21 October 2022

Stress delays aging

Aging is a risk factor for various disorders, including diabetes mellitus, cancer and neurodegenerative diseases. Identifying the cellular mechanisms underlying aging may bring humanity closer to developing new treatments for age-related disorders.

How is the cellular response to stress activated

A stress reaction is triggered when stress factors (in this study, excess glucose) cause the accumulation of "problematic" unstructured proteins in the cell. The stress response, called the unstructured protein response, aims to eliminate these proteins and restore balance in the cell.

Aging can also lead to the accumulation of unstructured proteins due to a natural decrease in the ability of cellular mechanisms to produce healthy proteins, causing the same stress response.

Molecular cellular mechanisms fight this accumulation with their own "stress sensors" that trigger a cascade of interactions to protect the cell. If the excess of unstructured proteins is not eliminated, the prolonged response of unstructured proteins causes cell death.

The response of unstructured proteins in old worms led to healthier aging

To study how the response of unstructured proteins affects the lifespan of animals, researchers from Singapore Nanyang Technological University (NTU Singapore) induced stress in adult C.elegans roundworms using glucose. Although these animals are anatomically much simpler than humans, they use almost the same genes as humans to control cell division and apoptosis of damaged cells.

Scientists gave the worms high-glucose food at two different stages of life: young at the beginning of their adult life (day 1) and at the post-productive age when the worms can no longer reproduce (day 5). The control group of worms were fed regular food.

The team found that old worms fed with a high glucose content lived for 24 days – almost twice the lifespan of young worms fed the same diet (13 days). Worms on a normal diet lived for an average of 20 days.

In addition to the fact that old worms on a high-glucose diet lived longer, they were more mobile and had more cells for energy storage compared to worms that received regular food, which indicates healthier aging.

Prolonged stress response in young worms led to cell death

The day after feeding high-glucose foods, scientists tracked the activity of three stress sensors in worms, each of which is responsible for a specific process within the response of unstructured proteins. They found that stress marker C was significantly more active in young worms compared to old ones.

When the researchers removed the gene encoding IRE1 to disable the cellular pathway initiated by this protein, they found that young worms fed high-glucose foods from day 1 lived for 25 days – twice as long as when the IRE1 gene was intact.

This suggests that the stress switch IRE1, active in young worms that have been fed a high-glucose diet since day 1, induces a long-term response of unstructured proteins and is responsible for shortening the lifespan of animals.

The authors explain the results of the study in this way: feeding old worms with food with a high glucose content caused a weak response of unstructured proteins and triggered certain cellular pathways to combat not only excess glucose, but also other stresses associated with aging, restoring cellular stability. On the contrary, young worms subjected to a stressful diet with a high glucose content showed overexpression of the IRE1 gene, which led to a prolonged stress reaction and cell death.

If a drug is developed that reduces the activity of IRE1 while simultaneously increasing the other two stress markers, it is likely to slow down cellular aging and, consequently, increase life expectancy. It will be necessary to conduct additional research in order to study more deeply the complex mechanism of prolongation of life caused by stress, as well as how this mechanism interacts with other processes in cells.

The authors draw attention to the fact that food with a high glucose content was used only to simulate stress in roundworms, and do not recommend elderly people to increase the carbohydrate content in the diet. This study only shows that triggering certain stress reactions in cells can lead to prolongation of life, and that activating this stress reaction with a drug may be crucial for slowing cellular aging.

Article by C.Beaudoin-Chabot et al. The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C.elegans is published in the journal Nature Communications.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on EurekAlert materials!: Manipulating stress response in cells could help slow down ageing, finds NTU Singapore study.

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