The Hunger Games
Who will live longer?
Alexander PanchinAs you know, life is a sluggish deadly sexually transmitted disease.
On May 14, 2014, an article appeared in the journal Nature demonstrating that the substance alpha-ketoglutarate is capable of approximately 1.5 times increasing the life expectancy of small roundworms of the species Caenorhabditis elegans [1]. This work confirms some modern ideas about the mechanisms of animal aging. Let's try to figure out what this theory of aging is and whether there is any hope of increasing a person's life expectancy through changing his diet. This question is especially relevant, given that we are already facing a choice: to take drugs that supposedly increase life expectancy, or not.
The observation that slightly starving mice have a longer life expectancy than mice with unlimited access to food was first made in 1935 [2]. This effect has been replicated in experiments using different animal species, including some species of mice, rats, fish and dogs [3]. But everything turned out to be not so unambiguous: the positive effect of starvation could not be found in our close relative, the macaque [4], as well as in some flies [5], some spiders [6] and a number of other organisms [3]. The lifespan of the housefly Musca domestica, on the contrary, decreased in conditions of reduced food intake [7].
The listed differences between different types of living organisms indicate that the relationship between the amount of food consumed and life expectancy is somewhat more complex. Perhaps it's not the positive effect of starvation itself, but the fact that starvation triggers some biochemical processes that contribute to longevity in some organisms, but not in others.
It is believed that one of the mechanisms through which fasting can increase life expectancy is the activation of the autophagy process [8]. During autophagy, the cell "digests" relatively unnecessary internal components, gets rid of "garbage". An ordinary well-fed cage can be imagined as a kind of "Plyushkin", a person who stores all kinds of garbage, arguing that "it can be useful for a rainy day." This garbage harms the cell, and its accumulation can contribute to the aging of the body and the development of a number of senile diseases. When a cell feels a lack of nutrients, it begins to get rid of junk by digesting it. In this case, to prevent senile diseases and aging, it is necessary to force cells to engage in autophagy more often. And, indeed, the inclusion of autophagy allowed to increase the life expectancy of some model organisms, and its shutdown prevented an increase in life expectancy under starvation conditions [9-12], which is in good agreement with this hypothesis about the mechanism of aging.
One of the main ways to activate autophagy in animals is through the suppression of the TOR (target of rapamycin) protein [13]. Substances that inhibit the work of TOR are of interest as potential means of increasing life expectancy and preventing certain diseases associated with the accumulation of "garbage" in cells, for example, Huntington's disease (Huntington's chorea) and Alzheimer's disease. These diseases of the central nervous system are accompanied by the accumulation of aggregates of improperly folded peptides that cells are unable to remove. It has recently been shown that TOR suppression leads to activation of autophagy in mice serving as model organisms for the study of Huntington's disease, and reduces damage and death of nerve cells [14].
The most well-known inhibitors of TOR and, accordingly, activators of autophagy are caffeine [15, 16], resveratol (a component of red wine) [16] and rapamycin [16]. Rapamycin, in honor of which the letter R stands in the name of the TOR protein, deserves a separate mention. Although it is a rather expensive antibiotic that suppresses the work of the immune system, rapamycin shows encouraging results in increasing the lifespan of mice [17, 18]. Rapamycin in the future is a pharmacist's dream: an expensive medicine for the most common disease in the world. In addition, it is used to reduce organ rejection during transplantation.
(It should be added that the main reason why rapamycin is not suitable for the role of a geroprotector is that a potential long–lived person should not leave a sterile room all his life in order not to die from any infection due to weakened immunity - VM.)
The interest in resveratol was caused by the "French paradox" – low mortality among the French who consume large amounts of red wine, primarily from coronary heart disease. The effect of resveratol on life expectancy was indeed found in experiments on mice [19], but the concentration of resveratol at which the effect was observed (from 5.2 to 22.4 mg per kg of body weight per day) is approximately equivalent to drinking a liter of red wine per kilogram of body weight per day (red wine contains 0.2-5.8 mg/l resveratol). That is, wine should be drunk literally in barrels, to death from ethanol intoxication. This fact does not negate the value of resveratol, but it does not agree with the idea that it can explain the "French paradox". However, the value of resveratol itself, especially against the background of the existence of rapamycin, has also recently been questioned [20].
