012 Japanese study, men who take a capsule containing 3 milligrams of astaxanthin after both breakfast and dinner reduce wrinkles at the corners of their eyes.[17] The supplementation had no effect on the deepest wrinkles but did reduce smaller wrinkles in 4-8 weeks. Because the skin became more elastic and better hydrated, even the smallest wrinkles disappeared completely.

6 milligrams per day | alleviates diabetes

When type-2 diabetics take 8 milligrams of astaxanthin daily for 8 weeks, their systolic blood pressure drops and the amount of glucose, triglycerides, and LDL (the ‘bad cholesterol’) in their blood decreases.[18] The effects are not overwhelmingly large, but according to diabetologists they may be clinically relevant.

8 milligram per day | stimulates immune system

Astaxanthin enables Natural Killer Cells, part of the first line of defense of the immune system, to neutralize more pathogens within 8 weeks.[19] At the same time, astaxanthin increases the activity of interferon-gamma, a signaling protein that stimulates immune cells to neutralize pathogens. Through this or another mechanism, astaxanthin softens the inhibitory effect of intensive physical exertion on the immune system. During and after exercise, fewer antibodies circulate in the body. Astaxanthin supplementation not only reduced the impact on the IgG and IgM antibodies, but also accelerated their return to normal levels.[20]

9 milligram per day | better vision

If you list the experiences of users, the positive effect of astaxanthin on vision is perhaps the most reported. Screen workers who have passed the age of forty notice that they can see more clearly. Japanese researchers saw this effect occur after just 6 weeks of supplementation.[21]

12 milligram per day | more endurance

Trained cyclists who take 12 milligrams of astaxanthin every day for 7 days improve their endurance.[22] During a 40K time trial, astaxanthin reduces their time by 1.2 percent. This equates to a time saving of 50 seconds. In the last part of intensive exercise, astaxanthin stimulates muscle cells to convert fatty acids into energy more easily, allowing them to save carbohydrates.

16 milligram per day | more fertile

If infertile men combine regular treatment for infertility with supplementation with astaxanthin, their chance of fatherhood increases by a factor of 5. This is evident from a small Belgian trial that lasted 3 months.[23] In the group of men who were treated exclusively in a regular manner, 11 percent of their partners eventually became pregnant. In the astaxanthin group this was 55 percent. The researchers suspect that the spermatozoa producing Sertoli cells started to function better after they incorporated astaxanthin molecules into their membranes.

Absence of side effects

The above list is not complete, but the message is clear: supplementation with normal doses has a broad spectrum of positive health effects. In addition, there is no evidence that astaxanthin has any significant side effects. In any case, in the trails serious adverse effects are conspicuous by their absence.

However, when cataloging user experiences on internet forums, we came across a side effect that we would like to mention here: some users noticed that their libido was reduced by astaxanthin. One theory circulating on the web is that astaxanthin inhibits the conversion of testosterone to the androgenic hormone dihydrotestosterone (DHT). This hormonal shift should explain the decrease in libido.

We have not been able to find confirmation for this theory. Although a few studies have been published in which supplements with astaxanthin lower the concentration of DHT in the blood of men – and at the same time increase that of testosterone – these supplements contain extracts of saw palmetto (Seranoa repens) in addition to astaxanthin.[24] [25] We know that the latter component reduces the biosynthesis of DHT.[26] So we wouldn’t be surprised if the reports of these side effects relate to supplements that contain not only astaxanthin, but also Seranoa repens.

Conclusion

No, there are no studies yet from which we can conclude that astaxanthin supplementation can extend human life span. Nevertheless, astaxanthin appears to be an interesting supplement for life extensionists. Astaxanthin already has a wide range of positive health effects, while, as research continues, more health effects are likely to emerge. And in addition, everything indicates that astaxanthin is exceptionally safe.

References

[1] Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, Flurkey K, Ginsburg BC, Murrell MD, Javors MA, Lopez-Cruzan M, Nelson JF, Willcox BJ, Allsopp R, Watumull DM, Watumull DG, Cortopassi G, Kirkland JL, Tchkonia T, Choi YG, Yousefzadeh MJ, Robbins PD, Mitchell JR, Acar M, Sarnoski EA, Bene MR, Salmon A, Kumar N, Miller RA. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used..

[2] EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Bampidis V, Azimonti G, Bastos ML, Christensen H, Dusemund B, Kouba M, Kos Durjava M, López-Alonso M, López Puente S, Marcon F, Mayo B, Pechová A, Petkova M, Ramos F, Sanz Y, Villa RE, Woutersen R, Bories G, Brantom P, Renshaw D, Schlatter JR, Ackerl R, Holczknecht O, Steinkellner H, Vettori MV, Gropp J. Safety and efficacy of astaxanthin-dimethyldisuccinate (Carophyll® Stay-Pink 10%-CWS) for salmonids, crustaceans and other fish. EFSA J. 2019 Dec 18;17(12):e05920. [paragraph 3.2.5.]

[3] He W, Xie J, Xia Z, Chen X, Xiao J, Cao Y, Liu X. A novel peptide derived from Haematococcus pluvialis residue exhibits anti-aging activity in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway. Food Funct. 2023 Jun 19;14(12):5576-88.

[4] Sj S, Veerabhadrappa B, Subramaniyan S, Dyavaiah M. Astaxanthin enhances the longevity of Saccharomyces cerevisiae by decreasing oxidative stress and apoptosis. FEMS Yeast Res. 2019 Jan 1;19(1).

[5] Fu M, Zhang X, Zhang X, Yang L, Luo S, Liu H. Autophagy Plays a Role in the Prolongation of the Life Span of Caenorhabditis elegans by Astaxanthin. Rejuvenation Res. 2021 Jun;24(3):198-205.

[6] Liu X, Liu H, Chen Z, Xiao J, Cao Y. DAF-16 acts as the “hub” of astaxanthin’s anti-aging mechanism to improve aging-related physiological functions in Caenorhabditis elegans. Food Funct. 2021 Oct 4;12(19):9098-110.

[7] Morris BJ, Willcox DC, Donlon TA, Willcox BJ. FOXO3: A Major Gene for Human Longevity–A Mini-Review. Gerontology. 2015;61(6):515-25.

[8] Sorrenti V, Davinelli S, Scapagnini G, Willcox BJ, Allsopp RC, Willcox DC. Astaxanthin as a Putative Geroprotector: Molecular Basis and Focus on Brain Aging. Mar Drugs. 2020 Jul 5;18(7):351.

[9] DiNicolantonio JJ, McCarty MF, O’Keefe JH. Nutraceutical activation of Sirt1: a review. Open Heart. 2022 Dec;9(2):e002171.

[10] Zhang X, Lu Y, Wu Q, Dai H, Li W, Lv S, Zhou X, Zhang X, Hang C, Wang J. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway. FASEB J. 2019 Jan;33(1):722-37.

[11] Zhang J, Wang QZ, Zhao SH, Ji X, Qiu J, Wang J, Zhou Y, Cai Q, Zhang J, Gao HQ. Astaxanthin attenuated pressure overload-induced cardiac dysfunction and myocardial fibrosis: Partially by activating SIRT1. Biochim Biophys Acta Gen Subj. 2017 Jul;1861(7):1715-28.

[12] Chew BP, Mathison BD, Hayek MG, Massimino S, Reinhart GA, Park JS. Dietary astaxanthin enhances immune response in dogs. Vet Immunol Immunopathol. 2011 Apr 15;140(3-4):199-206.

[13] Jyonouchi H, Sun S, Iijima K, Gross MD. Antitumor activity of astaxanthin and its mode of action. Nutr Cancer. 2000;36(1):59-65.

[14] Wang L, Lu K, Lou X, Zhang S, Song W, Li R, Geng L, Cheng B. Astaxanthin ameliorates dopaminergic neuron damage in paraquat-induced SH-SY5Y cells and mouse models of Parkinson’s disease. Brain Res Bull. 2023 Oct 1;202:110762.

[15] Wu W, Wang X, Xiang Q, Meng X, Peng Y, Du N, Liu Z, Sun Q, Wang C, Liu X. Astaxanthin alleviates brain aging in rats by attenuating oxidative stress and increasing BDNF levels. Food Funct. 2014 Jan;5(1):158-66.

[16] Ito N, Seki S, Ueda F. The Protective Role of Astaxanthin for UV-Induced Skin Deterioration in Healthy People-A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2018 Jun 25;10(7):817.

[17] Tominaga K, Hongo N, Karato M, Yamashita E. Cosmetic benefits of astaxanthine on human subjects. Acta Biochim Pol. 2012;59(1):43-7.

[18] Mashhadi NS, Zakerkish M, Mohammadiasl J, Zarei M, Mohammadshahi M, Haghighizadeh MH. Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus. Asia Pac J Clin Nutr. 2018;27(2):341-6.

[19] Park JS, Chyun JH, Kim YK, Line LL, Chew BP. Astaxanthine decreased oxidative stress and inflammation and enhanced immune response in humans. Nutr Metab (Lond). 2010 Mar 5;7:18.

[20] Nieman DC, Woo J, Sakaguchi CA, Omar AM, Tang Y, Davis K, Pecorelli A, Valacchi G, Zhang Q. Astaxanthin supplementation counters exercise-induced decreases in immune-related plasma proteins. Front Nutr. 2023 Mar 21;10:1143385.

[21] Sekikawa T, Kizawa Y, Li Y, Miura N. Effects of diet containing astaxanthin on visual function in healthy individuals: a randomized, double-blind, placebo-controlled, parallel study. J Clin Biochem Nutr. 2023 Jan;72(1):74-81.

[22] Brown DR, Warner AR, Deb SK, Gough LA, Sparks SA, McNaughton LR. The effect of astaxanthin supplementation on performance and fat oxidation during a 40 km cycling time trial. J Sci Med Sport. 2021 Jan;24(1):92-97.

[23] Comhaire FH, El Garem Y, Mahmoud A, Eertmans F, Schoonjans F. Combined conventional/antioxidant “Astaxanthine” treatment for male infertility: a double blind, randomized trial. Asian J Androl. 2005 Sep;7(3):257-62.

[24] Anderson ML. Evaluation of Resettin® on serum hormone levels in sedentary males. J Int Soc Sports Nutr. 2014 Aug 23;11:43.

[25] Angwafor F 3rd, Anderson ML. An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J Int Soc Sports Nutr. 2008 Aug 12;5:12.

[26] Di Silverio F, Monti S, Sciarra A, Varasano PA, Martini C, Lanzara S, D’Eramo G, Di Nicola S, Toscano V. Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate. 1998 Oct 1;37(2):77-83.

The post Astaxanthin, the icing on the longevity cake appeared first on Increase Lifespan.

By Willem Koert

Most biomedical scientists are still convinced that it is mainly your genetic characteristics that determine whether you can live to a ripe old age – and how many years you can remain healthy. This idea is not entirely correct, as long-term epidemiological studies have shown in the last century. Genes play a role, but other factors have proven to be more important.

According to a Danish study conducted by researchers at Odense University, genes determine about a quarter of whether you can live to an exceptionally old age.[1] The Danes followed 2,872 twins born between 1870 and 1890 until 1994. At this time, less than 1 percent of the twins were still alive. Based on their data, the researchers were able to calculate that genes determine for 23 percent the age that women can reach. For men this was 26 percent.

The remaining 77-74 percent of the factors that determine how old you will become are lifestyle factors and environmental factors. How important these factors are, and which factors exactly we are talking about, has not been more clearly highlighted than by the Belgian demographer Michel Poulain and the Italian physician-researcher Gianni Pes. They discovered in 2000 that in Barbagia di Seùlo and Ogliastra, two adjacent regions of the Italian island of Sardinia, one of every 200 inhabitants managed to live to be over 100.[2]

There were more such areas, Poulain and Pes discovered in the years that followed. They also found unexpectedly many centenarians in, for example, Acciaroli, Italy, the islands of Okinawa in Japan, the Nicoya Peninsula in Costa Rica, the Greek island of Ikaria, Loma Linda in the US, and Skåne in Sweden.[3] Poulain and Pes called those areas ‘Blue Zones’.

The idea of ​​Blue Zones has become mainstream thanks to the American journalist Dan Buettner, who, in collaboration with Poulain and Pes, wrote books and made documentaries about the evocative zones where people had adopted a way of life that allowed them to remain optimally healthy.

