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

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 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.

The post The neglected dark side of Carbon 60 (C60) appeared first on Increase Lifespan.

By Willem Koert

Scientists can say little with absolute certainty about the how and why of aging, but that doesn’t stop them from launching theories. In 2016, Portuguese chemists published an exhaustive review article on aging mechanisms, in which they listed 300 theories.[1] We are now a few years further, and this number has undoubtedly only increased since then.

We are not going to confront you with all those theories in this blog. Many of them relate to factors beyond your control. In the first twenty years of the 21st century, for example, anti-aging researchers have devoted a lot of attention to longevity genes that should increase the chance of a long and healthy life. Scientists classify the contribution of our genes to aging as ‘intrinsic aging’.

Intrinsic versus extrinsic aging

Since we are mainly interested in things that we can change, let’s leave the theories about intrinsic aging for what they are. Instead, we focus on theories that might actually help you. These theories are about ‘extrinsic aging’. Extrinsic aging is aging that results from factors that you can influence, such as your lifestyle or the amount of stress you allow in your daily life.

Because scientific media still pays a lot of attention to the role of genes in longevity, it is easy to forget the role of lifestyle factors. Medical scientists estimate that about a quarter of the difference between individuals’ lifespans is due to genetic factors.[2] As far as longevity is concerned, lifestyle and environmental factors may carry more weight than genes.

In a publication, which appeared in 2008 in PLoS Medicine, epidemiologists from the University of Cambridge calculated the effect of 4 simple lifestyle factors – not drinking a lot of alcohol, exercising daily, eating five pieces of fruit and vegetables a day and not smoking – on life expectancy.[3] The scientists concluded that individuals who adhere to these 4 basic lifestyle rules live an average of 14 years longer than people who do not adhere to those rules.

A sub-optimal diet

A poor diet, which does not provide all the nutritional factors the body needs, can lead to cell damage. The body can replace those damaged cells, but this repair capacity is limited.

Cells can divide and form new cells to replace damaged and dead cells, but the more often they do this, the faster they age. In the long run, they lose their ability to function properly. The cells become less healthy, making biological processes less and less efficient.

American biochemist Bruce Ames, the inventor of the Ames test, suspects that we still do not know exactly how many nutrients, such as vitamins and minerals, we need to stay healthy. Based on his own fundamental research, Ames suspects that food scientists have estimated the intake of, for example, vitamin K[4] and selenium[5] at a level that does not cause direct or semi-acute cell damage.

However, Ames thinks that science has failed to look at processes that also require vitamin K and selenium, but whose health consequences only become visible in the longer term – read: at an advanced age. This implies that those who also want to stay healthy in the longer term may need vitamin K and selenium in larger amounts than the guidelines recommend. For this reason, Ames is a strong advocate of incorporating a basic multivitamin and mineral supplement into the daily diet.

Molecular research appears to confirm Ames’ theory. When researchers at the US National Institutes of Health measured the age of nearly 600 women at a cellular level, they found that using a simple multivitamin reduced their cell age by nearly ten years.[6] This may mean that such a simple and cheap supplement can extend life by ten years.

Hormonal aging

According to some aging researchers, an aging body produces fewer hormones necessary for healthy functioning. This theory of endocrinological aging is the foundation of many hormonal anti-aging treatments offered by clinics. In those treatments, doctors try to compensate for the drop in hormone levels due to aging by administering hormones such as DHEA, testosterone and growth hormone.

Although users of hormonal anti-aging treatments typically experience a significant improvement in their quality of life, it is not clear whether these treatments on their own indeed extend life. In animal experiments, older lab rats with an elevated growth hormone level do not live longer, but rather shorter than normal.[7] In addition, the hormones most frequently used in anti-aging treatments, such as testosterone and growth hormone, activate the mTOR molecule in cells. MTOR is a key molecule when it comes to processes such as building muscles, connective tissue and bones. Most anti-aging researchers see reducing mTOR activity as a key to a long and healthy life.[8]

MTOR

One of the most effective ways to reduce the activity of mTOR is to continuously consume several tens of percent fewer calories than your body actually needs. This gives the body a better chance of repair and detoxification processes and increases the lifespan of cells.