Another substance capable of suppressing TOR is ethanol. Perhaps this property of ethanol partly explains the positive association between the use of small doses of alcohol and increased life expectancy [21, 22], in particular, and the "French paradox". Alas, large doses of alcohol neutralize the positive effect, apparently due to the toxicity of the main metabolite of ethanol: acetaldehyde. By the way, in laboratory experiments on roundworms Caenorhabditis elegans, there was also a positive effect on the life expectancy of low concentrations of ethanol and a negative effect of high concentrations [23].
The TOR inhibitor alpha-ketoglutarate [1], which became the informational reason for this review due to its dramatic effect on increasing the lifespan of the roundworm Caenorhabditis elegans and increasing autophagy in mammalian cells, is remarkable for being an important metabolite of the so-called Krebs cycle. Alpha-ketoglutarate is constantly synthesized and metabolized in the body of any animal, and in large quantities, and unlike rapamycin, which is produced by the bacterium Streptomyces hygroscopicus, is a fairly cheap and affordable substance.
It is assumed that the mechanism of action of alpha-ketoglutarate is similar to the mechanism of action of rapamycin (TOR suppression). Alpha-ketoglutarate appears to have very low toxicity. In experiments on rats, it was shown that the dose of alpha-ketoglutarate, at which no negative effects are observed in rats, is 1 g per kg of body weight [24]. I could not find the values of the half-yearly dose of this substance (how much it should be eaten by rats so that half of the rats die from poisoning), but even a dose of 5 g per kg of body weight is not life-threatening for these rodents [21].
Today, alpha-ketoglutarate is being actively studied as an effective antidote for cyanide poisoning [25-27], as a remedy for cell damage due to lack of oxygen in injuries [28] and as a means to stimulate tissue regeneration in burns [29-31].
Alpha-ketoglutarate is already commercially available, most often in the form of creatine alpha-ketoglutarate or arginine alpha-ketoglutarate (although there are many options). Just not as a means to increase life expectancy, but as a "dietary supplement for athletes" designed to improve the results of physical training. However, I would not be in a hurry to draw conclusions about whether alpha-ketoglutarate fulfills the functions promised by suppliers. In some studies, some positive effects of arginine alpha-ketoglutarate on the effectiveness of training are found [32], in others such an effect is not detected [33]. The differences may be due to the fact that the first study tested the long-term effect of training with prolonged use of alpha-ketoglutarate (12g per day, for 8 weeks), and the second looked at the effect of the drug on the physical condition of a person shortly after ingestion. In another study, it was shown that arginine alpha-ketoglutarate has a negative effect on muscle endurance in the short term, so the expediency of taking it before training is questionable [34].
In addition, many advertised dietary supplements with alpha-ketoglutarate contain other substances, the effectiveness and safety of which is questionable. In particular, there are isolated cases of serious side effects that occurred after taking some of them [35-37]. This does not mean that alpha-ketoglutarate has side effects (although this is not excluded), but it means that you need to be careful about this kind of products. The use of pure alpha-ketoglutarate can help reduce possible risks.
Today, there are ways to significantly extend the life of some model organisms with the help of genetic engineering. Thus, the suppression of a number of Caenorhabditis elegans genes (including TOR suppression) makes it possible to achieve a fivefold increase in the lifespan of these roundworms [38]. Alas, genetic engineering is extremely difficult for already adult organisms (we do not yet know how to change the DNA in each individual cell of a multicellular one). Therefore, even if these mechanisms worked similarly in humans, they would be of interest rather as a possibility of breeding long-lived people in the distant bright future. These technologies would be of little use to people already living. The TOR inhibitor rapamycin is remarkable in that it seems to prolong life, even if they start feeding mice at the age of [39]. To be precise: at the age of 600 days, with the usual lifespan of mice in 2-3 years. But the question of drinking or not drinking rapamycin for most people is not worth it: the course would cost a person several thousand dollars a month, and theoretically you need to take it for the rest of your (possibly long) life. The constant use of alpha-ketoglutarate in reasonable quantities will cost $ 10-20 per month, and its mechanism of action seems to be similar to the mechanism of action of rapamycin, so the question "to drink or not to drink" is already relevant for the general public.