To begin with, the Blue Zones had in common that they were relatively isolated. Many ‘modern’ negative lifestyle habits that were encouraged by multinationals and marketing in centuries past, such as smoking and the consumption of ultra-processed foods, never fully penetrated the Blue Zones.

The absence of those factors undoubtedly has a positive effect. Smokers generally live 10 years shorter than non-smokers.[4] A diet with a lot of ultra-processed foods like sweets, soft drinks and fast food probably shortens human life span as well. We still do not have a complete picture of the harmful impact of ultra-processed foods, soft drinks and junk food, but it is already clear that these foods promote cardiovascular disease[5] and the risk of type 2 diabetes[6] and cancer[7].

But this absence of negative lifestyle factors was only part of the explanation for the robust health of Blue Zones residents, Buettner emphasized in an interview following the release of his 4-part documentary series on Blue Zones on Netflix.[8]

“The essence of Blue Zones is people live a long time not because of the things we think. They’re not on diets, they’re not on exercise programs, they don’t take supplements,” he said. “They don’t pursue health, which is a big disconnect in America, because we think health is something that needs to be addressed.”

Anyone who lives the traditional way in the Blue Zones lives extremely healthily without having to think about it. In this blog we explain what that way of life looks like. In their articles and books, Buettner, Poulain and Pes distinguish nine different aspects of the Blue Zone lifestyle. In this blog we have reduced this to five.

#1 | Physical activity as a part of life

Residents of Blue Zones are still able to live their lives on their own, with minimal assistance from machines. When they must transport themselves from one place to another, they use their legs. They grow a large part of their food themselves in their vegetable gardens, pick it themselves in the forests or catch it themselves at sea. They process food, but also clean and make minor repairs themselves.

This implies that residents of Blue Zones are physically active for hours every day. We know from research that moderate-intensity exercise is healthy. Healthy people over 60 who walk for half an hour every day at a brisk pace halve their risk of death compared to peers who walk for less than fifteen minutes every day.[9]

Anyone who exercises moderately intensively for half an hour every day has a significantly lower risk of chronic conditions and death as they get older than someone who does not or hardly exercise. Research has shown that more exercise than this amount is even healthier.

This is evident, for example, from an Australian epidemiological study, in which researchers from the University of Sydney followed a group of almost 1,600 people over the age of 50 for ten years.[10] The researchers wanted to know whether there was an association between the amount of exercise and the odds of ‘successful aging’ – that is, growing older without depression, diabetes, cardiovascular disease, cancer, dementia or other chronic aging-related conditions. This association indeed appeared to exist. The group that exercised the most, and was moderately active, for more than 4 hours a day, was more than twice as likely to ‘age successfully’ than the study participants who exercised less than 40 minutes a day. When it comes to moderate-intensity exercise, ‘more’ seems to be synonymous with ‘better’.

Outside the Blue Zones, there is only a small group that exercises daily. A large part of that group consists of athletes who, compared to the residents of Blue Zones, still exercise relatively little in terms of time – but when they do exercise, they exercise more intensively. It’s beyond doubt that intensive exercise has added value when it comes to longevity, but there seems to be an optimal amount of intensive exercise. More hours of exercise per week than this optimal amount adds little. There are even studies that suggest that in the case of endurance athletes, an excess of hours of intensive training per week may even increase the risk of premature death.[11]

#2 | Real foods as building blocks for diet

Dietary patterns in the different Blue Zones vary considerably, but there is one major similarity between all diets: all diets consist almost entirely of whole foods that have been traditionally produced. In the Blue Zone diet, ultra-processed foods are conspicuous by their absence, but hardly processed plant products take a prominent place.

In the Blue Zone dietary patterns there are no snacks from plastic bags and containers, but there are beans, fruit, vegetables, nuts, and whole grain products. There are no soft drinks, but there are tea, coffee, and herbal infusions. There are no hamburgers and other intensively processed meat products, but there are eggs, fresh fish, and unprocessed meats. The food of the residents of Blue Zones does not come from a factory, but from a kitchen. And before the ingredients entered a kitchen, they grew in nature.

Nutrition scientists believe that people eat healthy if they eat 5 servings of vegetables or fruit daily. This amounts to 400-500 grams of fruit and vegetables per day. According to many epidemiological studies, each serving of fruit or vegetables per day reduces the risk of death by 5 percent – until an intake of 5 servings per day is reached.[12] These 5 servings per day would be the optimal intake, but there are also studies that suggest that the optimal intake is higher.[13]

These figures probably underestimate the positive impact of the Blue Zone diet. Because Blue Zone residents grow much of what they eat, their intake of chemicals such as insecticides, pesticides and fungicides is lower – making the Blue Zone diet healthier. Moreover, because they use few ready-made foods, Blue Zone residents also consume more flavorful herbs and spices. So they consume more turmeric,[14] cinnamon,[15] red[16] and black pepper[17], chamomile[18] and many other spices that scientists have discovered sometimes have unexpectedly strong health-promoting and anti-aging properties.

Finally, plant foods that have not been intensively processed contain a variety of phytochemicals that protect health and slow down aging processes. Hundreds of these natural substances have already been described in biomedical literature, but we probably still do not have a good picture of most of these phytochemicals – and so we cannot yet process them in supplements. And even if we do know them, administering phytochemicals as a supplement is not always successful.

For example, a well-studied phytochemical in fruits and vegetables with anti-aging qualities is beta-carotene. If you find a relatively large amount of this in the blood of elderly people, their molecular clock ticks less quickly and their risk of dementia is smaller.[19] However, experiments in which test subjects received supplements with a high dose of beta-carotene for years had to be stopped prematurely because the supplements increased the risk of lung cancer in smokers and people who came into contact with asbestos.[20]

There are probably no phytochemicals that protect health if you ingest them in high doses. If it were that simple, a healthy diet would be a matter of taking pills. The example of beta-carotene shows that it is not that simple. The optimal diet probably does not contain a handful of phytochemicals in large quantities, but an immense spectrum of phytochemicals in not excessively large, but sufficient quantities. And that is exactly what the diet in the Blue Zones offers.

#3 | Part of something bigger

In Blue Zones, individuals are still included in a larger whole. For example, family ties are particularly close, as are the social networks in the neighborhood and region. In most Westernized societies, the elderly often no longer play a significant role after retirement, while they still play a role of significance in the networks in Blue Zones.

Research shows that feelings of loneliness, which are present in tens of percent of the population in Western societies, increase the risk of death. The more people over 70 have less contact with other people, have fewer people to rely on and feel connected to fewer people, the greater their risk of dying.[21] Good friends have the opposite effect – the more friends you have in old age, the lower your risk of death.[22]

There are several types of social groups that can extend the lifespan of individuals. One of these is the dyad with a life partner. That is why a long-term marriage reduces the risk of death[23] – especially if the life partner in question is happy.[24] But on the other hand, participating in social movements, for example by being active in groups that are committed to preserving nature, also reduces the risk of death.[25] There is even evidence of life-prolonging effects of being part of social media networks.[26]

Being part of social groups is likely to extend lifespan because family members, friends, and close acquaintances can provide help and support. Under difficult conditions this can make a big difference. Talking, exchanging ideas, and developing solutions to problems together also stimulates the brain to continue developing – which reduces the risk of dementia by perhaps 50 percent.[27] Elderly people diagnosed with dementia usually have a life expectancy of a few years at most. Finally, participation in groups can ensure that older people remain physically active.

In Blue Zones, people are interconnected through a tightly knit network of relationships. Older people occupy a prominent place in many of these networks – and therefore older people are active until an exceptionally old age. They attend parties and events, they receive neighbors, friends, and family, they work in the garden with others, they pickle fruit and vegetables with family members, they teach their grandchildren to cook, they are respected for their experience and knowledge and are asked for advice.

Outside the Blue Zones, these networks have largely disappeared – and with them the incentives that allow older people to remain mentally and physically active. When individuals outside the Blue Zones no longer participate in the workforce, they all too often become marginal. What this does to their health is anyone’s guess.

#4 | No chronic psychological stress

In modern societies everyone is constantly under stress. That needs no explanation. Time has become a precious commodity. The agendas are full, work and personal social life are increasingly demanding, while the media machine creates unrealistic expectations of life and ourselves. In such a world, disappointed people burn out more and more quickly. This aspect of modern everyday life has also not penetrated Blue Zones. Stress does occur in everyday life in Blue Zones, but the chronic stress of modern society does not.

Scientific research into the health effects of stress is still relatively scarce. This is not due to a lack of interest, but mainly due to methodological problems. It is not easy to get a good picture of a phenomenon to which we are all exposed. But the research we have suggests that stress has little effect on life expectancy if you’re healthy. If you have one or more chronic conditions, this is different. Then stress reduces the number of years you will live.[28] Crucial in this are the positive emotions you experience in everyday life. The more these positive mood states decrease, the stronger the negative effect of stress.[29]

Stress can trigger or worsen diseases.[30] An important mechanism may be that stress suppresses the immune system. Athletes who suffer from stress are therefore more likely to catch a cold or flu.[31] According to a Danish epidemiological study, people who experience a traumatic event such as a divorce are therefore more likely to be admitted to hospital due to an infectious disease.[32] The effect of a divorce appears to last more than 15 years.

If stress has such a negative impact on health, it is not surprising that the effect of chronic stress is visible in the DNA. More stress in personal life[33] and in the sphere of work[34] is associated with more molecular aging of the genetic codes.

#5 | Faith

Religion and spirituality are at odds with life in modern Western societies. Science, mass media, pop culture, the education system, multinationals, and governments in Western societies seem to be in a constant battle with religion and spirituality. This did not happen in Blue Zones. Residents of the Blue Zones still live in a world that not only gains meaning through economy, knowledge, science, and bureaucracy, but also through a higher reality that governments, universities, and major corporations have no control over.

Faith, in the form of religion or spirituality, extends lifespan, according to epidemiological research. American psychologists from Ohio State University analyzed several thousand obituaries that appeared in American newspapers between 2010 and 2012 and estimated that people with religious beliefs lived four years longer than people without religious beliefs.[35] The more serious people are about their faith, the greater the life-extending effect.[36]

Researchers explain the positive health effects of philosophy in several ways. Two obvious explanations are being part of a social group, with all the positives that entails, and being physically and mentally active in volunteer work in a philosophical community until an old age. Less tangible, but perhaps even more important, are the psychological effects of a faith-based life philosophy. In every faith, life has a meaning, a purpose, or a meaning. The realization that life has a purpose also has a life-prolonging effect.[37] In such a philosophy of life, the world ‘makes sense’ and the rules – not the rules of our governments, but the rules from a higher dimension – apply to everyone. This belief in a ‘just world’ appears to extend lifespan as well.[38]

The Blue Zones & you

Studying the Blue Zones teaches us how to extend our lifespan, but applying these insights is sometimes impossible. For example, the Blue Zones have taught the importance of social connections, but applying this insight is not so easy for people living outside these areas. If you were not born in a Blue Zone, and therefore have not been part of the multitude of close-knit social networks in the Blue Zone all your life, it is impossible to organize these social networks on your own.

The same applies to spirituality and religion. If you have nothing to do with religion and spirituality, you cannot force yourself to be spiritual or religious. But in this blog, we have also discussed a few things that you can use. We mention three.

The first is that Blue Zones have taught the importance of a lifestyle that includes lots of physical activity. The positive effect of a lifestyle in which you spend a relatively large amount of time in motion throughout the day is more favorable than a lifestyle in which you exercise intensively for an hour every day but are inactive the rest of the time.

Of course, exercising intensively for an hour or even more every day is one of the healthiest things you can do. If you belong to the select group that trains with weights in a gym every day, then definitely continue. But you could also incorporate moderate-intensive modes of physical activity e into your lifestyle. Maybe you can walk distances that you currently cover in a car. Maybe you can trade in the hours you currently spend staring aimlessly at a screen for gardening or hiking. Maybe you can make your phone calls while walking. We can’t tell you exactly how to do this. It’s about incorporating physical activity into your daily routines in a way that you experience as enjoyable and that adds value to your way of life.

