Difficulties of finding the pill of immortality (5)

Resveratrol and other sirtuin-activating compounds

(Continued. See the beginning of the article here.)

Sirtuins are a family of NAD+-dependent deacetylases/ADP-ribosyltransferases/deacylases involved in the regulation of reactions to nutrients and other aspects of cell biology. Overexpression of Sir2, the most important member of the sirtuin family, increases the replicative lifespan of budding yeast Saccharomyces cerevisiae by suppressing the accumulation of extrachromosomal rDNA plasmids, leading to the movement of the intact proteome into the daughter cell, which, in turn, forcibly triggers the silencing of subtelomeric DNA and possibly other mechanisms. Some, but not all, researchers have demonstrated that overexpression of sirtuins in worms and fruit flies moderately increases the lifespan of these organisms. Interestingly, Sir-2.1, which is a homologue of Sir2, can increase the lifespan of C.elegans regardless of deacetylase activity. In mammals, the closest homologue of Sir2 is SIRT1. Overexpression of this protein in the brain (but not in the whole body) increases life expectancy, probably by activating the function of the hypothalamus in the aging process. Global overexpression of another sirtuin, SIRT6, increases the life expectancy of exclusively male mice, at least partially by preventing the development of lung cancer, which is the main cause of death of males of the mouse line used in the work. Overexpression of SIRT2 stabilizes the levels of the BubR1 protein regulating the mitosis process in progeroid (premature aging model) mice of the BubR1H/H line and increases both the median and maximum life expectancy of males of this line. However, researchers do not have data on the potential effects of chronic SIRT2 overexpression on wild-type animals. More and more new scientific evidence suggests that NAD+ levels may decrease with aging, disrupting the activity of sirtuins, and that the ability of sirtuin overexpression to increase life expectancy partially counteracts this effect by maintaining the functioning of sirtuins against the background of a reduction in the pool of NAD+ in aging organisms.

Resveratrol and some other polyphenols were initially identified as Sir2/SIRT1 activators that increase the average and maximum lifespan of yeast. It should be noted that resveratrol has a very diverse functionally important effects on many cellular targets. Effects of resveratrol on nematodes and fruit flies (100 mmol for worms and 10-100 mmol for fruit flies) it also increased the life expectancy depending on the availability of functional Sir-2.1 or dSir2, respectively. However, according to the results of the study by Bass et al., resveratrol therapy (1-1000 mmol) did not have significant effects on the life expectancy of fruit flies. In the same study, it was shown that resveratrol therapy at a dose of 100 mmol induced only a small and sporadic increase in the life expectancy of both wild-type nematodes and mutant sir-2.1 models. Based on this, it can be assumed that the observed increase in life expectancy under the action of resveratrol may be independent of Sir-2.1. Resveratrol protects nematodes It protects against oxidative stress, radiation-induced damage and amyloid toxicity, and also protects fruit flies from radiation exposure. Resveratrol therapy increases the average and maximum life expectancy of honey bees and short-lived fish Nothobranchius furzeri and Nothobranchius guentheri.

There is evidence that resveratrol and other sirtuin-activating compounds allosterically activate Sir2/SIRT1. However, other researchers have found that these compounds are not able to enhance the activity of SIRT1 against native peptides in vitro. In this context, it has been suggested that the increased activity of SIRT1 induced by resveratrol depends on the presence of non-native fluorophores conjugated with the peptide sequence originally used for screening of SIRT1 activators. At the same time, according to recently obtained data, resveratrol and other sirtuin-activating compounds bind directly to SIRT1 and allosterically enhance its deacetylase activity against unlabeled peptide substrates. In addition, the ability of resveratrol to stimulate NAD+-dependent activation of poly has been demonstrated by inhibiting the catalytic activity of the human enzyme tyrosyl transfer-RNA (tRNA) synthetase (TyrRS).(ADP-ribose)polymerase (PARP1), which plays important roles in damage repair and DNA transcription.