One of the problems with potentially life-prolonging drugs is that most people will have to start taking them now in order (assuming that these drugs actually work) to live to the time when their effectiveness will be definitively proven. On the other hand, additional data on possible side effects and data on life extension in experiments on mice may appear in the near future. In contrast, it is also worth noting that at one time great hopes for an increase in life expectancy were pinned on ascorbic acid, recommended twice by Nobel laureate Linus Pauling. Alas, so far the research results are extremely contradictory and do not allow us to draw an unambiguous conclusion about whether this vitamin prolongs life at least in animal models [40]. Regardless of whether alpha-ketoglutarate prolongs a person's life, it can be expected that sales of this substance will grow significantly in the near future. There will definitely be those who want to try it. Whether this will lead to deep disappointments or to an increase in life expectancy around the world and the need for a series of new pension reforms, we will find out, though not very soon.
List of literature
1. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC et al: The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 2014.
2. 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, 5(3):155-171; discussion 172.
3. Szafranski K, Mekhail K: The fine line between lifespan extension and shortening in response to caloric restriction. Nucleus 2014, 5(1):56-65.
4. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M et al: Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012, 489(7415):318-321.
5. Carey JR, Liedo P, Harshman L, Zhang Y, Muller HG, Partridge L, Wang JL: Life history response of Mediterranean fruit flies to dietary restriction. Aging cell 2002, 1(2):140-148.
6. Kasumovic MM, Brooks RC, Andrade MC: Body condition but not dietary restriction prolongs lifespan in a semelparous capital breeder. Biology letters 2009, 5(5):636-638.
7. Cooper TM, Mockett RJ, Sohal BH, Sohal RS, Orr WC: Effect of caloric restriction on life span of the housefly, Musca domestica. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2004, 18(13):1591-1593.
8. Madeo F, Tavernarakis N, Kroemer G: Can autophagy promote longevity? Nature cell biology 2010, 12(9):842-846.
9. Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L et al: Induction of autophagy by spermidine promotes longevity. Nature cell biology 2009, 11(11):1305-1314.
10. Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K, Criollo A, Galluzzi L, Malik SA, Vitale I et al: Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell death & disease 2010, 1:e10.
11. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C: A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS genetics 2008, 4(2):e24.
12. Jia K, Levine B: Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 2007, 3(6):597-599.
13. Lum JJ, DeBerardinis RJ, Thompson CB: Autophagy in metazoans: cell survival in the land of plenty. Nature reviews Molecular cell biology 2005, 6(6):439-448.
14. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ et al: Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature genetics 2004, 36(6):585-595.
15. Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I, Kobayashi H, Sato F, Sato S, Ishikawa K et al: Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy 2011, 7(2):176-187.
16. Zhou H, Luo Y, Huang S: Updates of mTOR inhibitors. Anti-cancer agents in medicinal chemistry 2010, 10(7):571-581.
17. Leontieva OV, Paszkiewicz GM, Blagosklonny MV: Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging cell 2014.
18. Fok WC, Chen Y, Bokov A, Zhang Y, Salmon AB, Diaz V, Javors M, Wood WH, 3rd, Zhang Y, Becker KG et al: Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PloS one 2014, 9(1):e83988.
19. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444(7117):337-342.
20. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF et al: Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. The journals of gerontology Series A, Biological sciences and medical sciences 2011, 66(2):191-201.
21. Elmadhun NY, Sabe AA, Lassaletta AD, Sellke FW: Alcohol Consumption Mitigates Apoptosis and Mammalian Target of Rapamycin Signaling in Myocardium. Journal of the American College of Surgeons 2014.
22. Foster DA: Reduced mortality and moderate alcohol consumption: the phospholipase D-mTOR connection. Cell cycle 2010, 9(7):1291-1294.
23. Yu X, Zhao W, Ma J, Fu X, Zhao ZJ: Beneficial and harmful effects of alcohol exposure on Caenorhabditis elegans worms. Biochemical and biophysical research communications 2011, 412(4):757-762.
