04 March 2008

Immortality in exchange for infertility?

Alexey Timoshenko, "Elements"A group of scientists from Arkansas Medical University (Little Rock, USA), led by Robert Schmuckler Rice, managed to achieve a tenfold - record to date – increase in the life expectancy of the nematode worm.

Due to just one change in the age-1 gene, they managed to obtain individuals that gave long-lived, resistant to various poisons, but at the same time completely sterile offspring.

The nematode (roundworm) Caenorhabditis elegans is a favorite model organism of biologists. If biologists study prokaryotes by the example of E. coli bacteria, and unicellular organisms by the example of yeast Saccharomyces cerevisiae, then C.elegans, along with the drosophila fly and the laboratory mouse, is an indispensable object for the study of multicellular animals.

Biologists' love for the worm is partly caused by its transparency and the speed of reproduction (the full development cycle of C.elegans is about three days). And although C.elegans is barely distinguishable by the human eye (it reaches a length of only 1 mm), over several decades of research, some of which is devoted to the problems of aging organisms, this tiny worm has already brought a lot of benefits to humanity – molecular biologists, embryologists and even neuroscientists have worked with it and continue to work with it (the worm has a nervous system of three hundred neurons).

To date, about 80 mutations affecting life expectancy are known in C.elegans. In particular, it was previously noted that violations of molecular cascades associated with an important hormone (present in humans) – insulin-like growth factor IGF-1 (insulin-like growth factor, IGF-1), led to a three-fold excess of the natural two-week life span of C.elegans nematodes (and gave a slightly smaller effect when working with other species, such as mice). However, in a paper published recently in the journal Aging Cell, this record was surpassed more than three times. The "knocking out" of one of the enzymes in the cascade of insulin-like growth factor gave not a three- but a tenfold increase in life expectancy: some of the experimental nematodes lived for nine months.

In any organism, even a unicellular one, there are a number of molecular cascades designed to transmit information about external influences or changes in the internal environment to a complex mechanism for regulating gene expression. The signal that comes to the receptors of the cell membrane (for example, if the receptor molecule interacts with the signaling molecule of a hormone, neurotransmitter or drug) triggers a chain of complex transformations, such as changing protein conformations, adding and removing phosphate groups, catalysis and inhibition of various biochemical reactions). At each stage of transformation, both signal amplification and its transmission in the necessary direction occurs – to the nucleus and transcription factors regulating DNA transcription from certain genes.

Substances capable of triggering molecular cascades include, in particular, insulin and insulin-like growth factor IGF-1. The branching of molecular cascades triggered by insulin receptors leads to the fact that this relatively short (51 amino acids) peptide affects processes from glucose metabolism and blood pressure regulation to the occurrence of neurodegenerative diseases. And a chain of 70 amino acids similar in molecular structure – IGF-1 – already plays a different role. Insulin–like growth factor is involved in the processes of cell differentiation and growth and can even lead to blocking of apoptosis - programmed cell death. IGF-1 is also involved in the regulation of the synthesis of somatotropic hormone (which in humans, already at the level of the body as a whole, is responsible for bone growth in children and adolescents), simultaneously affecting the synthesis and breakdown of protein and, again, the level of glucose in the blood.

The signaling cascade triggered by the insulin-like growth factor is very complex. IGF-1 first interacts with special receptors, then the signal is transmitted with the participation of the enzyme phosphatidylinositol-3-kinase of the first class (PI3K CS) to four different kinase proteins and from kinases to the nucleus and genome (where gene expression starts or stops). It is possible to interfere with the work of this cascade at different stages by disabling certain genes, and such interventions often lead to a change in the life expectancy of the worm.

Схема молекулярного каскада с участием ИФР-1 (Signaling Pathway mediated by IGF-1)

The scheme of the molecular cascade involving IGF-1 (Signaling Pathway mediated by IGF-1).
Fig. from the website www.grt.kyushu-u.ac.jp (there all the factors in the figure are clickable)

In the work of American scientists, a nonsense mutation was studied (leading to the interruption of protein synthesis: instead of a codon encoding the next amino acid in the chain, a stop codon appears) of the age-1 gene encoding the PI3K CS protein. Previously, the violation of other links of the signal chain was studied on mutations of other genes – for example, the daf-2 gene (encoding the IGF-1 receptor) and daf-12 (encoding the transcription factor). The "knocking out" of both of these genes gave one of the previous records – the life of the nematode was extended by 4.4 times. But this is still not an order of magnitude and, moreover, due to a combination of two mutations (and not one, as in the case of age-1).

Rice and colleagues managed to obtain offspring from mutants in the age-1 gene, which until then were considered fundamentally not reaching adulthood. The parents of mutant nematodes were heterozygous – with a working copy of the gene and, due to this, with normal physiology. That is, in their diploid cells, only one set of chromosomes carried the age-1 gene mutation of interest to us. The effect of this mutation was manifested only in 1/4 of the offspring, which (in full accordance with the Mendelian laws of inheritance) received both sets of genetic material with a mutation in the age-1 gene. This quarter of homozygous mutants of the first generation carried some amount of the maternal enzyme and due to this was able to produce offspring (without PI3K, the process of germ cell formation is not completed). Mutants were able to grow at a reduced temperature (15-20 ° C instead of the normal 25 ° C, at which, as a number of authors showed earlier, development stopped at the larval stage) and get the second generation – interesting because they did not have the PI3K CS enzyme inherited from the maternal egg; in the strict sense, these the nematodes have experienced all the effects of the mutation.

Homozygous mutants of the second generation lived ten times longer than ordinary C.elegans. But at the same time they were sterile: the complete absence of PI3K CS, including parental, led not only to prolongation of life, but also to infertility. So disabling the existing molecular cascade (it is disabling existing ones, not adding any new genes!) after all, it didn't go in vain for them.

A natural question arises: is it possible, in principle, to extend the results of the study to mammals? After all, mice with mutations affecting the IGF-1 cascade also lived longer than usual, though only by 1.7 times, and at the same time additional dietary restrictions were introduced for them. So, maybe it is possible to somehow compensate for the infertility associated with the age-1 gene and leave only a long life?

A number of data points to the fact that it is impossible – at least in one action. IGF-1 and its associated enzymes are involved, at least, also in the processes of metabolism (the same team of authors promises to publish a detailed study in the near future). In addition, the long-lived worms also turned out to be more resistant to the action of hydrogen peroxide, but less resistant to high temperatures (35 ° C) compared to ordinary worms. If one gene affects such a variety of processes, then what can we say about the interaction of several genes in relation to the maturation of eggs?

Source: Srinivas Ayyadevara, Ramani Alla, John J. Thaden, Robert J. Shmookler Reis. Remarkable longevity and stress resistance of nematode PI3K-null mutants // Aging Cell. 2208. V. 7. No. 1. P. 13-22(10) (full text – PDF, 450 KB).

Portal "Eternal youth" www.vechnayamolodost.ru04.03.2008

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