How to check "pills for old age": drugs that slow down aging
Checking the effectiveness of aging-slowing drugs by treating age-related diseases
(continuation, beginning of the article – Checking the effectiveness of aging-slowing drugs by treating age-related diseases).
Comparison of drugs specific to certain diseases and drugs that slow down agingSlowing down the aging process would delay the development of age-related diseases.
If the drug is effective against one specific disease, it cannot be considered to slow down aging. Currently used drugs do not slow down aging. For example, insulin compensates for diabetes, but does not cure cancer. Conversely, chemotherapy can destroy the tumor, but does not cure diabetes. Thus, neither chemotherapy nor insulin is an anti-aging agent. Moreover, both insulin and chemotherapy can accelerate the aging process.
MetforminThe reason for the development of age-associated type 2 diabetes is insulin resistance.
Insulin therapy does not eliminate the cause, it only compensates for resistance. Unlike insulin, metformin, an antidiabetic drug for oral administration, restores insulin sensitivity in type 2 diabetes. It should also be noted that metformin reduces the likelihood of developing breast cancer [7, 8]. Metoformin is also considered as a cancer treatment agent [9] and is able to suppress the development of atherosclerosis in mice with diabetes [10]. Metformin is used to induce ovulation in patients with polycystic ovarian syndrome (PCOS). Metformin therapy at a dose of 1,700 mg/day for six months increased the fertility rates of women with PCOS and lack of ovulation [11, 12]. Given the described effects on infertility, type 2 diabetes, cancer and atherosclerosis, it is likely that metformin is able to slow down the aging process. It is known that it increases the life expectancy of rodents [13-15].
Low-calorie dietA low-calorie diet (ND) increases the life expectancy of various organisms, ranging from yeast and worms to rodents and possibly humans [16-18].
If we didn't know that ND slows down the aging process, how could we come to this conclusion based solely on clinical data? Unlimited food consumption leads to obesity associated with diabetes, atherosclerosis, thrombosis, hypertension, cancer (especially breast, prostate and colon cancer), coronary heart disease, stroke, osteoporosis and Alzheimer's disease [19-25]. In other words, the unlimited consumption of food by humans (or, if the reader wishes, by rodents) accelerates the development of most, if not all, age-related diseases. Thus, we can conclude that ND delays the development of all diseases of aging. This fact indicates that ND is a means of slowing down aging.
From metformin and a low-calorie diet to rapamycinMany factors, including insulin, glucose, and amino acids, activate the protein-mediated TOR (rapamycin target) mechanism of nutrient recognition.
When the TOR-mediated mechanism is activated, it reduces the amount of insulin receptor substrate (IRS1/2) by means of the protein kinase S6K1 (S6-kinase) specifically associated with TOR, which leads to the development of insulin resistance (Fig. 1). As shown in Figure 1, metformin indirectly (by activating the enzyme AMP-dependent kinase) suppresses the activity of TOR, thus restoring the sensitivity of cells to insulin [26].
A low-calorie diet reduces the levels of nutrients and insulin in the body, thus inactivating TOR (Fig. 1). It is possible that the aging-slowing effects of ND and metformin are due to the suppression of the activity of the TOR-mediated signaling mechanism. Like ND, rapamycin reduces the size of fat cells and body weight of the animal. When rats (at the age of 15 weeks) used rapamycin at a dose of 1 mg / kg 3 times a week for 12 weeks, their weight significantly decreased. The average diameter of adipocytes decreased from 36 to 25 microns. At the end of the study, the average body weight of rats treated with rapamycin was 356 g instead of 507 g, despite eating comparable amounts of food [27]. Thus, rapamycin mimics the effects of ND. ND can also increase life expectancy by activating sirtuins. It is possible that sirtuins, AMP-dependent kinase and mammalian TOR are components of the same molecular system [28].