24. Bhattacharya R, Gujar N, Singh P, Rao P, Vijayaraghavan R: Toxicity of alpha-ketoglutarate following 14-days repeated oral administration in Wistar rats. Cellular and molecular biology 2011, 57 Suppl:OL1543-1549.
25. Bhattacharya R, Vijayaraghavan R: Promising role of alpha-ketoglutarate in protecting against the lethal effects of cyanide. Human & experimental toxicology 2002, 21(6):297-303.
26. Bhattacharya R, Rao P, Singh P, Yadav SK, Upadhyay P, Malla S, Gujar NL, Lomash V, Pant SC: Biochemical, oxidative and histological changes caused by sub-acute oral exposure of some synthetic cyanogens in rats: Ameliorative effect of alpha-ketoglutarate. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2014, 67:201-211.
27. Hariharakrishnan J, Satpute RM, Bhattacharya R: Cyanide-induced changes in the levels of neurotransmitters in discrete brain regions of rats and their response to oral treatment with alpha-ketoglutarate. Indian journal of experimental biology 2010, 48(7):731-736.
28. Bienholz A, Petrat F, Wenzel P, Ickerott P, Weinberg JM, Witzke O, Kribben A, de Groot H, Feldkamp T: Adverse effects of alpha-ketoglutarate/malate in a rat model of acute kidney injury. American journal of physiology Renal physiology 2012, 303(1):F56-63.
29. Coudray-Lucas C, Le Bever H, Cynober L, De Bandt JP, Carsin H: Ornithine alpha-ketoglutarate improves wound healing in severe burn patients: a prospective randomized double-blind trial versus isonitrogenous controls. Critical care medicine 2000, 28(6):1772-1776.
30. Donati L, Ziegler F, Pongelli G, Signorini MS: Nutritional and clinical efficacy of ornithine alpha-ketoglutarate in severe burn patients. Clinical nutrition 1999, 18(5):307-311.
31. De Bandt JP, Coudray-Lucas C, Lioret N, Lim SK, Saizy R, Giboudeau J, Cynober L: A randomized controlled trial of the influence of the mode of enteral ornithine alpha-ketoglutarate administration in burn patients. The Journal of nutrition 1998, 128(3):563-569.
32. Campbell B, Roberts M, Kerksick C, Wilborn C, Marcello B, Taylor L, Nassar E, Leutholtz B, Bowden R, Rasmussen C et al: Pharmacokinetics, safety, and effects on exercise performance of L-arginine alpha-ketoglutarate in trained adult men. Nutrition 2006, 22(9):872-881.
33. Wax B, Kavazis AN, Webb HE, Brown SP: Acute L-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men. Journal of the International Society of Sports Nutrition 2012, 9(1):17.
34. Greer BK, Jones BT: Acute arginine supplementation fails to improve muscle endurance or affect blood pressure responses to resistance training. Journal of strength and conditioning research / National Strength & Conditioning Association 2011, 25(7):1789-1794.
35. Young C, Oladipo O, Frasier S, Putko R, Chronister S, Marovich M: Hemorrhagic stroke in young healthy male following use of sports supplement Jack3d. Military medicine 2012, 177(12):1450-1454.
36. Prosser JM, Majlesi N, Chan GM, Olsen D, Hoffman RS, Nelson LS: Adverse effects associated with arginine alpha-ketoglutarate containing supplements. Human & experimental toxicology 2009, 28(5):259-262.
37. Randhawa S, Abowd M, Sharma A, Weiss JS: Anterior segment complications of a nutritional supplement. Journal of cataract and refractive surgery 2007, 33(5):918-920.
38. Chen D, Li PW, Goldstein BA, Cai W, Thomas EL, Chen F, Hubbard AE, Melov S, Kapahi P: Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell reports 2013, 5(6):1600-1610.
39. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS et al: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460(7253):392-395.
40. Pallauf K, Bendall JK, Scheiermann C, Watschinger K, Hoffmann J, Roeder T, Rimbach G: Vitamin C and lifespan in model organisms. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2013, 58:255-263.
Portal "Eternal youth" http://vechnayamolodost.ru20.005.2014