A second lesson you can learn from the Blue Zone research is the importance of a diet that consists of wholesome and minimally processed foods. This means that you cook as much as possible yourself or prepare your food in your own kitchen. Use as much fresh produce as possible, which your great-grandparents might have eaten, and stay away from ultra-processed foods that lack bioactive substances as much as possible. Even if you know little about nutrition and cooking, the food you prepare yourself will almost always be healthier than ready-made food that you mindlessly buy.

And then there is stress. Not the stress that is simply part of life and that you experience occasionally, but the modern stress that is continuous. Modern stress is caused by full schedules, constant pressure to perform, countless obligations you must fulfill and a never-ending participation in a pointless rat race. But how do you escape or reduce modern stress if don’t want to withdraw from society? We don’t have the answer to that question. But hopefully we have been able to explain why it is worth trying anyway.

[1] Herskind AM, McGue M, Holm NV, Sørensen TI, Harvald B, Vaupel JW. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet. 1996 Mar;97(3):319-23.

[2] Poulain M, Pes GM, Grasland C, Carru C, Ferrucci L, Baggio G, Franceschi C, Deiana L. Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study. Exp Gerontol. 2004 Sep;39(9):1423-9.

[3] Poulain M, Herm A, Pes G. The Blue Zones: areas of exceptional longevity around the world. Vienna Yearbook of Population Research. 2013 Jan;(11):87-108.

[4] National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2014.

[5] Srour B, Fezeu LK, Kesse-Guyot E, Allès B, Méjean C, Andrianasolo RM, Chazelas E, Deschasaux M, Hercberg S, Galan P, Monteiro CA, Julia C, Touvier M. Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé). BMJ. 2019 May 29;365:l1451.

[6] Srour B, Fezeu LK, Kesse-Guyot E, Allès B, Debras C, Druesne-Pecollo N, Chazelas E, Deschasaux M, Hercberg S, Galan P, Monteiro CA, Julia C, Touvier M. Ultraprocessed Food Consumption and Risk of Type 2 Diabetes Among Participants of the NutriNet-Santé Prospective Cohort. JAMA Intern Med. 2020 Feb 1;180(2):283-91.

[7] Fiolet T, Srour B, Sellem L, Kesse-Guyot E, Allès B, Méjean C, Deschasaux M, Fassier P, Latino-Martel P, Beslay M, Hercberg S, Lavalette C, Monteiro CA, Julia C, Touvier M. Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ. 2018 Feb 14;360:k322.

[8] Moniuszko S. Want to live to 100? “Blue Zones” expert shares longevity lessons in new Netflix series. CBS News, August 30, 2023.

[9] Hakim AA, Petrovitch H, Burchfiel CM, Ross GW, Rodriguez BL, White LR, Yano K, Curb JD, Abbott RD. Effects of walking on mortality among nonsmoking retired men. N Engl J Med. 1998 Jan 8;338(2):94-9.

[10] Gopinath B, Kifley A, Flood VM, Mitchell P. Physical Activity as a Determinant of Successful Aging over Ten Years. Sci Rep. 2018 Jul 12;8(1):10522.

[11] Schnohr P, Marott JL, Lange P, Jensen GB. Longevity in male and female joggers: the Copenhagen City Heart Study. Am J Epidemiol. 2013 Apr 1;177(7):683-9.

[12] Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, Hu FB. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014 Jul 29;349:g4490.

[13] Root MM, McGinn MC, Nieman DC, Henson DA, Heinz SA, Shanely RA, Knab AM, Jin F. Combined fruit and vegetable intake is correlated with improved inflammatory and oxidant status from a cross-sectional study in a community setting. Nutrients. 2012 Jan;4(1):29-41.

[14] Ng TP, Nyunt MSZ, Gao Q, Gwee X, Chua DQL, Yap KB. Curcumin-Rich Curry Consumption and Neurocognitive Function from 4.5-Year Follow-Up of Community-Dwelling Older Adults (Singapore Longitudinal Ageing Study). Nutrients. 2022 Mar 11;14(6):1189.

[15] Daneshvar M, Musazadeh V, Faghfouri AH. The effect of cinnamon supplementation on glycemic control in patients with type 2 diabetes mellitus: An updated systematic review and dose-response meta-analysis of randomized controlled trials. Phytother Res. 2023 Oct 11. doi: 10.1002/ptr.8026.

[16] Hernández-Pérez T, Gómez-García MDR, Valverde ME, Paredes-López O. Capsicum annuum (hot pepper): An ancient Latin-American crop with outstanding bioactive compounds and nutraceutical potential. A review. Compr Rev Food Sci Food Saf. 2020 Nov;19(6):2972-93.

[17] Balakrishnan R, Azam S, Kim IS, Choi DK. Neuroprotective Effects of Black Pepper and Its Bioactive Compounds in Age-Related Neurological Disorders. Aging Dis. 2023 Jun 1;14(3):750-77.

[18] Howrey BT, Peek MK, McKee JM, Raji MA, Ottenbacher KJ, Markides KS. Chamomile Consumption and Mortality: A Prospective Study of Mexican Origin Older Adults. Gerontologist. 2016 Dec;56(6):1146-52.

[19] Boccardi V, Arosio B, Cari L, Bastiani P, Scamosci M, Casati M, Ferri E, Bertagnoli L, Ciccone S, Rossi PD, Nocentini G, Mecocci P. Beta-carotene, telomerase activity and Alzheimer’s disease in old age subjects. Eur J Nutr. 2020 Feb;59(1):119-26.

[20] Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S. Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. Int J Cancer. 2010 Jul 1;127(1):172-84.

[21] OʼSúilleabháin PS, Gallagher S, Steptoe A. Loneliness, Living Alone, and All-Cause Mortality: The Role of Emotional and Social Loneliness in the Elderly During 19 Years of Follow-Up. Psychosom Med. 2019 Jul/Aug;81(6):521-26.

[22] Thomas PA. Trajectories of social engagement and mortality in late life. J Aging Health. 2012 Jun;24(4):547-68.

[23] Dupre ME, Beck AN, Meadows SO. Marital trajectories and mortality among US adults. Am J Epidemiol. 2009 Sep 1;170(5):546-55.

[24] Stavrova O. Having a Happy Spouse Is Associated With Lowered Risk of Mortality. Psychol Sci. 2019 May;30(5):798-803.

[25] Pillemer K, Fuller-Rowell TE, Reid MC, Wells NM. Environmental volunteering and health outcomes over a 20-year period. Gerontologist. 2010 Oct;50(5):594-602.

[26] Hobbs WR, Burke M, Christakis NA, Fowler JH. Online social integration is associated with reduced mortality risk. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):12980-4.

[27] Sommerlad A, Kivimäki M, Larson EB, Röhr S, Shirai K, Singh-Manoux A, Livingston G. Social participation and risk of developing dementia. Nat Aging. 2023 May;3(5):532-45.

[28] Chiang JJ, Turiano NA, Mroczek DK, Miller GE. Affective reactivity to daily stress and 20-year mortality risk in adults with chronic illness: Findings from the National Study of Daily Experiences. Health Psychol. 2018 Feb;37(2):170-8.

[29] Mroczek DK, Stawski RS, Turiano NA, Chan W, Almeida DM, Neupert SD, Spiro A 3rd. Emotional Reactivity and Mortality: Longitudinal Findings From the VA Normative Aging Study. J Gerontol B Psychol Sci Soc Sci. 2015 May;70(3):398-406.

[30] Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI J. 2017 Jul 21;16:1057-1072.

[31] Perna FM, Antoni MH, Baum A, Gordon P, Schneiderman N. Cognitive behavioral stress management effects on injury and illness among competitive athletes: a randomized clinical trial. Ann Behav Med. 2003 Winter;25(1):66-73.

[32] Nielsen NM, Davidsen RB, Hviid A, Wohlfahrt J. Divorce and risk of hospital-diagnosed infectious diseases. Scand J Public Health. 2014 Nov;42(7):705-11.

[33] Parks CG, Miller DB, McCanlies EC, Cawthon RM, Andrew ME, DeRoo LA, Sandler DP. Telomere length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):551-60.

[34] Parks CG, DeRoo LA, Miller DB, McCanlies EC, Cawthon RM, Sandler DP. Employment and work schedule are related to telomere length in women. Occup Environ Med. 2011 Aug;68(8):582-9.

[35] Wallace LE, Anthony R, End CM, Way BM. Does Religion Stave Off the Grave? Religious Affiliation in One’s Obituary and Longevity. Social Psychological and Personality Science. 2019;10(5):662-70.

[36] McCullough ME, Friedman HS, Enders CK, Martin LR. Does devoutness delay death? Psychological investment in religion and its association with longevity in the Terman sample. J Pers Soc Psychol. 2009 Nov;97(5):866-82.

[37] Krause N. Meaning in life and mortality. J Gerontol B Psychol Sci Soc Sci. 2009 Jun;64(4):517-27.

[38] Fry PS, Debats DL. Cognitive beliefs and future time perspectives: predictors of mortality and longevity. J Aging Res. 2011;2011:367902.

The post Five longevity lessons from the Blue Zones appeared first on Increase Lifespan.

If both their genetic characteristics and living conditions are perfect, people can live up to about 120 years old. Reaching such a high age is, however, reserved for only a few. The life span of the average human is about 75-80 years, 30 to 40 percent less than the maximum achievable human life span.

The aim of the research project that Vladimir Anisimov, affiliated with the Petrov Research Institute of Oncology in Saint Petersburg, started in the 1970s is to reduce the gap between the average and the maximum life span. A key role in this is the administration of peptides that Anisimov and his collaborators call ‘bioregulators’.[1]

Most of the bioregulators that the Russians are studying are small peptides. They are chains of 2, 3 or 4 amino acids. The Russians synthesize them, but suspect them to be bioidentical to peptides present and active in the body. The best way of administration is by injection, but administration via a nebulizer or a capsule is also an option. And all bioregulatory peptides are able to reach the cell nucleus and interact with the DNA there. In this interaction, the peptides in old cells can ‘rejuvenate’ the DNA.

The DNA contains a collection of instructions to manufacture proteins that collectively form and function cells. As a cell has divided more often and has aged, the cell can no longer read parts of those instructions properly and can no longer produce proteins properly. The bioregulators created by Anisimov and his collaborator Vladimir Khavinson at the Institute of Bioregulation and Gerontology in St. Petersburg are making the inactive parts of ancient DNA accessible again. Bioregulating peptides allow old DNA to function as young DNA again.[2]

Animisov, Khavinson and colleagues have demonstrated these effects in a variety of organisms – in nematodes, insects, mice, rats, monkeys and humans. They even found them in plants.[3]

‘Anyone can live to be 120 years old’

“Nobody would want to live a long and unhealthy life”, Khavinson explained the Russian research project at a conference on longevity in 2017.[4] “The main goal for us now must be to allow people to stay healthy for as long as possible into their old age.”

“We have come to the conclusion that it is possible to restore it to a normal level with the use of peptide bioregulators and have found an optimal way to maintain natural peptide production of a sufficient quantity.”

In combination with a healthy lifestyle, with a healthy diet and a lot of exercise, the Russian peptides should be able to ensure that in the near future everyone can live to 120 years old in optimal health, Khavinson concluded. “The trials have already started.”

Gray market

We have not heard much about these trials since then. Perhaps commercial parties with sufficient finances to set up such trials were not interested. That is hard to imagine, when you know that Khavinson and Anisimov have managed to extend lifespan by up to 60 percent in animal models. On the other hand, the bioregulatory peptides developed by the Russians may not be patentable. Perhaps this explains the lack of interest.

Anyway, the Russian bioregulators are not officially on the market in the EU and the USA. They are available in the gray circuit. This also applies to Epitalon, the bioregulator that this blog is about [structure shown below].

Ala-Glu-Asp-Gly

Epitalon is a peptide consisting of 4 amino acids. The sequence is alanine-glutamic acid-asparagine-glycine. In the early 1990s, the Russians discovered this tetrapetide in an extract of epiphyses from the brains of cows. This extract is marketed in Russia as Epitalimin.

Anisimov has been experimenting with extracts from cow epiphyses since 1973. If he injected old rats with it, the animals lived fifty percent longer.[5] Anisimov achieved similar results with other lab animals, such as fruit flies and mice.[6]

The subjects, who all struggled with various aging symptoms, received 6 short cycles over 3 years. The researcher then followed the subjects for another 9 years. During this period, the subjects treated with the extract had a 28 percent lower risk of death than subjects who had received a placebo. Epitalimin even reduced the risk of death from heart attacks, heart failure and respiratory diseases by 50 percent.

