09 November 2015

"Underfed" primates

By yeast and mice?

Elena Veshnyakovskaya, "Science and Life" No. 5, 2015Published on the website "Elements" 

It has long been known that calorie restriction significantly increases the lifespan of microorganisms and rodents (more precisely, their individual tissues). But whether a person is following their path in this matter still remains one of the main intrigues of the biomolecular science of aging. Two recent large-scale studies on primates have come to contradictory results, but they do not exclude that "underfed" primates may still live longer. And much better – for sure.

The molecular platform of aging is the "energy factories" of a living cell – mitochondria. These factories represent a "system within a system" or a "fortress within a fortress" – intracellular structures of "special purpose" with their own membrane and their own, in a sense, autonomous genetic resources.

"Energy conversion in mitochondria, phosphorylation, takes place directly on the membranes and thanks to the membranes," says Norbert Dencher, professor at the Faculty of Chemistry at Darmstadt Technical University (Germany). – If you work, no matter using your brain or muscles, your body produces from 65 to 75 kg of energy every day in the form of ATP (abbreviated as adenosine triphosphate). At a particular moment, there is always about 100 g of ATP in the body, but its metabolic turnover is rapid: every second it is consumed and formed again. Moreover, about 20% of ATP is used for brain work. It is the most important energy currency in the world, and 95% of it is formed in mitochondria."

Age-related changes in mitochondria are associated with the decline of their function as power stations. The fact is that the very work of such a "station" contains a mechanism of its own destruction: the by–product of energy production and consumption in the cell turns out to be superoxide - oxygen in a highly active form, a kind of those very free radicals that the broadest segments of the population know about today or think they know about. Superoxide, before it is neutralized naturally, may have time to attack the surrounding molecular structures. For many of the most complex molecular signaling chains that ensure the vital activity of the cell, such an attack does not pass without a trace, triggering a variety of vicious circles of functional disorders, including an increase in the number of free radicals. Self-reproducing "technical failures" accumulate, tissues begin to lose functionality dramatically. Old age comes.

The only candidate for outside interference in this genetically determined process is still an energy starvation ration for cells and tissues: limiting the amount of calories available to the cell.

"Our experiments show that it is precisely the restriction of the caloric content of the diet of experimental animals, provided that they receive all the other nutrients, that leads to an increase in life expectancy in all organisms that have been studied so far, from such simple ones as bacteria or fungi, nematodes or drosophila, to our main object – rat tissues: their liver, brain, and so on," says Professor Dencher. – In studies on simple animals, with a reduction in the energy received from food by 30-40%, their life expectancy increased by almost 50%. However, the question of whether this will work for human tissues remains open for now."

More than 30 years ago, Professor Don Ingram of the American National Institute of Aging began a multi-year experiment to establish how a low-calorie diet affects the lifespan of primates. In 2012, the journal Nature finally published the results of this unprecedented study in terms of duration. They were discouraging: the life expectancy of the control group of monkeys and the experimental group, which received half as many calories, turned out to be almost the same. The society sighed in disappointment, and the skeptics asked: "Did you really expect yeast and primates to age according to the same scenario?" – and even created several convincing evolutionary explanations why this could not be.

The general public, however, with its inherent inertia continued to hope and lose weight. As it turned out two years later, not without reason.

Last year, the journal Nature Communications published the results of another experiment. Professor Anderson and colleagues from the University of Wisconsin completed a similar and also long-term study on rhesus monkeys with a much more optimistic result. According to him, aging primates still go the way of mushrooms and yeast. In the experimental group, which received a diet 30% less caloric than the control group, which ate as much as it wanted, the risk of diabetes and cardiac diseases, usually accompanying aging, was about 3 times lower, and, accordingly, mortality among the "underfed" was lower.

The contradictory results of the experimenters are of great interest to researchers. Among the possible reasons for the discrepancy is the difference in approaches to the diet of experimental animals, that is, to the "technique of under-feeding" itself.

"An adequate indicator of energy consumption is not the volume of feed, but the weight of the animal," explains Professor Dencher. – In experimental "underfed" groups, animals weigh on average 30-40% less than in the control group. Then it is not the maximum life expectancy that is measured, because there are not very many long-lived individuals, but the median survival rate: the time elapsed before the extinction of half of the individuals in the group. In our laboratory, we studied calorie restriction scenarios throughout our lives. For example, if the object was rats, then during the first 6-8 weeks of development they received food as usual, ad libitum, that is, they ate as much as they wanted. Then the control group continued in the same spirit, and the other received a diet reduced by half: either they were given half as much food every day as the control group, or – this is a more common way in such studies – the experimental group was fed every other day."

