Laminopathies and the aging process

The problem of genetic control of life expectancy and the aging process has many facets, one of them was highlighted in the study of hereditary diseases included in the group of laminopathies. Laminopathies are a group of hereditary diseases caused by mutations in the genes encoding proteins of the nuclear lamina, which is part of the shell of the cell nucleus and plays an important role in maintaining its rigidity.

The nuclear envelope includes a two-layer nuclear membrane consisting of outer and inner layers, a complex of nuclear pores and a nuclear lamina located under the surface of the inner membrane of the nucleus. Initially, lamina was found as a fibrous component of the nucleus, consisting of filaments corresponding in size to intermediate filaments (10-13 nm) [intermediate filaments (intermediate filaments – IF) are elements of cytoskeletal multicellular structures and are found both in the cytoplasm and in the nucleus]. The structural features of the filament lamina are determined by the proteins forming them, called lamins.

Lamins belong to the superfamily of IF proteins, group 5 (the other 4 groups are cytoplasmic) and, due to their structural features, are able to undergo posttranslational modification. The number of lamin proteins found in various multicellular organisms varies. Humans (and other mammals) have 3 genes that encode 7 different proteins. These proteins are divided into two types – A-type and B-type, which differ in genetic control, method of synthesis, nature of expression and other features (Table 1 – according to C.J. Hutchison, 2002 with changes).

* - this lamin has also been found in some tumor cell lines.

[Alternative splicing is a controlled "rearrangement" of matrix RNA (mRNA) molecules read from one gene, accompanied by the combination of gene exons in different combinations to form various mature mRNA molecules, this ensures the coding of various end products by one gene and is one of the main mechanisms for generating protein diversity in higher eukaryotes.]

The expression of lamins B1 and B2 is observed in most cells in both embryos and adult organisms. The integrity of the nucleus, cell survival and normal development depend on them. Lamins of type A have a different expression pattern, which correlates with cell differentiation. Due to this, it has been suggested that B-type lamins determine the viability of the organism, while type A lamins have more specialized functions. There is evidence of the participation of lamins in the processes of transcription and post-transcriptional processing of RNA.

In the last decade, mutations in LMNA have been found to be associated with a number of clinically diverse diseases that are grouped into laminopathies. The intensification of research in this direction has led to a significant surge in publications: in 2005 alone, their number exceeded 200. With laminopathies, disorders are observed that lead to changes in the structure of striated muscles and obesity, to polyneuropathy, lipodystrophy, cardiomyopathy, contributing to the development of insulin resistance, skin disorders, etc.

But the most dramatic phenotype caused by mutations in LMNA and subsequent splicing disorder is progeria, or premature aging syndrome – Hutchinson-Guilford syndrome. The presence of defective lamin in the cell nucleus leads to a variety of pathological changes: the content of a number of proteins in the nucleus sharply decreases, the nuclear shell shrinks, the process of repairing errors that occur during DNA synthesis is disrupted. As a result, the cells lose their ability to divide, there is no replacement of dead cells with new ones, which leads to premature aging of the body. These patients do not live to be 20 years old and already have the appearance of small ancient old men in 10-12 years.

The real boom was the report of P. Scaffidi and T. Misteli in the journal Science (2006), which showed that the LMNA gene is directly related not only to the development of progeria syndrome, but also to the process of "normal" (not accelerated - physiological) aging. Scientists have found that incorrect splicing of lamin information RNA occurs not only in patients with progeria, but also in healthy people, but with a much lower frequency. Although the amount of defective lamin does not increase with age, but over time (in the elderly) changes similar to those in patients with progeria are observed in the cells. In an experiment on fibroblasts taken from old people, it was shown that the suppression of improper splicing led to cell rejuvenation.

In an experimental animal study conducted by a group of scientists from the USA and Sweden led by L.G. Fong, it was shown that for the normal functioning of the core shells and the prevention of premature aging of the body, first of all, the presence of lamin C is necessary.

In the report of a group of scientists from the University of Massachusetts (July 2007), an interesting fact is presented: mutations in the LMNB1 gene led to the fact that the axis of the nucleus in cells changed its position and as a result, the rotation of the nuclei was observed.  These mutations did not affect the mobility of the cytoskeleton. If the researchers expressed wild-type cDNA in the cells of LMNB1-/- mice, the rotation of the nuclei stopped. According to scientists, lamin B1 probably performs an anchor function, providing a connection between the shell of the nucleus and the cytoskeleton. Mice defective in the LMNB1 gene died at an early stage of development.

Thus, to date, very interesting and intriguing data have been obtained, indicating the fundamental importance of genes controlling the structure and function of lamins. However, the effect of lamins on the vital activity and functioning of the body as a whole is still poorly understood and requires further study. Perhaps this will lead to the discovery of new opportunities to combat old age and open up real ways to active longevity.