Dozens of studies have led the Russians to the conclusion that Epitalon is the main active substance in Epitalimin – or at least can imitate the effects of other proteins in Epitalimin. For example, the researchers discovered that Epitalon stimulates the enzyme telomerase in cells in vitro. Telomerase lengthens the telomeres in the DNA of cells, theoretically allowing the cells to divide more often.[8]

Human cells [this does not include human stem cells] can divide anywhere from 40-60 times. Divide more often than not is not possible, pathologist Leonard Hayflick discovered in the 1960s.[9] In biology, this maximum number of cell divisions is called the Hayflick Limit. However, in 2004, Khavinson published a study in which exposure to Epitalon enabled human cells to divide an additional ten times.[10]

Cancer prevention

Molecular oncologists are cautious with agents that activate telomerase. In many cancer cell types, the genes that produce telomerase are turned on all the time. As a result, they can continue to divide themselves unbridled. With any phenomenon or agent that causes telomerase elongation, oncologists reflexively ask whether it can promote cancer cells.

In the case of Epitalon, this fear is not justified, Anisimov and Khavinson showed in their studies. Administration of Epitalon to mice genetically prone to cancer reduced tumor growth and extended lifespan by 40 percent.[11] In laboratory animals that age rapidly and have an increased risk of cancer, Epitalon reduced the risk of tumors developing.[12]

Human data

The Russians have published few human studies in English-language scientific journals in which test subjects were not given Epitalimin but Epitalon. There is a study in which injections of Epitalon in patients with retitinis pigmentosa protected the retina.[13] There is also a human study in which Epitalon restored the day-night rhythm and improved sleep in the elderly.[14] That’s all. There may be more studies, but we have not been able to find them.

More is known about Epitalimin. Epitalimin has been well researched and approved in Russia. In the decades that Russian doctors have used Epitalimin, no serious side effects have come to light. We have already mentioned above that Anisimov and Khavinson assume that Epitalon is the main active substance in Epitalimin. In their reviews they assume that what applies to Epitalimin also applies to Epitalon. Because we only have access to a fraction of the relevant Russian studies, we cannot say whether this is correct.

Cycles & dosages

Websites for peptide users list schedules for using Epitalon.[15] For example, a frequent schedule includes a daily subcutaneous injection of 10 milligrams of Epitalon for 10 consecutive days. An alternative is 2 injections of 5 milligrams of Epitalon daily for 10 days.

After a period of just under 6 months, this schedule can then be repeated. Users can therefore apply such an Epitalon treatment twice a year.

This treatment schedule seems to be taken from the publications of Anisimov and Khavinson.[16] However, that schedule refers to the extract Epitalimin, not Epitalon. We have not been able to find any Epitalon cycles intended for humans in the scientific literature.

In animal studies, the Russian scientists used Epitalon in a completely different way. They usually injected their test animals with a relatively low dose 5 days a week for a longer period of time.[17] [18] The human equivalent of the doses administered is – for an adult of normal body weight – approximately 30-40 micrograms of Epitalon per injection.

An alternative to injections is oral use. Medical research on other but comparable peptides shows that oral administration of a peptide requires 100 times the injectable dose to produce some bioactivity. Applying this rule of thumb, we arrive at 3-4 milligrams per daily dosage for use in a supplement. Webshops offer supplements that contain such amounts.

Real life effects and adverse effects

Judging by the experiences that Epitalon users share on internet forums, the anti-aging effects of Epitalon are not immediately visible. However, athletes notice that they recover faster, almost all users report an improvement in sleep.

Incidentally, users say that they have had their telomere length measured. They confirm that their telomere length is indeed increased by Epitalon. Remarkably, however, there is no noticeable and acute reversal of aging in these posts either. Although Epitalon may rejuvenate skin cells in vitro,[19] in real life Epitalon users do not notice that they look younger. A factor here may be the relatively young age of the users. People in their thirties and forties may not experience much from Epitalon cycles.

Finally, on social media, Epitalon users report surprisingly few side effects. A few mention red irritated injection sites. More frequent are the reports of intense dreams, which not everyone finds unpleasant.

[1] Anisimov VN, Khavinson VKh. Peptide bioregulation of aging: results and prospects. Biogerontology. 2010 Apr;11(2):139-49.

[2] Vanyushin BF, Khavinson VK (2016). Short Biologically Active Peptides as Epigenetic Modulators of Gene Activity. In: Doerfler W, Böhm P (eds). Epigenetics – A Different Way of Looking at Genetics, pp 69-90. Springer.

[3] Fedoreyeva LI, Dilovarova TA, Ashapkin VV, Martirosyan YT, Khavinson VK, Kharchenko PN, Vanyushin BF. Short Exogenous Peptides Regulate Expression of CLE, KNOX1, and GRF Family Genes in Nicotiana tabacum. Biochemistry (Mosc). 2017 Apr;82(4):521-28.

[4] Thompson A. Humans may live to 120 in just 60 years time as new drugs interact with our DNA to slow ‘inner’ ageing, according to a leading expert. Daily Mail, 30 May 2017.

[5] Anisimov VN, Bondarenko LA, Khavinson VKh. Effect of pineal peptide preparation (epithalamin) on life span and pineal and serum melatonin level in old rats. Ann N Y Acad Sci. 1992 Dec 26;673:53-7.

[6] Anisimov VN, Mylnikov SV, Khavinson VK. Pineal peptide preparation epithalamin increases the lifespan of fruit flies, mice and rats. Mech Ageing Dev. 1998 Jun 15;103(2):123-32. 

[7] Korkushko OV, Khavinson VKh, Shatilo VB, Antonyuk-Shcheglova IA. Geroprotective effect of epithalamine (pineal gland peptide preparation) in elderly subjects with accelerated aging. Bull Exp Biol Med. 2006 Sep;142(3):356-9.

[8] Khavinson VKh, Bondarev IE, Butyugov AA. Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bull Exp Biol Med. 2003 Jun;135(6):590-2.

[9] Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961 Dec;25:585-621.

[10] Khavinson VKh, Bondarev IE, Butyugov AA, Smirnova TD. Peptide promotes overcoming of the division limit in human somatic cell. Bull Exp Biol Med. 2004 May;137(5):503-6.

[11] Anisimov VN, Khavinson VKh, Alimova IN, Semchenko AV, Yashin AI. Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice. Bull Exp Biol Med. 2002 Aug;134(2):187-90.

[12] Rosenfeld SV, Togo EF, Mikheev VS, Popovich IG, Khavinson VKh, Anisimov VN. Effect of epithalon on the incidence of chromosome aberrations in senescence-accelerated mice. Bull Exp Biol Med. 2002 Mar;133(3):274-6.

[13] Khavinson V, Razumovsky M, Trofimova S, Grigorian R, Razumovskaya A. Pineal-regulating tetrapeptide Epitalon improves eye retina condition in retinitis pigmentosa. Neuro Endocrinol Lett. 2002 Aug;23(4):365-8.

[14] Korkushko OV, Lapin BA, Goncharova ND, Khavinson VKh, Shatilo VB, Vengerin AA, Antoniuk-Shcheglova IA, Magdich LV. [Normalizing effect of the pineal gland peptides on the daily melatonin rhythm in old monkeys and elderly people]. Adv Gerontol. 2007;20(1):74-85.

[15] Epithalon dosage calculator and guide | What researchers must know. Peptides.org. Last visit: 29-8-2023.

[16] Khavinson V, Popovich I (2017). In Anti-aging Drugs: From Basic Research to Clinical Practice, ed. Vaiserman AM. The Royal Society of Chemistry, pp 496-513.

[17] 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.

[18] Kossoy G, Zandbank J, Tendler E, Anisimov V, Khavinson V, Popovich I, Zabezhinski M, Zusman I, Ben-Hur H. Epitalon and colon carcinogenesis in rats: proliferative activity and apoptosis in colon tumors and mucosa. Int J Mol Med. 2003 Oct;12(4):473-7.

[19] Lin’kova NS, Drobintseva AO, Orlova OA, Kuznetsova EP, Polyakova VO, Kvetnoy IM, Khavinson VKh. Peptide Regulation of Skin Fibroblast Functions during Their Aging In Vitro. Bull Exp Biol Med. 2016 May;161(1):175-8.

The post Bioregulator Epitalon | Rejuvenating at the genetic level appeared first on Increase Lifespan.

By Willem Koert

In the 1960s, a microbiologist from Canada’s McGill University in Canada collected 73 soil samples from Easter Island and sent them to the lab of pharmacologist Suren Sehgal in Montreal, then associated with the pharmaceutical company Wyeth. Wyeth has since been acquired by Pfizer. In the samples, Seghal found the bacterium Streptomyces hygroscopicus, which fought off competing fungi and bacteria by producing a surprising toxin effect. Rapamycin, Seghal’s lab called the substance. Initially, Seghal thought he had discovered a new antibiotic and antifungal agent, but the side effects of rapamycin turned out to be a bit too harsh for this application. The new substance also inhibited the immune system, and this effect was certainly interesting from a medical point of view. The US Medical Authority approved rapamycin in 1999 as an immunosuppressant, useful in helping to prevent organ transplant rejection.[1]

Research in the early 1990s revealed the mechanism of action of rapamycin. Rapamycin blocked one of the most crucial signaling molecules in cells. It is noteworthy that molecular biologists were able to discover that molecule when they performed in vitro experiments with rapamycin. In mammals and humans, this signaling molecule is called Mammalian Target of Rapamycin (mTOR or also sometimes referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1)).

Extending life span

When cells receive stimuli in the form of insulin, growth factors such as IGF-I, amino acids or a large supply of nutrients, all these signals activate mTOR. It is mTOR that prompts the cell to activate growth and proliferation processes. Rapamycin stops mTOR from functioning. In this way, rapamycin interferes with the functioning of the immune system, including the immune cells that would normally attack and break down foreign tissues. Of course, the biological effects of rapamycin go even further than this. Rapamycin imitates the effects of fasting, but in a much more rigorous way than AKG or resveratrol.

Fasting reduces the risk of death and, at least in animal models, extends lifespan. This is why anti-aging researchers suspected that the administration of rapamycin has a similar effect. In 2009, American researchers published an animal study in Nature that confirmed this suspicion. The researchers fed rapamycin to old lab mice at the end of their natural lifespan and found that the immunosuppressant was able to extend the lifespan of animals by up to 14 percent.[3] If the mice had been adult humans, they would have received 12-20 milligrams of rapamycin daily. Scientists use doses of the same order of magnitude in other animal studies.

Effects

It should be noted that the doses at which patients use rapamycin are considerably lower than the human equivalent of the doses used in the animal studies. Organ recipients use 1-2 milligrams of rapamycin per day, one-tenth the human equivalent of the doses of rapamycin that anti-aging researchers give their mice. Even at those doses, side effects such as malaise, poor wound healing, nausea, diarrhoea, anemia, elevated cholesterol and increased insulin resistance are by no means rare.

Despite this, the biological effects are impressive. Even in animal studies in which rapamycin was not able to inhibit hormonal, cardiological and immunological signs of aging across the board, administration of the drug did extend lifespan.[4] In other animal studies, conducted with older and not very fit lab rats, rapamycin did increase muscle strength and endurance.[5] In yet other animal studies, everolimus, a slightly modified variant of rapamycin, appeared to rejuvenate the immune system of older test animals.[6] Although strict caloric restriction can weaken the immune system and make successful infection attempts by viruses, bacteria and other germs more likely, rapamycin seems to strengthen the immune system of laboratory animals.[7] By administering rapamycin, test animals reacted to a flu vaccine as if they were still young. And in yet another animal study, conducted with a type of lab mouse that is prone to cancer, rapamycin reduced the chance of developing tumors.[8]

In animal studies, it is not necessary to administer rapamycin for life to still achieve good results. When researchers give middle-aged lab mice rapamycin for 3 months, the dosing regimen increases their lifespan by up to 60 percent.[9]

Trials

If administration of a drug that was already approved several decades ago in animal studies has such good results, it is obvious that physicians will study in clinical trials whether administration of rapamycin can also counteract aging symptoms in humans. At the time of writing this post, the National Center for Biotechnology Information’s clinicaltrials.gov database listed ten trials. Two of them had already been completed.

