Accumulation of long-lived proteins stimulates cell aging
As we age, many parts of the body wear out and cannot be restored. The same applies to cells. New data obtained by researchers at the Fred Hutchinson Cancer Research Center indicate the existence of microscopic systems that degenerate over time and thereby trigger the aging process of cells, which, in turn, stimulates the aging of the entire body and the development of age-related diseases. They also partially explain the relationship between a low-calorie diet and an increase in life expectancy.
The molecular and cellular components of most parts of the body undergo a rapid cycle. The skin is completely renewed within a month, and the cells of the intestinal mucosa – in just a few days. However, there are exceptions: some components of the eye, joints and brain are present in the body throughout life.
For example, the lens of the eye consists of proteins synthesized shortly after birth and preserved until death. Age–related changes in these proteins lead to the formation of cataracts - irreversible clouding of the lens.
Researchers working under the guidance of Dr. Daniel Gottschling have suggested that long-lived lens proteins are no exception to the rule and similar proteins may underlie the aging of cells in other parts of the body. Their experiments on yeast confirmed this hypothesis.
Long-lived proteins of the eye, brain and joints are unique, as they are contained in the extracellular space or inside non-dividing cells. Stem cells grow and divide throughout life, but over time they also "give up". According to one of the theories of aging, the trigger mechanism of aging is a reduction in the number of stem cells, leading to the extinction of the body's ability to restore and renew aging tissues and organs.
Like stem cells, yeast cells divide asymmetrically. At the same time, aging "mother" cells give rise to new "daughter" cells. Yeast mother cells can generate 30-35 daughter cells, after which they die. Their normal life expectancy with active division is less than two days.
To study long-lived proteins in yeast cells, the authors used a special protein tagging technique to track the molecules of maternal cells from the moment of their appearance to their death. They identified 135 proteins present only in the mother cells and not renewing during their entire lifespan. Unexpectedly for the researchers, it turned out that 21 of the proteins were non-functional fragments.
Somehow these proteins are preserved inside the mother cell. It can be assumed that this happens to "facilitate" the fate of daughter cells, but the exact reason is currently unclear.
Yeast mother cells bud and give rise to daughter cells.
Researchers have identified the relationship between long-lived proteins (marked in red)
and the nature of aging of maternal cells.
One of the intact long-lived proteins of the mother cells attracted the attention of researchers. This protein, known as Pma1, regulates the acid-base balance of the intracellular environment. In 2012, Gottschling's group found that the level of acidity inside certain cellular structures – vacuoles – is a critical factor in maintaining the functionality of the energy centers of the cell – mitochondria. The level of acidity of cells decreases over time, which leads to the gradual destruction of mitochondria.
Subsequent experiments of the authors showed that with each division, the intracellular environment of the mother yeast cells becomes more alkaline and this process is mediated by the Pma1 protein. Due to the uneven distribution of protein molecules, daughter cells do not have this protein and, accordingly, are characterized by higher acidity compared to the mother cells.
At the same time, a decrease in Pma1 expression increased the lifespan of the mother cells, and an increase in its expression led to the appearance of more "alkaline" daughter cells.
Pma1 plays an important role in cell nutrition. It localizes on their surface and facilitates the flow of nutrients from the medium into the cell. Based on this, the authors suggested that maternal cells retain this protein not for the benefit of daughter cells, but to facilitate their own nutrition and, accordingly, increase the ability to reproduce.
This explains the faster death of maternal cells in a nutrient-rich environment, as well as the ability of a low-calorie diet to increase the lifespan of yeast. If the cell absorbs less nutrients, its acidity decreases at a slower rate, which is accompanied by a decrease in the activity of reproduction.
The authors note that they are not looking for a simple answer or a "magic drug" that can reverse the aging process. The biology of aging is so complex and poorly understood that it makes no sense to try to guess which anti-aging strategies the data they have obtained can lead to. They emphasize that the primary task is a detailed study of the aging process and its possible disorders.
Article by Nathaniel H. Thayer et al. Identification of long-lived proteins retained in cells undergoing repeated asymmetric divisions is published in the journal Proceedings of the National Academy of Sciences.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Fred Hutchinson Cancer Research Center:
Long-term hoarding of cellular ‘garbage’ could trigger old age.
30.09.2014