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

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

Metformin

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

The chemical structure of metformin is shown below.

METFORMIN

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

Safety

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

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

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

Longevity

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

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

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

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

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

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

Trials

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

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

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

Human data

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

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

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

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

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

1  Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care. 1989 Sep;12(8):553-64.

2  Watanabe C. Studies in the metabolic changes induced by administration of guanidine bases. J Biol Chem. 1918;33:253–65.

3  Gottlieb B, Auld WH. Metformin in treatment of diabetes mellitus. Br Med J. 1962 Mar 10;1(5279):680-2.

4  Sterne J. [Treatment of diabetes mellitus with N,N-dimethylguanylguanidine (LA. 6023, glucophage)]. Therapie. 1959;14:625-30.

5  American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S90-S102.

6  Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, Wiley C, Selvin E, Wilson R, Bass EB, Brancati FL. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007 Sep 18;147(6):386-99.

7  Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005 Jun 4;330(7503):1304-5.

8  Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prevention Research (Philadelphia, Pa) 2014;7(9):867-85.

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

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

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

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

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

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

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

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

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

The post Metformin, the old school anti-diabetic that may prolong lifespan 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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