In one such study, cardiologists at the American Mayo Clinic found that rapamycin in the blood of elderly people with coronary artery disease reduced markers of inflammation and aging at the molecular level.[10] In this study, the subjects took 2 milligrams of rapamycin daily for 12 weeks. In another completed trial, researchers at Texas A&M University at Galveston gave elderly people a single dose of 16 milligrams of rapamycin and then measured its effects on muscle growth. The results of this trial have not yet been published.

While the scientific evidence of a life-prolonging effect of rapamycin is piling up, the pharmaceutical industry seems at first to stay aloof from the emerging longevity drug. That may be because pharmaceutical researchers view rapamycin as having too many side effects to be marketed as a lifestyle drug. Another possible factor is that the patents on rapamycin have expired, which has lost the opportunity for attractive profit margins for the industry.

However, on closer inspection it is evident that the industry is following developments. For example, innovators have filed patents in recent years for applications where rapamycin is delivered via other routes, such as via the lungs.[11] At the same time, a pharmaceutical company such as Novartis, which has a long history with rapamycin, is working on rapamycin analogs that “selectively inhibit” mTOR.[12]

Longevity scene

Meanwhile, in the global longevity scene, tens of thousands of individuals have already started experimenting with rapamycin on their own initiative. One of them is Ross Pelton, pharmacist and author of the book Rapamycin, mTOR, Autophagy & Treating mTOR Syndrom. In an interview with Life Extension Magazine, Pelton said that in the summer of 2021 he himself started taking a weekly dose of 6 milligrams of rapamycin.[13] In November of that year he thought it wise to take this dose once every two weeks.

“I had blood drawn for routine lab work in November 2021 and discovered that I was anemic,” says Pelton. “My red blood cell count, hemoglobin, and iron levels were below normal and my lymphocyte count was slightly low, which is an indicator of immune status. Based on my lab values, I reduced my rapamycin intake to 6 mg every other week. I rechecked my labs a month later and everything had returned to normal.”

Pelton’s protocol is in line with protocols currently in vogue in the longevity scene. In addition, users take a dose of 3 to a maximum of 10 milligrams of rapamycin once a week or once every 2 weeks.[14]

Taking a small dose once for 2 weeks seems like a very small intake, which may seem to be modest to be effective, but you should bear in mind that rapamycin remains in the body for a long time. The half-life of rapamycin is 2-3 days. By taking a dose of rapamycin once every 2 weeks, the body gets enough time to literally get rid of all rapamcyin.[15]

Those schedules in which users take a single dose of rapamycin every 1-2 weeks are based, among other things, on the theory that it is not necessary – and indeed not possible – to use rapamycin to completely inactivate the mTOR molecule for an extended period of time. During a limited period of mTOR inactivity, cells repair themselves. Health cells clear out non-functional molecules and repair damaged structures.[16] Senescent and malfunctioning cells kill themselves. It is these processes, which cell biologists classify as ‘autophagy’, that according to most rapamycin experts underlie the anti-aging effects of rapamcyin. These effects are still present for some time after taking rapamycin.

Rapamycin users in the longevity scene experience a variety of positive health effects, according to a survey by the (excellent) website Rapamycin.News.[14] They range from less pain, less joint pain, more energy, improved sexual function, more stamina and improved sleep.

The same survey also shows that just over half of users experience side effects, such as a sore mouth, skin problems such as acne, nausea, diarrhea, headache and fatigue. For some users, these adverse effects are reason to stop. A limited number of users also stop after tests showed that values such as lipids or insulin resistance markers deteriorated.

There are not yet many rapamycin users who also train with weights. There are therefore still insufficient user experiences on the basis of which it can be deduced whether, and if so: to what extent, rapamycin reduces anabolism. In a clinical study, in which subjects did weight training a few hours after taking a single dose of 16 milligrams of rapamycin, rapamycin reduced the anabolic response by several tens of percent.[17] However, what this means in practice is not yet clear.

‘A serious drug’

Since it is still not completely clear whether rapamycin indeed extends lifespan, it is not possible to properly weigh up the positive health effects on the one hand and adverse effects on the other. However, according to Rapamycin.News, it is beyond dispute that rapamycin is ‘a serious drug’, ‘that can have serious side effects if you dose too high’.[18]

“This is not a risk-free drug”, the website warns. “If you are considering using rapamycin be sure to spend a few months reading all the information here and elsewhere on it so you can make an informed decision, ideally working in concert with a doctor. Don’t just rush into taking rapamycin because you heard a podcast mention it.”

[1] Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S.

[2] Abraham RT, Wiederrecht GJ. Immunopharmacology of rap. Annu Rev Immunol. 1996;14:483-510.

[3] Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Sirolimus fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5.

[4] Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Hölter SM, Moreth K, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Höfler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D.. Sirolimus extends murine lifespan but has limited effects on aging. J Clin Invest. 2013 Aug;123(8):3272-91.

[5] Xue QL, Yang H, Li HF, Abadir PM, Burks TN, Koch LG, Britton SL, Carlson J, Chen L, Walston JD, Leng SX. Sirolimus increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats. Aging (Albany NY). 2016 Apr;8(4):769-76.

[6] Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179.

[7] Phillips EJ, Simons MJP. Sirolimus not dietary restriction improves resilience against pathogens: a meta-analysis. Geroscience. 2023 Apr;45(2):1263-70.

[8] Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Sirolimus increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011 Dec 15;10(24):4230-6.

[9] Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, Meza D, Yajima M, Beyer RP, Kerr KF, Davis DJ, Gillespie CH, Snyder JM, Treuting PM, Kaeberlein M. Transient Sirolimus treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016 Aug 23;5:e16351.

[10] Singh M, Jensen MD, Lerman A, Kushwaha S, Rihal CS, Gersh BJ, Behfar A, Tchkonia T, Thomas RJ, Lennon RJ, Keenan LR, Moore AG, Kirkland JL. Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study. J Frailty Aging. 2016;5(4):204-7.

[11] An inhalable RAP formulation for treating age-related conditions. European Patent EP 325875 B1.

[12] Cambrian Biopharma. Cambrian Biopharma Announces Licensing Agreement to Develop Selective mTOR Inhibitors. Press Release, 16 Feb, 2022.

[13] The RAP Story. Life Extension Magazine, 2022 June.

[14] RAP User Poll | Survey. LINK.

[15] Modern Healthspan. RAP: Practical Dosage & Benefits | Dr Alan Green Episode 4. YouTube, 2021 August 21.

[16] Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett. 2010 Apr 2;584(7):1287-95.

[17] Gundermann DM, Walker DK, Reidy PT, Borack MS, Dickinson JM, Volpi E, Rasmussen BB. Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by RAP. Am J Physiol Endocrinol Metab. 2014 May 15;306(10):E1198-204.

[18] New To RAP? LINK.

The post Rapamycin | The unknowns of an emerging longevity drug appeared first on Increase Lifespan.

By Willem Koert

In scientific literature, NMN appears for the very first time in an article from 1906. The paper has nothing to do with longevity, but everything with yeast and fermentation.[1] In this article, two British biochemists describe how they find vulnerable molecules in yeast cells that convert sugars into alcohol. These were, as we now know, enzymes. If the temperature rises too high, the enzymes break down and stop working.

The British discovered that yeast cells also contain substances that are resistant to heat. One of the substances they describe is NMN. The enzymes need NMN, plus its analogues, to do their job, the British discovered. If they mix the NMN analogues with the yeast cells, the fermentation of glucose proceeds more quickly.

NAD+

At that time, no one suspected that the British discoveries were also relevant to humans. Only about ten years later will the Polish biochemist Casimir Funk discover the first vitamin in rice germ.[2] It’s vitamin B3. In experiments in orphanages and prisons, American clinical epidemiologist Joseph Goldberger discovered that a deficiency of vitamin B3 causes pellagra.[3]

After the Second World War, biochemists gradually elucidated what vitamin B3 exactly is during a few decades. The vitamin, which is present in various forms in food, metabolizes in the body into more complex molecules such as NMN. NMN then metabolizes into nicotinamide adenine dinucleotide [NAD+]. NAD+ is a coenzyme. That means enzymes need NAD+ to function.

These enzymes that utilize NAD+ as a coenzyme also include a number of enzymes that repair vital parts of cells. One of these is PARP, which repairs damaged genetic material such as DNA, among other things. Another group of enzymes that require NAD+ are the sirtuins, of which SIRT1 is probably the most important.

You can compare SIRT1’s role in the cell to pressing a reset button on a computer that has crashed. If infections, toxic substances, a long-term high glucose level or other stressors have caused the cell to switch on or off all kinds of parts of the DNA, the DNA must eventually return to a normal state. That’s what SIRT1 and other sirtuins are supposed to do.

In this way, sirtuins allow cells to grow and develop, inflammatory reactions are inhibited, mitochondria continue to produce energy and cells that have become hopelessly aged or damaged kill themselves. A high activity of sirtuins is therefore synonymous with longevity.

Anti-aging

At the end of the 20th century, researchers at Washington University School of Medicine, who – like their British colleagues a century earlier – studied yeast cells, discovered that sirtuins needed NAD+ to function.[4] After it became clear that this was also true in mammals, the researchers suggested that supplementation with NAD+ precursors such as NMN or other interventions that increase cellular NAD+ biosynthesis may slow aging.[5]

Animal studies pointed in this direction. For example, as organisms age, the activity of sirtuins decreases. According to research with old lab mice, supplementation with NMN returns the activity of sirtuins to a level that you would expect from young laboratory animals. As a result, in old lab mice, the body’s ability to get cells to take up glucose improves.[6] This ability tends to decrease with age.

Aging also reduces muscle function. The ability to perform long-term exercise is therefore reduced in older organisms. In animal experiments, NMN also largely reverses this aging effect, probably by improving the functioning of the mitochondria.[7]

Researchers achieved similar successes when they used NMN supplementation to rejuvenate the blood vessels in older laboratory animals,[8] prevent the development of type 2 diabetes[9], reduce the risk of a murine equivalent of Alzheimer’s disease[10] and reduce osteoporosis[ 11] and cognitive decline [12]. It even proved possible to increase the fertility of older laboratory animals by supplementing with NMN.[13]

A problem that should not be underestimated with these animal studies is the dosage. If the test animals in the studies had been human adults, they would have taken 2-4 grams of NMN daily over a long period of time. The foods with the highest concentrations of NMN, such as young soybeans, cucumber peel and avocado, contain only about one milligram of NMN per hundred grams. (Some websites say that a large 100-gram tomato would contain tens of milligrams of NMN, but the analyses we’ve read so far don’t mention such quantities.)

78c

The human equivalent of the doses used in the promising animal studies is extreme. For this reason, some research departments studying anti-aging and NAD+ have opted not to further invest in research into the effects of NMN supplementation. Instead, they focus on developing pharmacological interventions that inhibit the activity of minor enzymes that deplete NAD+ in cells. This increases the amount of NAD+ that PARP and sirtuins can use to slow cell aging.

American researchers, for example, are studying the anti-aging effects of a substance they call 78c. 78C inhibits the enzyme cyclic ADP ribose hydrolase [spatial structure below], which uses NAD+.

Mice that receive 78c are more active in old age and have a healthier glucose metabolism and cardiovascular system than mice that do not receive 78c.[14] 78c also extends the lifespan of male mice by 10 percent and protects their muscle mass against degradation when mice reach old age.[15]

It remains to be seen whether safe and effective pharmacological anti-aging drugs such as 78c will ever come onto the market. And if it happens, the question is when. It could take decades. For the time being, the question of whether supplementation with NMN can slow down aging in humans appears therefore to be more relevant.

Human data

At the moment, in all, about a dozen trials have been published in which people have used NMN. There are also various trials whose results have not yet been published, and trials that are still ongoing. In these trials, subjects receive doses of up to 250-900 milligrams per day. Reported effects are often modest, and it is not always clear whether they are clinically relevant, but NMN supplementation seems to make people fitter. Side effects do not seem to occur.

In a Japanese study, conducted with healthy subjects over the age of 65, endurance improved through daily supplementation with 350 milligrams of NMN.[16] There was no effect on insulin action and body composition, but the study may have been too short for this.

