By Willem Koert

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

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

Extending life span

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

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

Effects

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

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

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

Trials

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

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

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

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

Longevity scene

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

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

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

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

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

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

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

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

‘A serious drug’

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[14] RAP User Poll | Survey. LINK.

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

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

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

[18] New To RAP? LINK.

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

By Willem Koert

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.

The post How we age (and how we can slow it down) appeared first on Increase Lifespan.