The genetic source of youth
By inactivating a gene involved in an important biochemical signaling mechanism, University College London researchers, working under the guidance of Professor of endocrinology Dominic Withers, were able to reproduce the well-known results of caloric restriction of the diet, significantly prolonging the life and improving the health of mice. The work, the results of which are published in the on-line version of the journal Science in the article "Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span", indicate the existence of a possible therapeutic target for combating numerous human diseases associated with aging.
It has been known for a long time that limiting the caloric content of the diet increases life expectancy and reduces the likelihood of age-related diseases in a wide range of organisms, ranging from yeast and roundworms to primates. However, the exact mechanisms by which a nutritionally balanced but strictly calorie-restricted diet leads to such results are not completely clear. According to the results of several recent studies, a certain signaling mechanism mediated by the TOR protein (from the English "target of rapamycin" – a target for rapamycin) may play a major role in this. This mechanism works as a kind of food detector involved in the regulation of metabolic reactions of the body to the availability of nutrients.
Withers and colleagues noted that young mice with a non-functional version of the protein S6 kinase-1 enzyme (protein S6 kinase 1, S6K1), which is normally activated directly by the TOR protein, are very similar to animals kept on a low-calorie diet: they are leaner and their cells are more sensitive to insulin than in ordinary mice.
The authors decided to find out what happens to such animals in adulthood and whether they live longer than ordinary mice.
To do this, they bred two large populations of "knocked out" mice that did not have the functional S6K1 gene. One of the groups was not subjected to any manipulation, and the animals included in it died of old age, providing information about their natural life expectancy. The animals of the second group were subjected to intensive testing for cognitive and motor functions, as well as for the state of metabolism.
The researchers were particularly impressed by the results obtained in the study of female mice. Genetically modified females lived significantly longer than normal animals. At the age of 600 days – the mouse equivalent of the average human age – they performed excellently on motor activity tests, surpassing ordinary mice in performing tasks that require the ability to maintain balance, strength and coordination of movements. They were also more curious and eager to study the environment, which indicates more developed cognitive abilities. Physiological tests also revealed a better state of health: the knocked-out mice had stronger bones, higher insulin sensitivity and more effective immunity.
(The picture on the left shows a mouse with the S6K1 gene knocked out, on the right – a normal mouse from the control group.)
The results of the S6K1 knockout were similar to the effects of caloric restriction, although less pronounced. Female mice lacking the S6K1 protein lived 20% longer than normal animals, while the maximum increase in life expectancy with calorie restriction can reach 50%. This means that inactivation of protein-S6-kinase-1 does not have all the effects of calorie restriction in the diet, but has a similar effect on health.
Unlike females, males did not have a longer life span, but in old age they were not inferior to females in physical form.
The new data develop the results of a study published in July, according to which the drug rapamycin, blocking the same mechanism by inhibiting the TOR protein, prolongs the life of mice. Despite the pronounced positive effect of rapamycin on life expectancy and health, the therapeutic potential of the drug is limited by its powerful immunosuppressive effect. (Rapamycin is currently used to prevent rejection of transplanted organs.) A direct effect on S6K1 that does not affect the TOR protein, which interacts with a number of other proteins, will avoid this dangerous side effect.
The authors believe that a promising potential therapeutic target is the AMPK protein, which is also a link in the TOR–mediated mechanism, but comes into play later than S6K1. AMPK is especially interesting because it is activated by metformin, a drug widely used for the treatment of type 2 diabetes. According to Withers, this means that in a couple of years it will be possible to start planning clinical trials of metformin as a means of preventing the development of age-related diseases.
In the near future, the authors plan to study the details of the relationship between the TOR-mediated signaling mechanism and aging. The results already obtained by them and other researchers indicate that the impact on this mechanism has pronounced effects on the aging processes in animals of various species and even types – from roundworms to mammals. It is very likely that the effects of calorie restriction of the diet are partly mediated by the TOR system, but at the moment it is unclear how.
The TOR-mediated mechanism is known as a kind of "fuel sensor" that reacts to the availability of nutrients by changing the efficiency of protein synthesis. For example, when there is a lack of food, it reduces the activity of synthesis. There is one still purely theoretical hypothesis, according to which, with the general suppression of protein production, the synthesis of a small number of specific proteins is activated, the identification of the functions of which may provide us with new information about the mechanisms of aging.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Technology Review: Genetic Fountain of Youth.
07.10.2009