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.

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.

Metformin is an ancient drug, with a history going back centuries. Metformin is based on natural components of Galega officinalis, commonly known as Goat’s Rue or French Lilac, an herbaceous plant that is native to parts of northern Africa, the Middle East and Europe. Medical manuals from ancient Egypt, found in burial vaults, already mention Galega officinalis. Since the Middle Ages, European traditional healers have prescribed extracts of Galega officinalis to treat multiple symptoms of diabetes.[1]

The main active substances in Galega officalalis are galegine, perhaps better known in chemistry as dimethyl-allylguanidine, and a number of biguanide analogues. Due to these substances, the plant is poisonous at a high intake. In the 1920s, Kayuki Watanabe, a Yale University chemist, accidentally discovered that biguanidines could lower glucose levels.[2]

Metformin

A few years after Watanabe’s discovery the first antidiabetic biguanides hit the market. These preparations were not without side effects, as patients and their physicians noted almost immediately. The first generation biguanides could damage the liver and kidneys. It was not until the 1950s that Jean Sterne, a physician and professor of Clinical Pharmacology at the Hopital Laennec in Paris, discovered that there was a biguanide analogue that could combat diabetes with relatively few side effects. That was metformin.[3] Sterne called metformin ‘glucophage’ (glucose eater).[4]

The chemical structure of metformin is shown below.

METFORMIN

In the mid-1970s, metformin was introduced as an anti-diabetes drug in France. In the United States this happened after 1995, when the FDA approved metformin. Endocrinologists now regard metformin therapy as the preferred first-line pharmacological action against type-2 diabetes.[5]

Safety

Although the mechanism of action of metformin is still not fully elucidated, scientists believe that the anti-diabetic effect of metformin is mainly due to a reduction in glucose release by the liver. In addition, metformin reduces the absorption of glucose by the small intestine. The latter explains perhaps the most commonly reported side effects of metformin: nausea, stomach ache, cramps, flatulence and diarrhoea. Metformin is more commonly associated with gastrointestinal adverse effects than other antidiabetic drugs.[6]

These gastrointestinal side effects are relatively harmless, and can often be resolved by dividing the daily dose into several small doses per day or by taking the drug with food. A rare but more serious side effect is the accumulation of lactate to toxic levels. This lactic acidosis may occur when metformin is taken by patients with other conditions that may cause metabolic acidosis, like liver disease or alcoholism. Another risk factor is kidney disease, which results in a compromised renal excretion of metformin.

In the 21st century it has become increasingly clear that metformin is more than an anti-diabetic drug. According to medical epidemiological studies, diabetics taking metformin develop cancer significantly less often than patients not taking metformin.[7] Meta-analyses show that metformin reduces both the risk of developing cancer and the risk of dying from cancer by more than thirty percent.[8]

Longevity

That in itself is already interesting, but animal studies have shown that the health-promoting properties of metformin may go even further. If you expose roundworms to metformin, the animals will live longer.[9]

In cells, metformin appears to alter the functioning of the mitochondria by inhibiting the transport of electrons. This reduces the activity of ATP and anabolic signaling molecules like mTOR that force cells to develop and grow. An important enzyme that inhibits metformin in mitochondria is glycerol-3-phosphate dehydrogenase. This enzyme is also involved in the formation of glucose. (Inhibition of this enzyme largely explains the antidiabetic activity of metformin.)

At the same time, the enzyme AMPK, which normally acts as a sensor for a state of deficient energy and nutrients, becomes more active. In turn, AMPK activates a spectrum of antioxidant and anti-inflammatory mechanisms.

A similar effect has been shown in experiments with mice.[10] Mice given metformin in the second half of their lives live 4-5 percent longer than normal. However, the length of time that the mice are plagued by an aging-related decline in their health throughout their lives is not increased by long-term administration of metformin. The increase in the life span equals the increase in the health span.

Incidentally, also in the case of the use of metformin as a longevity drug, the adage of ‘more is better’ is incorrect. Mice given ten times the optimal dose of metformin live 14 percent shorter than normal.

After the life-prolonging effect of metformin has been demonstrated in animal studies, fundamental scientists have extensively mapped all possible ways through which metformin could extend life. The figure below, taken from a review article by anti-aging researchers at the American Albert Einstein College of Medicine, summarizes all known metformin’s potential mechanisms of action on the molecular level.[11]

Trials

If there are so many indications that a relatively cheap, proven and safe drug can extend both the lifespan and the healthspan, it is obvious that anti-aging researchers will set up trials to answer the question whether metformin can also offset aging and extend lifespan.

One of those trials is the Metformin in Longevity Study (MILES), another Targeting Aging with Metformin (TAME).[12] In the latter study, three thousand Americans aged 65-79 will participate for 6 years. Researchers from the National Institutes of Health will determine the effect of metformin on mortality, but also on chronic diseases such as cardiovascular disease, cancer and dementia.

Expectations are high. Even doctors who still have reservations about the life-prolonging effect of metformin, keep open the possibility that metformin administration may extend the period of life spent in good health via its ability to reduce various diseases.[13]

Human data

It will be years before the results of these trials are available, but smaller human studies on the longevity effects of metformin are already being published in the scientific literature. A recent and evocative example appeared in Frontiers in Genetics a few weeks ago.[14] It is a Chinese study, conducted among 32 male diabetics with an average age of 73. Half of the men had taken 500 milligrams of metformin daily for the past five years, the other half had received other diabetes medications.

The researchers extracted cells from the blood of the study participants, isolated the DNA from the cells and then determined whether a number of crucial genes had methyl groups attached to the genes. As people age, the number of methylated genes increases. In a number of genes, the presence of such a methyl group prevents the gene from working fully as it should. The accumulation of methylated genes thus says something about the biological aging of an organism. It says something about the wear and tear of the genetic material.

The researchers used three different tests to map the genetic aging of the study participants. The tests were developed by Steve Horvath[15], Gregory Hannum[16] and Morgan Levine[17] (DNAm PhenoAge). The difference between the tests lies in the genes whose tests determine the methylation.

According to all tests, the metformin users had fewer methylated genes than the subjects who had not taken metformin. In Horvath and Hannum’s tests, the differences were statistically significant, but not in Levine’s test.

The Chinese study, as interesting as it is, doesn’t provide hard evidence. It suggests that metformin mag prolong life, that’s all. But the beginning is here.

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9  Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013 Mar 28;153(1):228-39.

10  Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. dimethylbiguanide improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.

11  Kulkarni AS, Gubbi S, Barzilai N. Benefits of Metformin in Attenuating the Hallmarks of Aging. Cell Metab. 2020 Jul 7;32(1):15-30.

12  Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, Hollenberg MD, Hill MA. dimethylbiguanide: Is it a drug for all reasons and diseases? Metabolism. 2022 Aug;133:155223.

13  Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That dimethylbiguanide Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol (Lausanne). 2021 Aug 5;12:718942.

14  Li M, Bao L, Zhu P, Wang S. Effect of dimethylbiguanide on the epigenetic age of peripheral blood in patients with diabetes mellitus. Front Genet. 2022 Sep 26;13:955835.

15  Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115.

16  Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I, Friend S, Ideker T, Zhang K. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013 Jan 24;49(2):359-67.

17  Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, Whitsel EA, Wilson JG, Reiner AP, Aviv A, Lohman K, Liu Y, Ferrucci L, Horvath S. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018 Apr 18;10(4):573-91.

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