Suppression of the activity of the TOR-mediated mechanism using genetic methods slows down the aging process of various organisms, including yeast, worms, flies and mice [29-33]. If inhibition of the TOR-mediated mechanism by genetic methods slows down the aging process, then rapamycin, which is a drug that suppresses the activity of TOR, should also slow down the aging process. If used for any indication, even not related to the treatment of age-related diseases (for example, kidney transplantation), the aging-slowing drug should slow down the development of age-related diseases such as cancer, osteoporosis and atherosclerosis. Rapamycin is already used in the treatment of patients who have undergone kidney transplantation.
Figure 1. Intracellular signaling mechanism mediated by TOR
Nutrients, growth factors (GF) and insulin activate the TOR-mediated signaling mechanism,
involved in the processes of aging and the development of age-related diseases.
Other genetic and environmental factors (e.g. smoking)
contribute to the development of certain age-related diseases.
All three potentially aging-slowing agents (metformin, low-calorie diet and rapamycin)
they suppress the TOR-mediated signaling mechanism.
Retrospective analysis of rapamycin use in clinical practiceRapamycin has been used in kidney transplantation for several years.
Given that rapamycin was considered as an immunosuppressive drug (not as a drug that slows down aging), it was expected that taking it would increase the likelihood of developing cancer.
Unexpectedly, it turned out that rapamycin prevented the development of cancer and even cured pre-existing tumors and Kaposi's sarcoma in patients who underwent kidney transplantation [34-44]. Moreover, an analogue of rapamycin – temsirolimus (tyrosine kinase inhibitor) has recently been approved for use as a cancer treatment agent [45]. The TOR inhibitor everolimus also significantly slowed the development of tumors in transgenic mice predisposed to the spontaneous occurrence of ovarian carcinomas [46]. Will TOR inhibitors increase the lifespan of transgenic mice? Given that rapamycin delays the development of cancer, it should increase the life expectancy of mice predisposed to the development of cancer, which otherwise would have died from malignant tumors. Of course, people die because of various age-related diseases, and not from one particular disease. For a significant increase in life expectancy, rapamycin should delay the development of most of them.
In patients who have undergone kidney transplantation, rapamycin increases the concentration of lipoproteins in the blood [47]. This is considered a negative side effect. However, this occurs as a result of fat mobilization from adipose tissue (lipolysis) [48, 49]. A similar effect is observed when fasting or limiting the caloric content of the diet. At the same time, it is known that a low-calorie diet increases life expectancy. Moreover, rapamycin reduces the accumulation of cholesterol in the arterial walls [50, 51]. Thus, both lipolysis of adipose tissue and a decrease in the absorption of cholesterol by tissues contribute to the appearance of high levels of lipids in the blood (Fig. 2).
Figure 2. Reinterpretation of the hyperlipidemic side effect of rapamycin
Rapamycin activates adipose tissue lipase, thus mobilizing adipose tissue lipids (lipolysis).
This effect mimics the effects of starvation. Rapamycin also inhibits lipoprotein lipase,
thereby preventing the utilization of lipids by adipose tissue and blocking their absorption by the arterial wall.
This leads to an increase in the concentration of lipids in the blood.
Despite hypercholesterolemia, rapamycin prevents the development of atherosclerosis in animals [52]. In experiments on animal models, systemic administration of rapamycin suppressed thickening of the neointima (fibrous membrane formed on the inner surface of the vascular prosthesis as a result of degeneration of the endothelium sprouting into it) and slowed down the progression of atherosclerosis in mice without apolipoprotein E with high blood cholesterol [53-55]. In patients with atherosclerosis of the coronary arteries, oral administration of rapamycin prevents repeated stenosis after implantation of metal stents [56]. A clinical case is described in which the transfer of a patient to receive everolimus (an analogue of rapamycin) led to a decrease in blood pressure [57]. Two years after kidney transplantation, the body mass index in patients of the therapeutic group taking rapamycin was significantly lower than in patients taking cyclosporine [27]
Ending: In search of a panacea.
Portal "Eternal youth" http://vechnayamolodost.ru
11.10.2011