Silencing a major cellular stress signal could be the key to a longer life, according to new University of Sheffield research.
While previous studies suggested that mild stress might help organisms live longer, new research published in the Proceedings of the National Academy of Sciences (PNAS) journal could turn this theory on its head.
Researchers focused on a molecular network called the Integrated Stress Response (ISR). This system acts as a cellular ‘emergency management’ system, helping cells adapt to challenges like nutrient shortages or viral infections.
Testing the theory that mild activation of stress via the ISR would increase lifespan in a complex organism for the first time, researchers discovered that suppressing rather than activating the fruit flies' internal stress management system actually extended their lifespan.
By studying tens of thousands of fruit flies, the team found that using genetic tools to ‘turn up’ the ISR - tricking the body into thinking it was under stress - shortened the flies' lives. Conversely, suppressing this signal allowed the flies to live longer, even when facing other challenges such as dietary changes.
These findings run counter to previous studies in simpler organisms, such as yeast and the roundworm C. elegans, where activating stress responses appeared to be beneficial to longevity. Prior work in mice has also implicated active ISR in longevity.
Dr Mirre Simons, from the University of Sheffield’s School of Biosciences, said: “We are looking for evidence that targeting aging itself can be effective. Ultimately, this could have profound implications for increasing human lifespan.
“One of the biggest societal risks we face is the demographic shift of an aging population. This will place a massive economic and care burden on future generations. If we want to intervene at scale, we must move beyond treating individual diseases and start targeting the aging process itself.”
The research team chose fruit flies for the study due to their complex biology and two month lifespan, which makes them ideal for longevity research. Regardless of other factors introduced such as dietary restrictions, the impact of suppressing the ISR pathway remained the same: the flies lived longer.
A deeper understanding of the ISR pathway could hold promise for other areas of medicine.
Miriam Götz, a University of Sheffield graduate and co-author who conducted the research during her Master’s studies, added: “The ISR pathway is already a major focus in cancer and immunology research. Our findings contribute to a better understanding of general biology that could lead to more effective treatments for various age-related conditions.”
The Sheffield team is now seeking funding to test whether existing drugs can replicate these genetic results, potentially opening the door to pharmacological treatments that slow down the ageing process.
Proceedings of the National Academy of Sciences
Observational study
Cells
Suppression rather than activation of the integrated stress response (GCN2–ATF4) pathway extends lifespan in the fly
29-Apr-2026