Difficulties of finding the pill of immortality (6)
(Continued. See the beginning of the article here.)
Other potential anti-aging drugs
In recent decades, quite a lot of compounds have been identified that have a positive effect on healthy life expectancy and longevity. However, this article describes only a few key small molecules that have positive effects on a wide range of organisms, ranging from invertebrate models to mice (Figure 2).
Figure 2. Pharmacological interventions targeting age-associated signaling pathways and processes. The most representative compounds (yellow rectangles) affect various processes or signaling pathways that contribute to aging and stimulate or inhibit their activity/progression, which ensures an improvement in health and an increase in life expectancy.
Belonging to the polyamine family, spermidine is involved in many critical cellular processes, including maintaining DNA stability, transcription, translation, apoptosis, cell proliferation and growth. Polyamine levels have been shown to decrease with age in many organs. The data obtained by Pucciarelli et al. suggest that maintaining high levels of spermidine during aging can contribute to longevity. Exposure to exogenous spermidine increased the life expectancy of yeast, fruit flies, roundworms and cultured human peripheral blood mononuclears. Spermidine also reduced the age-related extinction of motor function of fruit flies. Moreover, a polyamine-rich diet reduced the severity of age-related pathology and increased the life expectancy of male Jcl:ICR mice. On the other hand, blocking the assimilation of exogenous spermidine by genetic manipulation reduced the lifespan of yeast and mice. The addition of spermidine to the feed reduced the severity of age-related oxidative damage in the body of mice and increased the resistance of yeast and fruit flies to stress. The positive effects of spermidine are mediated mainly by the induction of autophagy, which ensures controlled degradation and processing of non-functional components of the cell. Violations of autophagy prevent the positive effect of spermidine.
Aspirin, a derivative of salicylic acid, is a prototypical cyclooxygenase inhibitor and a nonsteroidal anti–inflammatory agent. Chronic use of aspirin by humans reduces mortality from various age-related diseases, including atherosclerosis, diabetes mellitus and various types of cancer. The use of aspirin by humans is also associated with increased survival in very old age. A recent study by Ayyadevara et al. It was shown that aspirin increases the expression of antioxidant genes (superoxide dismutase, catalase and glutathione-S-transferase), which leads to a decrease in the levels of endogenous reactive oxygen species and an increase in the lifespan of C.elegans. The results of another study showed that aspirin therapy increases the life expectancy of domestic crickets. Also, the data obtained by the ITP consortium showed that aspirin therapy (21 mg/kg in feed) provided an increase in the average life expectancy of male mice, but had no effect on females.
Nordihydroguyretoic acid (NDKG), also known as masoprokol, is a natural dicatechol that has antioxidant, antineoplastic and anti-inflammatory effects. It has been established that it is a powerful antagonist of the proinflammatory cytokine – tumor necrosis factor-alpha (TNF-alpha). The addition of nordihydrogvayaretic acid to the feed delayed the extinction of motor function in the mouse model of amyotrophic lateral sclerosis and significantly increased the life expectancy of animals. In the ITP consortium study, the addition of this compound to feed at a dose of 2500 mg/kg increased the life expectancy of male UM-HET3 mice. However, this effect did not apply to females. One possible explanation for this is the fact that the life expectancy of male control groups in two of the three research centers was shorter for some reason. In order to fully understand this issue, further research is needed.
Acarbose is an inhibitor of alpha-glucosidase – intestinal enzymes that convert complex carbohydrates into simple sugars to facilitate their absorption. Acarbose therapy disrupts the digestion of carbohydrates and inhibits the normal increase in blood glucose levels after meals. Researchers of the ITP consortium found that acarbose (1000 mg/kg in feed) induced a significant increase in the average and maximum life expectancy of both sexes, but this effect was significantly more pronounced in males. Acarbose therapy increased the average life expectancy of males by 22% (p<0.0001), whereas for females – by only 5% (p=0.01). For maximum life expectancy, these indicators were 11% (p<0.001) and 9% (p=0.001), respectively. In mice treated with acarbose, there was a significant increase in the level of fibroblast growth factor-21 in the blood serum, as well as a moderate decrease in the level of insulin-like growth factor-1. Fibroblast growth factor-21 has important roles in regulating glucose and fat levels, as well as maintaining energy homeostasis. Transgenic mice with increased secretion of this factor are characterized by an increase in both average and maximum life expectancy, possibly due to suppression of the signaling pathway mediated by insulin/insulin-dependent growth factor-1.