Resveratrol protects mice from a number of damaging effects of a high-fat/calorie diet, having a pronounced suppressive effect on the growth and development of many types of cancer, as well as delaying or preventing the development of Alzheimer's disease. Moreover, resveratrol protects rodents and humans from type 1 and type 2 diabetes mellitus and diseases of the cardiovascular system, and also has anti-inflammatory and antiviral activity. The addition of resveratrol to the feed (at a dose of 0.016–0.1% of the total feed weight or 25 mg/ kg/day) increased the life expectancy of mouse models of obesity, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Resveratrol therapy (2-8 mg/kg/day) increased the lifespan of mice exposed to lipopolysaccharide and reduced catecholamine-induced mortality in obese rats (20 mg/kg/day). Moreover, resveratrol (10 mg/ml, intraperitoneal injection) increased the survival of a mouse model of sepsis-induced kidney damage and restored renal microcirculation. Adding resveratrol to feed (18 mg/kg/day) it also improved the survival of the rat model of hypertension. The important fact is that the effect of resveratrol (100-1200 mg / kg / day in food) it does not increase the lifespan of mice that consume normal food. Resveratrol-containing supplements induce changes in gene expression in some mouse tissues similar to changes associated with a low-calorie diet.

Taking a supplement with resveratrol (150 mg / day) for 30 days causes metabolic changes in obese men, including a decrease in the metabolic rate at rest and during sleep, intrahepatic lipid content, blood glucose concentration, levels of inflammatory markers and systolic blood pressure. Increased AMPK activity, increased levels of SIRT1 and PGC-1-alpha proteins, as well as improved mitochondrial fatty acid oxidation were recorded in the skeletal muscles of people who used resveratrol. On the contrary, taking resveratrol (75 mg/day) for 12 weeks by non-obese post-menopausal women with normal glucose tolerance did not cause any recorded changes in body composition, insulin sensitivity, resting metabolic rate, plasma lipid levels and inflammatory markers. Moreover, the use of resveratrol had no effect on its putative molecular targets, including AMPK, SIRT1, NAMPT and PPARGC1A, neither in skeletal muscles nor in adipose tissue.

Recently conducted by Cai et al. the study demonstrated a nonlinear dose-dependent protective effect on humans and mice. Against the background of a fat-rich diet, taking low doses of resveratrol (~0.07 mg / kg / day) more effectively reduced the number of adenomas and the overall tumor load in Apcmin mice, which is a model of intestinal carcinogenesis, than taking high doses (14 mg / kg / day). Interestingly, female mice receiving a low dose of resveratrol showed a significantly more pronounced increase in the expression and activation of AMPK in the intestinal mucosa than animals from the group receiving a higher dosage. Accordingly, human colon tissue samples exposed to low dietary concentrations of resveratrol (0.01-0.1 mmol) ex vivo demonstrated rapid activation of AMPK and increased autophagy activity at low concentrations and a less pronounced effect or its complete absence when exposed to higher doses (1-10 mmol). This unusual effect may help explain the conflicting data on the effects of resveratrol on humans. In the future, when planning clinical trials using resveratrol, special attention should be paid to the dosage and serum levels of the drug, as well as a thorough assessment of the effects of resveratrol on its intended molecular targets.

Other artificially synthesized sirtuin-activating compounds have also demonstrated the ability to increase the lifespan and healthy lifespan of mice. Thus, SRT1720 (100 mg/kg/day) increased the life expectancy of adult male mice of the C57BL/6J line, kept on a normal diet, by 8.8% (p=0.096) and by 21.7% (p=0.0193) – kept on a fat-rich diet, without increasing the maximum life expectancy in both cases. SRT1720 therapy improved the physiological parameters of animals receiving fat-rich feed, reducing the severity of fatty liver degeneration, increasing insulin sensitivity, improving motor activity, and also inducing the formation of a gene expression profile similar to the profile associated with the use of normal feed. The addition of SRT1720 to the feed inhibited the expression of proinflammatory genes in the liver and muscle tissue of mice receiving standard feed and delayed the development of age-related metabolic disease. Similarly, the addition of SRT2104 (100 mg/kg) to the feed increased both the average and maximum life expectancy of male mice of the C57BL/6J line receiving normal food by 9.7% (p<0.05) and 4.9% (p<0.001), respectively, and increased the sensitivity of their tissues to insulin, as well as coordination of movements with simultaneous suppression of inflammation. Short-term therapy with SRT2104 ensured the preservation of bone and muscle mass in an experimental model of atrophy. These data indicate that resveratrol and other sirtuin-activating compounds can have a positive effect on health, especially against the background of consumption of fat-rich foods, and some of these compounds can provide a moderate increase in life expectancy when consuming normal food. However, for a more detailed assessment of their effect on the longevity of females and mice of other lines, further research is required. In this regard, there is currently great interest in evaluating the effects of NAD+ precursors as drugs for the treatment of metabolic disease and potential anti-aging agents.

Continued: Other potential Anti-aging Drugs