The life-prolonging effect of ‘caloric restriction’, as this approach is called, was discovered as early as the 1930s by researchers at Cornell University in experiments on lab rats.[9] Already in these first studies, caloric restriction extended lifespan by 30-50 percent and at the same time reduced the risk of a variety of aging-related disorders.[10]

Studies are currently underway in which researchers follow people on caloric restriction regimens for years. Although the first results are mainly positive, side effects have certainly come to light. For starters, a small group develops osteoporosis or anemia.[11] A more frequent problem is that the caloric restriction reduces the quality of life. A permanent low intake of calories increases sensitivity to cold, irritability, lethargy, and feelings of irritation and reduced energy levels.[12]

Although the research into caloric restriction is far from complete, the search for alternatives has already started, which consist of natural and pharmacological substances that mimic the effect of caloric restriction. A prominent one is resveratrol, a phyto-chemical naturally found in red grapes and, in small amounts, in berries,.[13] In cells, resveratrol activates an enzyme called SIRT1. This enzyme also becomes active through caloric restriction. It allows cells to spend more energy on repair processes. We’ll be sharing a more about resveratrol and SIRT1 in follow-up blogs.

In a previous blog about the relationship between lifestyle and longevity, we wrote that a dietary pattern with a high intake of fruits and vegetables and exercise increases the chance of a long and healthy life. Those two factors seem to act on the same mechanism as caloric restriction.

This is probably because fruits and vegetables contain substances that do about the same as resveratrol,[14] while exercise seems to work in a different way. Exercise may mimic the effect of caloric restriction by extracting significant amounts of energy from the body.[15]

AGEs

One aging theorem that has gained popularity in particular over the past decade is the cross-linkage theory. According to this theory, aging is due to the buildup of cross-linked protein complexes, which damage cells and inhibit important repair enzymes. This theory was launched in the 1940s by Johan Bjorksten.[16] In the 1990s, the American biochemist Helen Vlassara called these complexes AGEs. AGEs is an abbreviation for ‘advanced glycation end products’. AGEs are more easily formed in the body when the glucose level is constantly high.

This explains why people are estimated to be older if their glucose level is continuously elevated.[17] A lifestyle with a lot of exercise and a low intake of sugars and other fast-absorbing carbohydrates, which keep the glucose level low, can inhibit the formation of these complexes and thus slow down the rate of aging.

AGEs can also enter the body directly through foods.[18] AGEs can be found in chips, cookies, fried snacks and other highly-processed industrial foods.

There isn’t much that everyone agrees on in contemporary nutritional science. But it is now beyond dispute that foods with a lot of ‘fast carbs’ and highly-processed foods are unhealthy.[19]

Free radicals

At the turn of the century, free radical theory was the most popular theory of aging in applied health sciences. According to this theory, devised in the mid-1950s by the American chemist Denham Harman, aging occurs because aggressive molecules, the free radicals, continuously attack complex molecules in the body.[20]

Harman initially suspected that these free radicals were formed by the action of various forms of radiation, but later he came to the conclusion that the cells themselves produced those free radicals. They were released when the mitochondria in the cells convert nutrients and energy, Denham theorized.[21]

In the 1970s, 1980s and 1990s, longevity researchers hoped that high doses of antioxidants such as vitamin C, vitamin E and beta-carotene could slow down the cellular destruction of free radicals, but that turned out not to be the case. However, scientists still use the free radical theory when they want to demonstrate why a large amount of radioactive radiation or smoking is unhealthy. Exposure to radioactive radiation creates free radicals in the body, while cigarette smoke is full of free radicals.

Defective mitochondria

According to Denham, mitochondria produce free radicals, which then damage the mitochondria over the long term. Thus, aging was not only a result of free-radical wrecking, but also a result of an increasingly serious cellular energy crisis due to less and less effective mitochondria. Towards the end of his academic career, Denham himself was pessimistic about the possibilities of solving this problem, but German biologists from the University of Jena took a different view.

The Germans did experiments in their laboratory with worms and mice, and discovered that there is a way to make organisms live longer via mitochondria. By challenging mitochondria, and by increasing the free radical production, cells were stimulated the cells to renew themselves. This resulted, among other things, in better functioning mitochondria. [22] This complex and paradoxical phenomenon is called hormesis.

Physical activity may be one way to achieve this type of hormesis.[23] Ingestion of natural chemicals that challenge the energy production in mitochondria, like EGCG[24] or alpha-ketoglutarate,[25] may be another.