The point may be, according to the authors of the Wisconsin experiment, that they started working with young, but adult macaques: at the age of 7 to 14 years. Everything was already empirically known about the caloric content of their diet ad libitum. It was this actual amount of calories that was then reduced by 30% for the experimental group. As for the project of the National Institute of Aging, a standard diet developed by the National Academy of Sciences was adopted there for 100%, possibly already implying a reduced calorie content. The co-head of the Wisconsin project, Ricky Coleman, drew attention to the fact that throughout the study, individuals of the alleged "pre-fed group" in the experiment of the Institute of Aging had a significantly reduced body weight compared to the indicators of full-fed macaques in Wisconsin.

Competing research teams are now doomed to a joint interpretation of their conditions and results, because these results are likely to remain the only available for a long time. An experiment of this scale is so complex and expensive that new ones cannot be expected in the near future.

"The purpose of such studies is not limited to a quantitative increase in life expectancy," Professor Dencher is sure. – At the moment, society as a whole is already living much longer, but people spend half of their extra time in hospitals. It is much more important both for a person and for society to increase the duration of a healthy, high–quality life. And here calorie restriction demonstrates its main advantage. In primates, as studies on monkeys show, the absolute life expectancy in conditions of calorie restriction of the diet may remain the same, but the proportion of its high–quality, healthy segment will increase. All studies on monkeys demonstrate the best indicators of overall health and the growth of a healthy segment in the "underfed"."

Biologists are extremely cautious about the alleged connection between calorie restriction and an increase in life expectancy. Firstly, it is difficult to raise starvation to the shield in our imperfect world, where millions of people in undeveloped countries are exposed to it without alternative and involuntarily with dramatic epidemiological consequences. The mass audience is unlikely to hear well the reservation that the restriction applies exclusively to calories, and not to proteins, vitamins and vital trace elements. Secondly, the very lack of "human" data does not allow a responsible scientist to connect one with the other. One of the most famous programs trying to collect such data about people is a long–term Japanese study of the population of Okinawa Prefecture – "the longest-lived people on the planet." The prefecture is famous for its record number of people who are over a hundred and even over a hundred and ten years old, maintaining good physical shape and high quality of life. In studies of the diet of Okinawans, led by Japanese gerontologist and cardiologist Makoto Suzuki, it was shown, among other things, that Okinawan schoolchildren consume only 62% of calories from the "recommended norm" characterizing the Japanese diet as a whole. As for the diet of Okinawan adults, it is 20% less caloric than that of the general population, with the proportion of proteins and fats the same as in the rest of Japan. The risk of vascular, oncological and cardiological diseases in Okinawa is significantly lower than the national one: by 59%, 69% and 59%, respectively. However, it would be premature to proclaim a connection between the two, because, in addition to the diet, there are still many significant differences between the inhabitants of Okinawa and the rest of Japan, both genetic and in living conditions. The contribution of these factors to the phenomenon of "Okinawan longevity" is indisputable and difficult to separate from the effect of calorie restriction.

While science is cautious, pharmacology is already trying to combine the best of both worlds and chasing a dream: eat as much as you want sweet and live happily ever after, maintaining health and good physical shape. To do this, firstly, it is necessary to decipher the molecular mechanism of energy consumption and energy consumption, and secondly, to create biological products that can correct the biomolecular signal, simulating calorie restriction.

The most popular target since the early 2000s is signaling proteins of the sirtuin family involved in metabolism and inflammatory processes. Mice in which increased production of this protein was activated were more resistant to diabetes; there is also preliminary evidence that activation of sirtuins has a positive effect on the cardiovascular system and inflammatory processes in the same mice. Resveratrol, well-known to all red wine lovers, was considered among the candidates for the role of a sirtuin activator agent (unfortunately, it is contained in such an insignificant proportion in wine that it can only be responsible for the moral satisfaction of the consumer). But today pharmacology places special hopes on the SRT1720 activator, which shows good results in experiments, including increasing the life expectancy of mice with an unhealthy (high fat content) diet.

However, there is a colossal distance between even impressive, but still mouse percentages and convincing studies on a person or at least his closest relative, so that the "pills for old age" wait for quite a long time. And it will most likely come in the guise of a drug against diabetes or cardiac diseases, because there is no such "disease" as "aging" in the international "VOZOVSKY" register of diseases.

Not yet.

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