17-alpha-estradiol is a non-feminizing estrogen with a reduced ability to bind to estrogen receptors. It inhibits the activity of the enzyme 5-alpha-reductase, responsible for the conversion of testosterone into a more powerful androgen dihydrotestosterone, which has a higher affinity for androgen receptors than testosterone. 17-alpha-estradiol has a neuroprotective effect in cerebral ischemia, Parkinson's disease and diseases of the cardiovascular system. Recently, its ability to reduce the severity of metabolic and inflammatory disorders in old mice has been established by reducing calories consumed and changes in nutrient-registering and inflammatory signaling pathways in visceral white adipose tissue without inducing feminization. In the ITP consortium studies, the use of 17-alpha-estradiol (4.8 mg/kg in feed) from the age of 10 months increased the median life expectancy of males by 12% without a pronounced effect on the maximum life expectancy and life expectancy of females. Similar to the case with nordihydrogvairetoic acid, this difference may be due to the shorter life expectancy of males in the control group and requires further research.
Beta-adrenergic receptor antagonists bind to beta-adrenergic receptors (beta-1, 2 and 3) and block the activity of endogenous catecholamines epinephrine and norepinephrine. Increased activity of beta-adrenergic receptors can accelerate the development of age-related pathologies and increase the mortality of genetically modified mice. Also, the chronic use of agonists of these receptors leads to an increase in mortality and morbidity. In humans, increased production of beta-2-adrenergic receptors due to specific genetic variants is associated with a decrease in life expectancy. On the other hand, the addition of beta-adrenergic receptor blockers metoprolol (1.1 g/kg of feed) and nebivolol (0.27 g/kg of feed) to the feed increased the median life expectancy of male mice of the C3B6F1 line by 10% (p=0.016) and 6.4% (p=0.023), respectively, without affecting the use of and food disposal. However, the maximum life expectancy did not change. Also, therapy with metoprolol (mg/ml of food) and nebivolol (100 mcg/ml of food) increased the median life expectancy of fruit flies by 23% (p≤0.0001) and 15% (p≤0.001), respectively, without affecting food intake and mobility. Similarly to beta-adrenergic receptor blockers, doxazosin, an antagonist of beta-1-adrenergic receptor blockers, inhibits the binding of norepinephrine to beta-1-adrenergic receptors on the membrane of vascular epithelial smooth muscle cells and increases the lifespan of C.elegans by 15%. Given that some of these agents are routinely used in the clinic as antihypertensive drugs and their safety profiles are well described, these drugs can be considered as potential anti-aging agents.
Antioxidants, compounds that provide resistance to oxidative stress, have also in some cases demonstrated the ability to increase life expectancy, especially in lower organisms. Dietary supplements containing glutathione precursor N-acetylcysteine increased resistance to oxidative stress, thermal stress and ultraviolet radiation, and also significantly increase both the average and maximum lifespan of C.elegans and drosophila nematodes. Moreover, therapy with EUK-134 and EUK-8 – synthetic small molecules that are catalytic mimetics of superoxide dismutase and catalase – in one of the studies increased the lifespan of C.elegans, while several other groups did not observe similar effects. Therapy of a heterosexual group of C57BL/6 mice with another carboxyfullerene superoxide dismutase mimetic (10 mg/kg/day) it reduced the severity of age-related oxidative stress and superoxide production in mitochondria, and also moderately increased average life expectancy. Also, oral administration of carboxyfullerene solution (4 mg/kg/day) in olive oil to male Wistar rats provided an increase in median life expectancy by 90% compared to the control group animals receiving water. In addition, a number of other studies have demonstrated the ability of antioxidants to increase the lifespan of many organisms.
In addition, there are a large number of publications that, on the contrary, do not support the idea that dietary supplements containing antioxidants generally increase the life expectancy of healthy animals and humans. Dietary supplements containing vitamin E (alpha-tocopherol) or vitamin C (ascorbic acid) significantly reduce the life expectancy of short-tailed voles. Similarly, the addition of nutraceutical composition enriched with antioxidants to the feed of male mice did not provide an increase in life expectancy. Moreover, in a recent review by Bjelakovic et al. It is noted that a systematic and meta-analysis of the results of a large number of clinical studies devoted to the study of the effect of dietary supplements containing various antioxidants (beta-carotene, vitamin A, vitamin C, vitamin E and selenium) on humans has not revealed any general beneficial effects. Instead, in some cases, the use of these agents has been associated with increased mortality. The detrimental effect of antioxidant supplements may be due to inadequate suppression of normal signaling functions performed by reactive oxygen species in cells, including in critical cell populations such as stem cells.
Continuation: Senolytic drugs
Portal "Eternal youth" http://vechnayamolodost.ru
12.09.2016