In another study, conducted by researchers at the Washington University School of Medicine, overweight postmenopausal prediabetic women were given 250 milligrams of NMN daily for 10 weeks.[17] In this study, NMN improved insulin action. Supplementation also increased the concentration of platelet-derived growth factor [PDGF]. This could mean that NMN supplementation can bring about muscle growth in the long run. PDGF is involved in the process in which muscle tissue recruits new stem cells and then grows them into mature muscle cells.[18]

In yet another Japanese study, conducted among healthy adults, researchers found a trend toward an increase in muscle mass.[19] The Japanese provide little information about their test subjects, but their biometrics suggest that they are people who were frequently physically active.

The anti-aging effects of NMN supplementation may only become apparent after a longer period of time. Although you would expect, based on the animal studies, that the effective doses of NMN are in the order of magnitude of a few grams per day, there are still few human studies that point in that direction. An exception in this regard is a recent and sponsored trial, in which a daily dose of 300 mg NMN had no significant effects in middle-aged subjects, but daily doses of 600 and 900 did.[20] These effects were – yet again – modest. In addition, in their tables, the researchers report a mild deterioration in glucose metabolism when the higher doses of NMN were administered, although the values remained in the normal range in most subjects.

Co-supplementation?

One possibility to make supplementation with NMN more effective is co-supplementation with natural substances that increase the activity of sirtuins, researchers from the Swiss Institute of Translational Medicine suggested in a review.[21] An interesting candidate, which has also been extensively researched, is resveratrol, according to the Swiss. But that’s something for a subsequent blog.

[1] Harden A, Young JW. The alcoholic ferment of yeast-juice. Part II. The co-ferment of yeast-juice. Proc R Soc Lond B. 1906;78(526):78369-375.

[2] Funk C. Who discovered vitamines? Science. 1926 Apr 30;63(1635):455-6.

[3] Nutrition classics from Public Health Reports. The prevention of pellagra. A test of diet among institutional inmates. Nutr Rev. 1973 May;31(5):152-3.

[4] Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb 17;403(6771):795-800.

[5] Imai S. A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis. Pharmacol Res. 2010 Jul;62(1):42-7.

[6] Ramsey KM, Mills KF, Satoh A, Imai S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell. 2008 Jan;7(1):78-88.

[7] Mendelsohn AR, Larrick JW. Partial reversal of skeletal muscle aging by restoration of normal NAD⁺ levels. Rejuvenation Res. 2014 Feb;17(1):62-9.

[8] De Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016 Jun;15(3):522-30.

[9] Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia. 2011 Dec;54(12):3083-92.

[10] Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016 Jul 15;1643:1-9.

[11] Lu Z, Jiang L, Lesani P, Zhang W, Li N, Luo D, Li Y, Ye Y, Bian J, Wang G, Dunstan CR, Jiang X, Zreiqat H. Nicotinamide Mononucleotide Alleviates Osteoblast Senescence Induction and Promotes Bone Healing in Osteoporotic Mice. J Gerontol A Biol Sci Med Sci. 2023 Feb 24;78(2):186-94.

[12] Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Süle Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019 Jun;24:101192.

[13] Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, Jin XL, Mahbub S, Campbell JM, Habibalahi A, Loh WN, Youngson NA, Maniam J, Wong ASA, Selesniemi K, Bustamante S, Li C, Zhao Y, Marinova MB, Kim LJ, Lau L, Wu RM, Mikolaizak AS, Araki T, Le Couteur DG, Turner N, Morris MJ, Walters KA, Goldys E, O’Neill C, Gilchrist RB, Sinclair DA, Homer HA, Wu LE. NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep. 2020 Feb 11;30(6):1670-1681.e7. 

[14] Tarragó MG, Chini CCS, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN. A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell Metab. 2018 May 1;27(5):1081-1095.e10.

[15] Peclat TR, Thompson KL, Warner GM, Chini CCS, Tarragó MG, Mazdeh DZ, Zhang C, Zavala-Solorio J, Kolumam G, Liang Wong Y, Cohen RL, Chini EN. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell. 2022 Apr;21(4):e13589.

[16] Igarashi M, Nakagawa-Nagahama Y, Miura M, Kashiwabara K, Yaku K, Sawada M, Sekine R, Fukamizu Y, Sato T, Sakurai T, Sato J, Ino K, Kubota N, Nakagawa T, Kadowaki T, Yamauchi T. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging. 2022 May 1;8(1):5.

[17] Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021 Jun 11;372(6547):1224-9.

[18] Contreras O, Córdova-Casanova A, Brandan E. PDGF-PDGFR network differentially regulates the fate, migration, proliferation, and cell cycle progression of myogenic cells. Cell Signal. 2021 Aug;84:110036.

[19] Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T, Tobe K, Nakagawa T. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Front Nutr. 2022 Apr 11;9:868640.

[20] Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, Thasma S, Andhalkar N, Avhad G, Kumbhar V. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. Geroscience. 2023 Feb;45(1):29-43.

[21] Sharma A, Chabloz S, Lapides RA, Roider E, Ewald CY. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients. 2023 Jan 14;15(2):445.

The post NMN | Boosting longevity enzymes appeared first on Increase Lifespan.

In 1939, Japanese biochemist Michio Takaoka discovered resveratrol and its analogues, including pterostilbene, while analyzing phytochemical substances from the plant Veratrum grandiflorum.[1] Decades later, in the 1960s, another Japanese scientist identified resveratrol in the roots of Japanese knotweed (Polygonum cuspidatum).[2] Today, the supplements industry still utilizes extracts from this plant.

In a Western diet, red wine and red grape juice are probably the best sources of resveratrol. A liter of red wine can provide about 2 milligrams of resveratrol.[3] In addition, resveratrol is also found in peanuts and peanut butter,[4] cacao, berries, and nuts. Through these sources, a healthy diet can provide approximately 0.1-1 milligram of resveratrol per day.

A diet consisting of organically grown produce may provide a bit more resveratrol than conventionally grown crops. Plants produce resveratrol as a defense against insects, viruses and fungi.[5] In conventional agriculture, farmers use pesticides to combat most of these factors, which are not allowed in organic farming. As a result, organically grown crops may contain a few percent, and sometimes even tens of percent, more resveratrol than their conventionally grown counterparts.

In 1997, American chemists from the University of Illinois published a study in the journal Science which revealed an impressive range of potential health benefits associated with resveratrol.[6] Resveratrol was not only found to be an antioxidant, but it also inhibited inflammation. Resveratrol was shown to prevent the development of cancer and stimulate the development of immune cells. After the publication of the Science paper, thousands of studies into the biological effects of resveratrol followed.

David Sinclair enters the building

Some of the most influential studies on resveratrol include publications from the molecular biologist David Sinclair. Sinclair, affiliated with Harvard Medical School, studies the role of a group of enzymes – the sirtuins, to be precise – in slowing down aging processes. In 2003, Sinclair and his colleagues published a study in Nature showing that resveratrol extended the lifespan of yeast cells in a way that, at least at the molecular level, closely resembled the way yeast cells live longer when given fewer nutrients.[7] Resveratrol stimulated sirtuin activity, just like caloric restriction. The precise mechanism is not yet known.

A year later, in 2004, Sinclair published another article in Nature.[8] In this publication, Sinclair demonstrated that resveratrol also slowed down aging in fruit flies and nematodes. In 2006, Sinclair and his co-workers published yet another study in Nature.[9] In this publication, they describe how supplementation with resveratrol keeps obese mice healthy and even gives them a lifespan that comes close to that of healthy mice.

The Sinclair studies inspired researchers worldwide to thoroughly study the anti-aging effects of resveratrol. In animal studies and, to a lesser extent, in human research, scientists found evidence of positive effects of resveratrol on a wide range of age-related conditions in the heart and blood vessels, skeleton, reproductive organs, muscle tissue, and brain.[10]

Human trials, conflicting results

In the years that followed, dozens of trials were published in which medical scientists tried to determine whether resveratrol supplementation had a positive effect on a variety of chronic conditions. These studies have consistently produced different outcomes, likely due to the varying doses and methods of administration used.

For example, when Danish researchers gave a group of diabetics 150 milligrams of resveratrol daily for 4 months, they saw no positive effects.[11] When they increased this dose to 1000 milligrams per day, small negative effects were observed, such as a slight increase in the blood levels of ‘bad cholesterol’ LDL.

There are also trials with more positive outcomes. In these trials, researchers usually tested doses ranging from 150 to 900 milligrams per day. In a recent trial published in Complementary Therapies in Medicine in 2022, for example, type-2 diabetics were given 200 milligrams of resveratrol daily. [12] The researchers noted a mild improvement in glucose metabolism and a decrease in the production of inflammatory factors. In a meta-study published by Chinese endocrinologists from Southeast University in Nutrition & Metabolism, supplementation with less than 100 milligrams of resveratrol per day was found to have no effect, while supplementation with higher doses generally did ameliorate diabetic symptoms.[13] In this category of trials, the studies in which researchers administered doses of 1000 milligrams or more were less convincing than the trials in which the daily administered dose remained somewhere between the range of 100 to 1000 milligrams.

In almost all studies where various concentrations have been tested, there is an optimal concentration range in which resveratrol has positive health effects. At lower concentrations, resveratrol has no effect, while at higher concentrations it may have negative side effects. In in vitro research, for example, resveratrol stimulates Natural Killer Cells to eliminate cancer cells at concentrations of 1.5-3 micromoles.[14] These concentrations can be found in the blood after taking approximately 200-400 milligrams of resveratrol. However, higher concentrations of resveratrol, on the order of several tens of micromoles, inhibit the activity of Natural Killer Cells.

Side effects

Resveratrol appears to not have any serious side effects even at high doses. Trials have been published in which users took resveratrol in doses of 1500-5000 milligrams per day, but even in those cases, there were no serious adverse effects. However, at doses of more than 500-1000 milligrams per day, some users may experience mild gastrointestinal side effects such as stomach pain, flatulence, soft stool, and diarrhea.[15]

Which supplement?

In this blog, we have highlighted a few challenging issues associated with the use of resveratrol. Firstly, it became clear that it is not possible to consume enough resveratrol through regular foods to achieve positive health effects. Supplements are therefore necessary.

A second problem is the dosage. The cells in the tissues of the small intestine, where resveratrol is absorbed, quickly convert resveratrol into non- and less-active compounds. As a result, only a fraction of the ingested resveratrol ultimately will organs, tissues and cells elsewhere in the body.

To some extent, users can solve this problem by resorting to high doses. But even this strategy, cannot prevent the resveratrol molecules that reach the blood from quickly being converted into inactive compounds. Moreover, the use of high doses of resveratrol briefly may leads to a level at which resveratrol may have some adverse effects.

Biochemists and pharmacologists have developed several solutions to this problem. One approach is the creation of supplements that not only contain resveratrol, but also substances that slow down the conversion of resveratrol.[16] One of these substances is piperine, a substance found in black pepper.[17] [18] Piperine inhibits an enzyme in the small intestine that deactivates resveratrol.

Another interesting phytochemical in this regard is quercetin. When resveratrol is administered in combination with quercetin, the bioavailability of resveratrol increases. The enzymes that convert resveratrol into less active compounds also convert quercetin. Because these enzymes have a preference for quercetin, simultaneous administration of both substances can lead to a higher resveratrol level.[19]

Another approach, which can be applied effectively in combination with co-administration with piperine and quercetin,[20] is the pre-packaging of resveratrol in small, fatty particles based on phospholipids. Application of this technology ensures that after ingestion of a relatively small dose of resveratrol, it is present in the bloodstream for several hours at effective but non-toxic concentrations.[21] [22]

In addition to the use of these advanced technologies, there is another way to enhance the anti-aging effects of resveratrol. But that’s something for a subsequent blog.

[1] Takaoka, M. (1939). trans-3,5,4′-trihydroxystilbene, a new phenolic compound, from Veratrum grandiflorum. Journal of the Chemical Society of Japan, 60, 1090-1100.

[2] Nonomura, S. et al. (1963). Chemical constituents of Polygonaceous plants. I. Studies on the components of Kojokon (Polygonum cuspidatum). Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan, 83, 988-90.

[3] Weiskirchen, S. et al. (2016). trans-3,5,4′-trihydroxystilbene: How much wine do you have to drink to stay healthy? Advances in Nutrition, 7(4), 706-18.

