Difficulties of finding the pill of immortality (3)

Mammalian Rapamycin Target Protein Inhibitor (mTOR)

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

mTOR is a serine/threonine kinase preserved in the course of evolution, registering the availability of nutrients, growth factors and external stress and reacting to them. This enzyme plays a key role in stimulating the growth process. In multicellular eukaryotes, mTOR exists as part of two distinct multi-protein complexes: mTORC1 and mTORC2, differing in association with the regulatory protein mTOR (RAPTOR) and rapamycin-insensitive companion mTOR (RICTOR), respectively. Rapamycin forms a complex with the protein FKBP12, which binds to mTORC1 and inhibits its activity. The important point is that chronic rapamycin therapy also suppresses the activity of mTORC. The activity of mTORC1 is regulated by nutrients (glucose and amino acids), cytokines, hormones (insulin or insulin-like growth factor-1), energy (ATP levels) and oxidative stress through signaling mechanisms mediated by phosphoinositol-3-kinase (PI3K), protein kinase B (AKT) and AMP-dependent kinase (AMPK). The key mediators of the lower links of the mTORC1-mediated signaling pathway are mechanisms that regulate cell growth, proliferation, stress response, and autophagy. Therefore, mTORC1 plays a key role in integrating the growth and maintenance of cell function with nutrient availability, hormonal signals and other environmental stimuli.

A number of studies have established a relationship between the mTORC-mediated signaling pathway and the longevity of a whole spectrum of organisms, ranging from yeast to mammals. Inhibition of mTORC signals by genetic and pharmacological methods increases the lifespan of yeast, nematodes, fruit flies and mice. Similarly, deletion of the mouse gene encoding the effector of the lower stages of the mTORC-mediated signaling mechanism S6-kinase increases oxidative metabolism, protects against the development of age-related and diet-induced obesity, and also increases the lifespan of females. Accordingly, the increased activity of the mTORC1 4E-BP1 target in skeletal muscles leads to an increase in oxidative metabolism and protects mice from diet- and age-induced metabolic disorders.

In a landmark study of the NIA's Interventions Testing Program (ITP), it was demonstrated that therapy of genetically heterogeneous mice with the mTORC inhibitor rapamycin (at a dose of 14 mg/kg of food; 2.24 mg/kg of body weight/day), started at the age of 9 or 20 months, increased the life expectancy of both sexes. Follow-up showed that rapamycin-induced increase in life expectancy is dose- and sex-dependent. With the indicated rapamycin content in the feed, female mice showed a more pronounced increase in life expectancy than males, which correlated with higher levels of rapamycin in the blood of females compared to males. Rapamycin therapy induced completely different changes in gene expression in females and males, which indicates the existence of sex-specific reactions to mTORC inhibition. Moreover, the expression profiles of xenobiotic-metabolizing enzymes in the liver of mice treated with rapamycin (14 mg/kg of feed) were very different from the expression profiles of 12-month-old mice kept on a low-calorie diet. In fact, a low-calorie diet less effectively increases life expectancy at the beginning of exposure in the later stages of life, whereas rapamycin therapy has its effect on mice even at the beginning in middle age. It is extremely important that the rapamycin-induced increase in life expectancy is observed in mice with different genotypes.

The mechanisms of increasing life expectancy under the action of rapamycin are a hotly debated topic in the field of aging biology. Rapamycin has antineoplastic properties, and cancer is the main cause of death in most mouse lines showing a rapamycin-mediated increase in life expectancy. In this context, a plausible explanation for the increased lifespan of mice under the action of rapamycin is the ability of the drug to suppress the appearance and/or aggressiveness of lethal tumors. However, some researchers have demonstrated that rapamycin, in addition to neoplasia, also inhibits age-related phenotypes, which indicates a high probability that the drug has broader anti-aging effects. On the contrary, according to the results of a recent very detailed study by Neff et al., the effect of rapamycin on age-related phenotypes is quite limited in itself. In this regard, contradictory observations have been made regarding the effect of rapamycin therapy on mouse models of Alzheimer's disease. Long-term therapy with rapamycin provided behavioral improvements in such models and induced an autophagy-mediated decrease in beta-amyloid and hyperphosphorylated tau protein levels. In other studies, rapamycin, on the contrary, stimulated the production of beta-amyloid and caused an increase in beta-amyloid-induced cell death.

Rapamycin has serious side effects that may limit the possibilities of its long-term use as an anti-aging therapy, especially with regard to metabolic dysfunction, cataracts and testicular atrophy. Most importantly, due to the immunomodulatory effects of mTOR inhibitors, the clinical use of rapamycin-like drugs such as everolimus/RAD001 is associated with a higher incidence of infections in patients with diseases such as cancer and tuberous sclerosis complex. The results of a recent study, on the contrary, demonstrated that the short-term use of everolimus/RAD001 by healthy elderly people increased the immune response to influenza vaccination with moderate side effects. Reduced response to influenza vaccination is an important clinical problem for the elderly. These data suggest that periodic or short-term administration of rapamycin or other mTOR inhibitors can suppress certain functionally important effects of aging, such as a weak response to immunization, without the negative consequences associated with the chronic use of such drugs. The results of recent work on mice support this hypothesis, confirming the ability of periodic administration of rapamycin to minimize the manifestations of metabolic dysfunction in mice, maintaining chronic suppression of mTOR in adipose tissue, but not in other tissues. It would be very interesting to evaluate the effects of such a periodic protocol on a wide range of age phenotypes and life expectancy.

Continuation: Metformin and other biguanidines