Waking up ‘stress response’ in cells may be key to delaying ageing process

A team of researchers from Singapore has discovered a way to potentially increase lifespan: switch on a ‘stress response’ in cells at postreprodutive age.

“Ageing is one of the most critical risk factors for the development of metabolic syndromes. Both type 2 diabetes (T2D) and insulin resistance have a strong association with endoplasmic reticulum (ER) stress,” which is a condition characterized by the build-up of the problematic “unfolded” proteins in the cell, according to the researchers led by Professor Guillaume Thibault from the Nanyang Technological University (NTU) School of Biological Sciences in Singapore.

In the face of ER stress, cells initiate a stress response, which is called the unfolded protein response, to get rid of the problematic proteins and restore balance in the cell, Thibault explained. [Science 2011;334:1081-1086; Biosci Rep 2014;34:e00118; Biochim Biophys Acta Mol Cell Biol Lipids 2020;1865:158449]

However, the activation of the unfolded protein response decreases and, along with it, the risk of developing metabolic syndromes increases with age. [Cell 2013;153:1435-1447; Brain Res 2016;1648:588-593]

Accordingly, Thibault and colleagues looked at inducing the unfolded protein response in adult roundworms (Caenorhabditis elegans) using glucose. These roundworms were fed a high-glucose diet at two different life stages: at day 1 or the start of adulthood (young age) and at day 5 or when the worms were aged and no longer able to reproduce (postreproductive age). Outcomes were compared against roundworms fed a normal diet.

Results showed that the lifespan of aged roundworms fed a high-glucose diet was longer than that of worms on a normal diet (24 vs 20 days). On the other hand, young worms given the same high-glucose diet had reduced lifespan and only lived for 13 days. [Nat Commun 2022;doi:10.1038/s41467-022-33630-0]

In addition to having increased lifespan, aged worms on a high-glucose diet appeared to have healthier ageing. They were nimbler and had a greater number of energy storage cells relative to worms given a normal diet.

The NTU team also monitored three unfolded protein response sensors a day after feeding the worms a high-glucose diet. They found that ATF-6 and PEK-1 promoted longevity in aged worms, whereas IRE-1 decreased the lifespan of young worms.

Specifically, IRE1 had greater activity in young than aged worms. When the gene coding for IRE1 was removed to deactivate the cellular pathway that the stress sensor initiates, the young worms fed a high-glucose diet lived for 25 days, which was twice as long as when the IRE1 gene was intact.

“We believe that the high-glucose diet fed to the aged worms stimulated their otherwise sluggish unfolded protein response and switched on certain cellular pathways, tackling not just the stress caused by excess glucose but also other ageing-related stress, restoring cellular stability,” Thibault said.

“In contrast, young worms subjected to a high-glucose diet provoked unresolved stress in the cells due to an overactivated IRE1. This prolonged activation led the cells to initiate cell death instead,” he added.

Taken together, the present data highlight the potential of developing a drug that reduces the activity of IRE1 while increasing the activity of the other two stress sensors, ATF-6 and PEK-1, to slow down the ageing process and consequently extend lifespan, as Thibault pointed out.

The NTU team called for more studies in the roundworms to shed light on the complex mechanism behind the lifespan extension induced by a high-glucose diet, in addition to how this mechanism interacts with other processes in cells.