[4] Sanders, T. H. et al. (2000). Occurrence of trans-3,5,4′-trihydroxystilbene in edible peanuts. Journal of Agricultural and Food Chemistry, 48(4), 1243-6.

[5] Song, P. et al. (2021). Natural phytoalexin stilbene compound trans-3,5,4′-trihydroxystilbene and its derivatives as anti-tobacco mosaic virus and anti-phytopathogenic fungus agents. Scientific Reports, 11(1), 16509.

[6] Jang, M. et al. (1997). Cancer chemopreventive activity of trans-3,5,4′-trihydroxystilbene, a natural product derived from grapes. Science (New York, N.Y.), 275(5297), 218-20.

[7] Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954), 191-6.

[8] Wood, J. G. et al. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430(7000), 686-9.

[9] Baur, J. A. et al. (2006). trans-3,5,4′-trihydroxystilbene improves health and survival of mice on a high-calorie diet. Nature, 444(7117), 337-42.

[10] Zhou, D. D. et al. (2021). Effects and mechanisms of trans-3,5,4′-trihydroxystilbene on aging and age-related diseases. Oxidative Medicine and Cellular Longevity, 2021, 9932218.

[11] Kjær, T. N. et al. (2017). No beneficial effects of trans-3,5,4′-trihydroxystilbene on the metabolic syndrome: A randomized placebo-controlled clinical trial. The Journal of Clinical Endocrinology and Metabolism, 102(5), 1642-51.

[12] Mahjabeen, W., Khan, D. A., & Mirza, S. A. (2022). Role of trans-3,5,4′-trihydroxystilbene supplementation in regulation of glucose hemostasis, inflammation and oxidative stress in patients with diabetes mellitus type 2: A randomized, placebo-controlled trial. Complementary Therapies in Medicine, 66, 102819.

[13] Zhu, X. et al. (2017). Effects of trans-3,5,4′-trihydroxystilbene on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis. Nutrition & Metabolism, 14, 60.

[14] Li, Q., Huyan, T., Ye, L. J., Li, J., Shi, J. L., & Huang, Q. S. (2014). Concentration-dependent biphasic effects of resveratrol on human natural killer cells in vitro. Journal of Agricultural and Food Chemistry, 62(45), 10928-35.

[15] Cottart, C. H. et al. (2014). Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. Molecular Nutrition & Food Research, 58(1), 7-21.

[16] Vesely, O. et al. (2021). Enhancing bioavailability of nutraceutically used trans-3,5,4′-trihydroxystilbene and other stilbenoids. Nutrients, 13(9), 3095.

[17] Johnson, J. J. et al. (2011). Enhancing the bioavailability of trans-3,5,4′-trihydroxystilbene by combining it with piperine. Molecular Nutrition & Food Research, 55(8), 1169-76.

[18] Bailey, H. H. et al. A randomized, double-blind, dose-ranging, pilot trial of piperine with trans-3,5,4′-trihydroxystilbene on the effects on serum levels of trans-3,5,4′-trihydroxystilbene. European Journal of Cancer Prevention, 30(3), 285-90.

[19] Jaisamut, P. et al. (2021). Enhanced oral bioavailability and improved biological activities of a quercetin/ trans-3,5,4′-trihydroxystilbene combination using a liquid self-microemulsifying drug delivery system. Planta Medica, 87(4), 336-46.

[20] Guseva, D. A. et. (2015). Influence of trans-3,5,4′-trihydroxystilbene and dihydroquercetin inclusion into phospholipid nanopatricles on their bioavailability and specific activity. Biomeditsinskaia Khimiia, 61(5), 598-605.

[21] Gausuzzaman, S. A. L. et al. (2022). A QbD Approach to design and to optimize the self-emulsifying resveratrolphospholipid complex to enhance drug bioavailability through lymphatic transport. Polymers, 14(15), 3220.

[22] Li, T. P. et al. (2017). Physical and pharmacokinetic characterizations of transresveratrol (t-Rev) encapsulated with self-assembling lecithin-based mixed polymeric micelles (saLMPMs). Scientific reports, 7(1), 10674.

The post How to solve the resveratrol puzzle appeared first on Increase Lifespan.

In the 1990s, quercetin was a promising supplement, in which everyone in what is now called the bio-hacker scene was extremely interested. In the 2020s, quercetin seems to have lost a lot of its luster. Other supplements became popular, displacing quercetin from its once prominent place. In this blog we explain why we still consider quercetin to be an interesting and useful supplement.

By Willem Koert

In the eyes of biochemists, the man who discovered quercetin was also the discoverer of vitamin C. Albert Szent Gyorgyi, the Hungarian biochemist who in 1928 was the first modern scientist to isolate vitamin C from foods such as Hungarian bell peppers[1], discovered in the 1930s a group of ingredients in food that enhanced the effect of vitamin C.

Szent-Gyorgyi published a letter in 1936 in the prestigious scientific journal Nature, in which he described his experiments on a subject who suffered from leaky blood vessels due to a vitamin C deficiency.[2] Remedying that defect went considerably more smoothly by administering an extract from citrus fruits that contained other substances in addition to vitamin C than by administering purified vitamin C.

Citrus contained flavonoids, Szent-Gyorgyi discovered, which apparently stimulated the absorption of vitamin C. The biochemist half-seriously called that group of substances vitamin P. However, nutritional scientists have never considered flavonoids to be a vitamin.

A few years later, Szent-Gyorgyi would receive the Nobel Prize for his research into the biological properties of vitamin C.[3] [4] After the Second World War, the institute to which he was affiliated would intensively study flavonoids in food and discover that the average Westerner ingests somewhere between 50 and 100 milligrams of flavonoids. The most common flavonoids are quercetin [chemical structure below] and its analogs.

quercetin

Cancer prevention

Quercetin belongs to the subgroup of flavonoids that biochemists call flavonols. In theory, the best dietary sources of quercetin analogs are lovage and capers, but the intake of those products is too small to carry much weight. In practice, onions and apples (with red skin) are the main sources of quercetin.

The exact function of flavonoids is still not fully known, but animal studies in the 1980s showed that quercetin supplementation could reduce the chance that laboratory animals actually developed cancer after exposure to carcinogens.[5] [6]

That research inspired the American oncologist and biologist Lee Wattenberg to write influential review articles, in which he launched the theory that the presence of substances such as quercetin in natural plant foods could protect against cancer by a diet containing as many unprocessed products as possible.[7] Wattenberg not only had in mind flavonoids such as quercetin, but also the sulfur-containing phytochemicals in cabbage vegetables and garlic, such as sulforaphane and alliin respectively.

Around the turn of the century, Wattenberg’s theories about natural substances in food that protect against cancer faded into the background. However, research into substances such as flavonoids such as quercetin continued.

Life extension

In 2012, German researchers from the Technische Universität München published an animal study in which they exposed the nematode Caenorhabditis elegans to four flavonoids. One of them was quercetin.[8] The researchers discovered that the administration of quercetin allowed the nematodes to live longer.

Initially, scientists suspected that substances such as quercetin could extend life and prevent disease by acting as an antioxidant. This was not the case, the Germans discovered. Antioxidants neutralize aggressive molecules in tissues that chemists call free radicals, thereby preventing those aggressive molecules from damaging cells. However, the Germans also conducted tests with genetically modified nematodes that produce extremely high levels of free radicals, and found that quercetin did not work in these test animals.

The mechanism of action of quercetin as a life extender is of a different order than the scavenging of free radicals, Chinese researchers discovered through further fundamental research with nematodes. In a study published in the International Journal of Molecular Sciences, they found that flavonols such as quercetin activate a key molecule called nuclear factor-erythroid 2 related factor-2 [Nrf-2] in humans.[9] In human cells, Nrf-2 acts as a kind of master switch when it comes to repair mechanisms and activation of antioxidant, detoxification and anti-inflammatory pathways.[10]

When the Nrf-2-switch flips, cells start with a major cleaning and the cell produces more peroxisomes. Peroxisomes can be described as a kind of molecular shredders. They break down molecules that no longer function properly due to damage. An increased yet controlled activity of peroxisomes makes aging cells function better.

Endurance

At the same time, quercetin also leads cells to construct more mitochondria.[11] Mitochondria are the parts of a cell that convert nutrients into energy. If people increase their physical activity, the production of mitochondria increases. This implies that quercetin in theory mimics the effect of exercise on a molecular level.[12]

This probably also explains why supplementation with several hundred milligrams of quercetin per day can improve the endurance of both laboratory animals[13] and humans[14]. According to meta-studies, although the performance enhancing effect of quercetin on humans is not large, and probably even too small to be relevant in real life, it is statistically significant.[15] [16]

Quercetin as an anti-viral

Another biological effect of quercetin supplementation, which may also be related to the activation of the Nrf-2 pathways, is antiviral in nature. Because quercetin mainly accumulates in the lungs,[17] this antiviral effect of quercetin is especially relevant when it comes to respiratory viruses.

In animal studies in which mice are subjected to intensive physical exertion, as a result of which their immune system is temporarily less active, the chance of illness and death as a result of exposure to a dangerous influenza virus was less if the test animals were given quercetin.[18] The human equivalent of the dose in these studies was approximately 80-100 milligrams per day.

In 2007, exercise scientists at Appalachian State University in the US published a human study in which cyclists had to cycle for three hours a day for 3 days in a row. If the test subjects also took 1000 milligrams of quercetin daily, this reduced their risk of infection with circulating cold and flu viruses.[19]

Optimal dose unknown

It is not exactly in which dose of quercetin is most suitable for anti-aging purposes. As long as that question has not been answered, some caution should be exercised when using quercetin as most scientists who study quercetin currently believe that the mechanism of action behind quercetin’s positive health effects is hormetic in nature.[20] This means that quercetin, when administered in the correct dosage, behaves like a mild toxin. In this dose, quercetin does not harm the organism, but it does activate a variety of defense mechanisms – such as the Nrf-2 pathway.

IncreaseLifespan has written about hormesis before. Like here.

From the above it’s clear that, although according to toxicological research quercetin in doses up to 1000 milligrams should not entail significant health risks, quercetin can indeed be toxic in very high concentrations. This may explain why mice live shorter when given such high doses of quercetin for life.[21]

A problem with substances such as quercetin is their low bio-availability. High doses are required to achieve biological effects. These lead to high peaks in the blood, in which the concentration of quercetin may even acquire toxic properties. Fortunately, those toxic peaks are short-lived.[22] The human metabolism neutralizes quercetin at lightning speed. But this also means that, even at high doses, quercetin will only have the desired hormetic effect for a limited time.

Enhanced bio-availability

The most convincing longevity effects of quercetin supplementation in the scientific literature relate to trials where researchers used quercetin preparations with increased bio-availability. Extreme doses were not necessary.

Scientists from the Chinese Academy of Sciences published an animal study in Protein Cell in which an extremely small dose of quercetin, in the form of such a preparation, was not able to extend the lifespan of mice, but it did ensure that the mice also were more often healthy in their last phase of life.[23] Older mice had better conditioned fur and were physically stronger thanks to supplementation.

If you want to slow down the aging process by using quercetin supplements, you may want to choose a reasonably dosed product with an increased bio-availability, such as a quercetin-phospholipid complex. According to animal studies[24] and human studies[25], the bio-availability of quercetin in such a form is significantly higher.

An extremely interesting property of quercetin is also that it increases the absorption of other phytochemicals – including another natural substance with a life-extending effect: resveratrol. For the life extension movement, resveratrol is perhaps even more interesting than quercetin.

But that is a topic for another blog.

References

[1] Banga I, Szent-Györgyi A. The large scale preparation of ascorbic acid from Hungarian pepper (Capsicum annuum). Biochem J. 1934;28(5):1625-8.

[2] Rusznyák S, Szent-Györgyi A. Vitamin P: Flavonols as Vitamins. Nature. 1936 July 4;138:27.

[3] Svirbely JL, Szent-Györgyi A. The chemical nature of vitamin C. Biochem J. 1932;26(3):865-70.

[4] Svirbely JL, Szent-Györgyi A. The chemical nature of vitamin C. Biochem J. 1933;27(1):279-85.

[5] Kato R, Nakadate T, Yamamoto S, Sugimura T. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxygenase inhibition. Carcinogenesis. 1983 Oct;4(10):1301-5.

