Completed Cells, Biochemistry & Physiology Genetics & Molecular Biology

ROS via RET: a redox regulated pathway to extend lifespan

Funder Wellcome Charity-funded
Recipient organisation Newcastle University
Funding £1.5M
Period Jan 2019 — Dec 2023

In plain English

AI plain-English summary

Mitochondria—the cell’s power plants—can produce small bursts of reactive oxygen molecules that actively extend lifespan, rather than simply damaging cells as previously assumed. This project tackles a long-standing contradiction in ageing research. For decades, reactive oxygen species (ROS) were seen as toxic byproducts that cause ageing, yet antioxidant supplements have failed to lengthen lifespan in clinical trials. Meanwhile, experiments show that boosting mitochondrial ROS can actually make animals live longer. The researcher has identified a specific mechanism—reverse electron transport (RET) at mitochondrial complex I—that generates ROS in a controlled, site-specific way to regulate lifespan. This work aims to map the full signalling pathway: which genes and proteins initiate, amplify, and neutralise this ROS signal; when and where in the body it must be activated to extend lifespan; and what goes wrong when the pathway is dysregulated. This is fundamental science. It does not promise an immediate anti-ageing pill. However, understanding how a precise ROS signal extends lifespan could eventually inform therapies for age-related diseases—such as neurodegeneration or muscle wasting—where mitochondrial dysfunction is a hallmark. It may also explain why blanket antioxidant approaches have failed, pointing instead toward interventions that tune specific redox signals.

View original technical description
Reactive Oxygen Species (ROS) play a dual role in cellular physiology. On one hand, ROS are damaging oxidants that have been proposed to cause ageing. On the other, ROS are essential messengers required for maintaining cellular homeostasis. The aged and sick accumulate defective mitochondria that generate high levels of ROS, but antioxidant therapies fail to improve prognosis or extend lifespan. Furthermore, increasing mitochondrial ROS levels in animals extends lifespan rather than reducing it. A new paradigm explains these contradictory results proposing that under normal physiological conditions, ROS are only produced at specific sites (e.g. mitochondria) by specific ROS generators (e.g. respiratory complex I) which regulate distinct redox signalling pathways. Conversely under pathological conditions ROS are produced at unspecific places causing oxidative stress. My laboratory has characterized the first site-specific ROS signalling pathway which regulates animal lifespan: ROS produced via reverse electron transport (RET) at respiratory complex I. This proposal will fully characterize this new redox signalling pathway by addressing three aims: (i) identify the genes and proteins involved in the initiation, amplification and neutralization of ROS-RET, (ii) understand when and where ROS-RET needs to be activated to extend lifespan, and (iii) dissect the pathological consequences of dysregulation of ROS-RET signalling.

View the original record at the funder ↗

Researchers

Alberto Sanz (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Role of Mitochondrial Reactive Oxygen Species in Stress Adaptation during Ageing
Peroxiredoxinylation; a new post-translational modification promoting redox signal transduction?
Investigation of cell responses to reactive oxygen species
A novel ageing-related pathway regulating ROS homeostasis
Targeting new redox-signalling mechanisms as a therapeutic target to prevent age-associated diseases

Original classification

Senior Research Fellowship Basic

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.