What secrets of longevity do studies on model objects tell about
To date, significant progress in the study of aging genetics has been achieved thanks to work on various model objects. These include invertebrates - nematodes, drosophila, vertebrates – mice, also some significant results were obtained on unicellular organisms – yeast.
Genes have been discovered that can rightfully be called "longevity genes", in contrast to another group – "aging genes". First of all, this is a family of genes responsible for the body's ability to withstand stress. At the same time, these genes provide the action of protective mechanisms and regeneration systems, regardless of age. The complex action of these genes determines the optimal functioning of the body and increases its chances of overcoming the crisis. In other words, the activity of these genes helps to keep the body in working order and, thereby, contributes to an increase in its life expectancy. Many of these newly discovered genes affect not only the ability of laboratory animals to cope with stress, but also life expectancy.
The age-1 gene controlling nematode lifespan has been identified in Caenorhabditis elegans nematodes: modification or suppression of the product of this gene led to a significant increase in the lifespan of worms. The age-1 gene controls a whole group of genes (daf-2, daf-23, spe-26, clk-1) that in one way or another affect life expectancy. Further studies have shown that only one of these daf-2 genes is a homologue of the insulin receptor and a decrease in its activity was accompanied by an increase in the lifespan of nematodes.
On another model object, the fruit fly Drosophila melanogaster demonstrated a link between life expectancy and resistance to oxidative stress. It has been shown that it depends primarily on the activity of the enzyme superoxide dismutase (sod1 gene), as well as catalase. In addition, on fruit flies, as well as on nematodes, it was possible to establish the presence of regulation of life expectancy with the participation of the homologue of the insulin receptor (chico) and insulin-like factor-1 (IGF-1). At the same time, depending on the mutation, life expectancy increased from 45% to 85%. These mutations were also characterized by increased activity of the enzyme superoxide dismutase. A drosophila line with the mth mutation (from Methuselah – Methuselach) is known, which has not only an increased lifespan (by 35%), but also increased resistance to stress caused by a variety of factors: starvation, heating or the addition of compounds generating reactive oxygen species (for example, paraquat) to the feed.
Interesting results were obtained on mouse lines with the growth hormone receptor gene (ghr-/-) switched off. They have been shown to live significantly longer than heterozygous mice (ghr+/-) or wild-type mice (ghr+.+). GHR-/- mice are proportional dwarfs whose growth is slowed down, there is no growth hormone receptor and its binding protein, and the content of insulin-like factor in the blood is reduced.
In female mice with a partially knocked out IGF-1 receptor gene (Igf1r+/-), the average life expectancy was increased by 33% compared to wild–type females, and in males - only by 16%. These mice were not dwarfs, the basic metabolism, body temperature, feed intake, physical activity and fertility did not differ from the control, but they had increased resistance to oxidative stress compared to Igf1r+/+.
One of these genes has also been identified in humans, the allelic diversity of which affects life expectancy. This is the apolipoprotein E (ApoU) gene. In centenarians (over 100 years old), the ApoE-E2 allele prevails. At the same time, in carriers of the E4 allele, a decrease in life expectancy is accompanied by a risk of developing coronary heart disease, hypercholesterolemia and Alzheimer's disease.
These examples illustrate one of the promising directions in modern gerontology. They clearly indicate the presence of genetic control of life expectancy, in which many genes are involved. And using these examples, it was shown that inactivation of a number of genes led to both a change in metabolism and resistance to stress, and an increase in life expectancy could be observed at the output. Other genes ensure the prolongation of life by increasing the number of their copies or hyperactivation of the products encoded by them.