Senescent cells

Yet another theory, which is remarkably popular in the academic community at the time of writing this blog, is the senescent cells hypothesis. According to this theory, we age because senescent cells that no longer function properly accumulate in our tissues.[26] As a result, these tissues are less able to do what they are supposed to do. There are all kinds of systems out there that are supposed to clean up these stale cells, but the cells have found ways to get around them.

One way to limit the accumulation of aging cells is to prevent obesity.[27] Another way is probably a diet high in vegetables and other sources of natural phenols.[28] A phenol like fisetin,[29] which is chemically closely related to quercetin, kills senescent cells in animal studies, thereby extending lifespan.

Epilogue

The theories we have mentioned in this blog are not mutually exclusive, but complement each other. We will return to these theories in future blogs, where we will discuss substantiated ways to extend the human life span and health span.

1  Da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T. A synopsis on aging-Theories, mechanisms and future prospects. Ageing Res Rev. 2016 Aug;29:90-112.

2  Passarino G, De Rango F, Montesanto A. Human longevity: Genetics or Lifestyle? It takes two to tango. Immun Ageing. 2016 Apr 5;13:12.

3  Khaw KT, Wareham N, Bingham S, Welch A, Luben R, Day N. Combined impact of health behaviours and mortality in men and women: the EPIC-Norfolk prospective population study. PLoS Med. 2008 Jan 8;5(1):e12.

4  McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 2009 Oct;90(4):889-907.

5  McCann JC, Ames BN. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J. 2011 Jun;25(6):1793-814.

6  Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009 Jun;89(6):1857-63.

7  Bartke A. Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology. 2003 Oct;78(4):210-6.

8  Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res. 2019 Jul 2;8:F1000 Faculty Rev-998.

9  McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 1989 May-Jun;5(3):155-71.

10  Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010 Apr 16;328(5976):321-6.

11  Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB; CALERIE Study Group. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1097-104.

12  Dirks AJ, Leeuwenburgh C. Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev. 2006 Jan;127(1):1-7.

13  Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol. 2012 Oct;22(10):546-54.

14  Iside C, Scafuro M, Nebbioso A, Altucci L. SIRT1 Activation by Natural Phytochemicals: An Overview. Front Pharmacol. 2020 Aug 7;11:1225.

15  Hofer T, Fontana L, Anton SD, Weiss EP, Villareal D, Malayappan B, Leeuwenburgh C. Long-term effects of caloric restriction or exercise on DNA and RNA oxidation levels in white blood cells and urine in humans. Rejuvenation Res. 2008 Aug;11(4):793-9.

16  Bjorksten J. Pathways to the decisive extension of the human specific lifespan. J Am Geriatr Soc. 1977 Sep;25(9):396-9.

17  Noordam R, Gunn DA, Tomlin CC, Maier AB, Mooijaart SP, Slagboom PE, Westendorp RG, de Craen AJ, van Heemst D; Leiden Longevity Study Group. High serum glucose levels are associated with a higher perceived age. Age (Dordr). 2013 Feb;35(1):189-95.

18  Uribarri J, Cai W, Peppa M, Goodman S, Ferrucci L, Striker G, Vlassara H. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol A Biol Sci Med Sci. 2007 Apr;62(4):427-33.

19  Schwingshackl L, Schwedhelm C, Hoffmann G, Lampousi AM, Knüppel S, Iqbal K, Bechthold A, Schlesinger S, Boeing H. Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2017 Jun;105(6):1462-73.

20  Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956 Jul;11(3):298-300.

21  Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145-7.

22  Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med. 2011 Jul 15;51(2):327-36.

23  Merry TL, Ristow M. Mitohormesis in exercise training. Free Radic Biol Med. 2016 Sep;98:123-130.

24  Tian J, Geiss C, Zarse K, Madreiter-Sokolowski CT, Ristow M. Green tea catechins EGCG and ECG enhance the fitness and lifespan of Caenorhabditis elegans by complex I inhibition. Aging (Albany NY). 2021 Oct 4;13(19):22629-48.

25  Bayliak MM, Lushchak VI. Pleiotropic effects of alpha-ketoglutarate as a potential anti-ageing agent. Ageing Res Rev. 2021 Mar;66:101237.

26  McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018 Jan 2;217(1):65-77.

27  Maduro AT, Luís C, Soares R. Ageing, cellular senescence and the impact of diet: an overview. Porto Biomed J. 2021 Feb 11;6(1):e120.

28  Meccariello R, D’Angelo S. Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview. Antioxidants (Basel). 2021 Mar 24;10(4):507.

29  Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28.

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