[6] Verma AK, Johnson JA, Gould MN, Tanner MA. Inhibition of 7,12-dimethylbenz(a)anthracene- and N-nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin. Cancer Res. 1988 Oct 15;48(20):5754-8.

[7] Wattenberg LW. Inhibition of carcinogenesis by minor dietary constituents. Cancer Res. 1992 Apr 1;52(7 Suppl):2085s-2091s.

[8] Grünz G, Haas K, Soukup S, Klingenspor M, Kulling SE, Daniel H, Spanier B. Structural features and bioavailability of four flavonoids and their implications for lifespan-extending and antioxidant actions in C. elegans. Mech Ageing Dev. 2012 Jan;133(1):1-10.

[9] He F, Ru X, Wen T. NRF2, a Transcription Factor for Stress Response and Beyond. Int J Mol Sci. 2020 Jul 6;21(13):4777.

[10] Zhu Y, Yang Q, Liu H, Song Z, Chen W. Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer. Eur J Pharmacol. 2020 Nov 15;887:173588.

[11] Rayamajhi N, Kim SK, Go H, Joe Y, Callaway Z, Kang JG, Ryter SW, Chung HT. Quercetin induces mitochondrial biogenesis through activation of HO-1 in HepG2 cells. Oxid Med Cell Longev. 2013;2013:154279.

[12] De Sousa Lages A, Lopes V, Horta J, Espregueira-Mendes J, Andrade R, Rebelo-Marques A. Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise. Int J Mol Sci. 2022 Sep 1;23(17):9957.

[13] Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1071-7.

[14] Nieman DC, Williams AS, Shanely RA, Jin F, McAnulty SR, Triplett NT, Austin MD, Henson DA. Quercetin’s influence on exercise performance and muscle mitochondrial biogenesis. Med Sci Sports Exerc. 2010 Feb;42(2):338-45.

[15] Kressler J, Millard-Stafford M, Warren GL. Quercetin and endurance exercise capacity: a systematic review and meta-analysis. Med Sci Sports Exerc. 2011 Dec;43(12):2396-404.

[16] Pelletier DM, Lacerte G, Goulet ED. Effects of quercetin supplementation on endurance performance and maximal oxygen consumption: a meta-analysis. Int J Sport Nutr Exerc Metab. 2013 Feb;23(1):73-82.

[17] De Boer VC, Dihal AA, van der Woude H, Arts IC, Wolffram S, Alink GM, Rietjens IM, Keijer J, Hollman PC. Tissue distribution of quercetin in rats and pigs. J Nutr. 2005 Jul;135(7):1718-25.

[18] Davis JM, Murphy EA, McClellan JL, Carmichael MD, Gangemi JD. 3,3′,4′,5,7-pentahydroxyflavone reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R505-9.

[19] Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, Carmichael MD, Dumke CL, Utter AC, McAnulty SR, McAnulty LS, Mayer EP. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc. 2007 Sep;39(9):1561-9.

[20] Calabrese EJ, Kozumbo WJ. The hormetic dose-response mechanism: Nrf2 activation. Pharmacol Res. 2021 May;167:105526.

[21] Jones E, Hughes RE. 3,3′,4′,5,7-pentahydroxyflavone, flavonoids and the life-span of mice. Exp Gerontol. 1982;17(3):213-7.

[22] Egert S, Wolffram S, Bosy-Westphal A, Boesch-Saadatmandi C, Wagner AE, Frank J, Rimbach G, Mueller MJ. Daily 3,3′,4′,5,7-pentahydroxyflavone supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J Nutr. 2008 Sep;138(9):1615-21.

[23] Geng L, Liu Z, Wang S, Sun S, Ma S, Liu X, Chan P, Sun L, Song M, Zhang W, Liu GH, Qu J. Low-dose 3,3′,4′,5,7-pentahydroxyflavone positively regulates mouse healthspan. Protein Cell. 2019 Oct;10(10):770-775.

[24] Zhang K, Zhang M, Liu Z, Zhang Y, Gu L, Hu G, Chen X, Jia J. Development of quercetin-phospholipid complex to improve the bioavailability and protection effects against carbon tetrachloride-induced hepatotoxicity in SD rats. Fitoterapia. 2016 Sep;113:102-9.

[25] Wang H, Cui Y, Fu Q, Deng B, Li G, Yang J, Wu T, Xie Y. A phospholipid complex to improve the oral bioavailability of flavonoids. Drug Dev Ind Pharm. 2015;41(10):1693-703.

[26] Jaisamut P, Wanna S, Limsuwan S, Chusri S, Wiwattanawongsa K, Wiwattanapatapee R. Enhanced Oral Bioavailability and Improved Biological Activities of a Quercetin/Resveratrol Combination Using a Liquid Self-Microemulsifying Drug Delivery System. Planta Med. 2021 Apr;87(4):336-46.

[27] Vesely O, Baldovska S, Kolesarova A. Enhancing Bioavailability of Nutraceutically Used Resveratrol and Other Stilbenoids. Nutrients. 2021 Sep 2;13(9):3095.

The post Quercetin, a longevity supplement appeared first on Increase Lifespan.

By Willem Koert

Most hypes in the wonderful world of nutritional supplements last a few months, and very rarely a few years. This is certainly not the case with the hype around Carbon 60, which already started in 2012, the year in which French scientists discovered that laboratory animals live almost twice as long if they frequently consume a small amount of C60. Since 2012, the number of webshops selling the weird nanomolecule continues to increase.

Carbon 60 is a sphere made up of carbon molecules. You can see the structure below.

Carbon 60 (C60)

Nanotechnology

Harry Kroto, at the time a chemist at the University of Sussex in the UK, discovered the molecule when he fired one of the previous lasers at graphite in the 1980s. He discovered that this created countless molecules that were usually made up of 60 carbon atoms that together formed a cage in the shape of a football.[1]

Since the Carbon 60 molecules were quite stable, Kroto foresaw all kinds of interesting applications for the molecules he discovered. Perhaps pharmacologists could put drugs in the spheres and use them as a transport vehicle. Few of these possible applications actually materialized, but Kroto’s discovery did give the first generation of nano technologists the inspiration they needed. It is mainly for this reason that Kroto and his close associates were awarded the Nobel Prize in chemistry in 1996.[2]

When biomedical scientists started experimenting with C60 molecules in the 1990s, they discovered that the molecules could capture, store and release energy in the form of electrons or light. If oxygen was also present, the light-activated C60 molecules could turn oxygen molecules into oxygen radicals that in theory could clear up cancer cells.[3] By applying C60 molecules to the skin and then irradiating the molecules with light, dermatologists might be able to fight skin cancer cells or pathogens on the skin. Healthy skin cells seemed to be able to withstand the treatment.[4]

A longevity promise

Of course, before pharmacologists would seriously invest in applications for C60, they had to know whether C60 is safe. In theory, a molecule like C60 could be an antioxidant, protecting cells against aggressive molecules. But C60 could also increase the activity of those same aggressive molecules, the oxygen radicals in the lead. In the latter case, C60 may be to toxic for human use. In the now famous study published in 2012, which marked the start of the C60 hype, researchers from the Université Paris Sud XI wanted to learn more about the toxicity of C60.[5]

In this animal study, research leader Fathi Moussa and first author Tarek Baati gave rats olive oil in which they had dissolved C60. C60 is orally available when dissolved in oil. Every two weeks, the rats were given a dose of C60.

One control group of rats received only olive oil, another control group received nothing at all. The researchers studied the effect of orally administered C60 on the lifespan of the animals. If the rats had been adult humans, they would have consumed roughly 15-20 milligrams of C60 per dose.

C60 extended the life of the test animals by 90 percent, which almost equates to a doubling. “A longer treatment could have generated even longer lifespans”, the researchers wrote in their publication. “Anyway, this work should open the road towards the development of the considerable potential of C60 in the biomedical field.”

Doubts of a chemist

Tens of thousands of companies did not wait for this ‘development of the considerable potential of C60 in the biomedical field’ and started selling C60 supplements. In 2019, Jonathan Hare, a chemist who had worked with Harry Kroto in the 1990s, published an article on the Chemistry World website about his experiences with some of the organizations that sold C60.[6] Hare had developed a process to produce C60 on a lab scale and had been approached by companies asking if he could provide them with his C60 expertise. Kroto himself had passed away in 2016.[7]

Hare decided that for ethical reasons he could not accede to the request, even if it meant losing out on revenue. “It bothers me that C60 can be bought so easily, that there are no ‘stops’ or ‘checks’ in place to remind people that the scientific research is sparse – and that it needs repeating – and that there are no limits to the amount people might decide to ingest,” he wrote.

“Much more research needs to be performed – and, crucially, independently repeated and verified – especially when applying these results for fullerene ingestion by humans.”

Toxicity

Hare has a point. There is still virtually no scientific knowledge about the biological effects of C60 on humans. In addition, some in vitro and animal data suggests that in some circumstances the use of C60 may have negative health effects. One of the most disturbing studies published so far is the animal study that researchers at the State University of New York published in Geroscience in 2021.[8]

To begin with, the American researchers could not confirm the promising results of their French colleagues. Their laboratory animals, on the other hand, no longer lived after being given C60. It should be noted that the method of administration used by the Americans differed from that of the French.

More startling was what happened when the Americans exposed vials of C60 to a lamp that imitated daylight. Almost immediately the C60 molecules started to change.  After 8 days, in an opened vial almost all unmodified C60 had disappeared.

Besides, the modified C60 molecules had acquired dangerous properties. C60 exposed to daylight for 0-2 days was not overtly toxics, but after administration of C60 that had been exposed to longer light, half to a quarter of the test animals died within two weeks. In their bodies, the researchers found ‘numerous adhesions in the intestinal cavity, dilated small intestines, enlarged livers and spleens, and extensive fibrin formation’.

It should be noted that the Americans injected their preparations directly into the small intestines of their lab mice. The doses administered were also significantly higher than the doses used by users of C60 supplements. If the mice had been adult humans, they would have received about 20-30 milligrams of C60. But even with these nuances in mind, the animal study is not reassuring. As a consumer, how can you be sure that the C60 product you have purchased has not been exposed to light?

The chance that you as a consumer will get your hands on such a product is not imaginary. The New Yorkers bought 4 different commercial C60 preparations, analyzed them in their lab – and found in all four of the preparations components that did not belong there. None of the tested preparations was able to eliminate free oxygen radicals in vitro – and there was even one preparation that actually caused oxidative damage…

Maybe Jonathan Hare was more right than he realized.

1. Kroto HW, Heath JR, O’Brien SC, Curl RF, Smalley RE. C60: Buckminsterfullerene. Nature. 1985;318(6042:162-3.

2. Kroto H. The 2009 Lindau Nobel Laureate Meeting: Sir Harold Kroto, Chemistry 1996. J Vis Exp. 2010 Apr 7;(38):1576.

3. Sharma SK, Chiang LY, Hamblin MR. Photodynamic therapy with fullerenes in vivo: reality or a dream? Nanomedicine (Lond). 2011 Dec;6(10):1813-25.

4. Rondags A, Yuen WY, Jonkman MF, Horváth B. Fullerene C60 with cytoprotective and cytotoxic potential: prospects as a novel treatment agent in Dermatology? Exp Dermatol. 2017 Mar;26(3):220-224.

5. Baati T, Bourasset F, Gharbi N, Njim L, Abderrabba M, Kerkeni A, Szwarc H, Moussa F. The prolongation of the lifespan of rats by repeated oral administration of [60]fullerene. Biomaterials. 2012 Jun;33(19):4936-46.

6. Hare J. Should I help make fullerenes if people are going to eat them? Chemistry World, 7 February 2019.

7. Hagerty JR. Harry Kroto Helped Spur Wave of Research in Nanotechnology: 1939-2016 | British chemist and Nobel Prize winner extolled scientific education. Wall Street Journal, May 6, 2016.

8. Grohn KJ, Moyer BS, Wortel DC, Fisher CM, Lumen E, Bianchi AH, Kelly K, Campbell PS, Hagrman DE, Bagg RG, Clement J, Wolfe AJ, Basso A, Nicoletti C, Lai G, Provinciali M, Malavolta M, Moody KJ. C60 in olive oil causes light-dependent toxicity and does not extend lifespan in mice. Geroscience. 2021 Apr;43(2):579-91.

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