The Mitochondrial Paradox: Embracing Mitohormesis for Improved Metabolic and Aging Health

Informations projet

MitoHealth

N° de convention de subvention: 101157562

DOI

10.3030/101157562

Projet clôturé

Date de signature de la CE 6 Février 2024

Date de début 1 Mars 2024

Date de fin 31 Août 2025

Financé au titre de

• European Research Council (ERC)

Coût total

Aucune donnée

Contribution de l’UE

€ 150 000,00

Coordonné par

FUNDACIO DE RECERCA CLINIC BARCELONA-INSTITUT D INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER
Spain

Periodic Reporting for period 1 - MitoHealth (The Mitochondrial Paradox: Embracing Mitohormesis for Improved Metabolic and Aging Health)

Période du rapport: 2024-03-01 au 2025-08-31

Résumé du contexte et des objectifs généraux du projet

Obesity and its related metabolic diseases have become one of the greatest health challenges of our time. Despite major efforts, current treatments remain limited in their ability to stop, let alone reverse, the progression of these conditions. At the same time, societies worldwide are facing the challenge of ageing populations, with a growing need not only to extend lifespan but to preserve physical and cognitive function into old age. These pressing medical and societal needs call for new biological insights and innovative strategies.
Our project is built on the idea that the health of our metabolism is closely linked to the health of our blood vessels, and in particular to the function of mitochondria within endothelial cells. When mitochondria are exposed to mild stress, they can trigger a protective response known as mitohormesis. We proposed that harnessing this adaptive mechanism in the endothelium could have far-reaching benefits: preventing weight gain and metabolic decline, restoring metabolic balance in established obesity, and even slowing the functional decline associated with ageing.
Guided by this idea, the project set out to: a) Test whether endothelial mitohormesis can protect against diet-induced obesity and metabolic dysfunction; b) Explore whether it can also reverse established obesity and its complications; c) Investigate its ability to preserve function and promote healthy ageing; d) Identify new molecular mediators of mitohormesis with potential for future therapies.
Our findings show that triggering endothelial mitohormesis not only prevents the development of obesity and metabolic disease, but can also restore metabolic health once the disease has already set in. Beyond metabolism, it preserves motor, cognitive, and systemic functions in ageing animals, pointing to a new way of supporting healthy ageing.
The impact of these discoveries is potentially wide-ranging. Scientifically, they reveal a previously unrecognized role of endothelial mitochondria in shaping whole-body metabolism and ageing. Additionally, they suggest new therapeutic strategies for two of the most urgent health problems of our century: obesity and age-related decline. Societally, they offer hope for improving quality of life while reducing the growing healthcare burden.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

This project set out to test whether endothelial mitohormesis could influence body weight, metabolism, and ageing. To address this question, we used genetically engineered mice in which mitohormesis could be selectively activated in endothelial cells.

The main findings were:

a) Protection against obesity: When fed a high-fat diet, normal mice gained weight and developed metabolic disturbances, whereas mice with activated mitohormesis were resistant to obesity, maintained healthier blood sugar and lipid levels, and accumulated less fat in their tissues.
b) Reversal of obesity: Even after obesity was established, activating mitohormesis induced weight loss and restored metabolic health, despite continued exposure to a high-fat diet.
c) Healthy ageing: Ageing is typically accompanied by declines in movement, memory, as well as hematological and renal function. Mice with endothelial mitohormesis preserved these functions more effectively in old age, pointing to a protective role in healthspan.
d) New molecular signals: Proteomic analyses revealed candidate mediators of mitohormesis that are likely to contribute to these beneficial effects.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

This project has uncovered a new mechanism in which blood vessels help shape organisla health. By activating a protective stress response in the mitochondria of endothelial cells (known as mitohormesis) we found that it is possible not only to prevent obesity and its complications, but also to reverse them once they are established. Mice with endothelial mitohormesis stayed lean and metabolically healthy on a high-fat diet, and even when obesity was already present, triggering this response led to weight loss and restored metabolic balance. Beyond metabolism, mitohormesis also supported healthy ageing: animals maintained movement, memory, blood and kidney function far better than their peers.
Our analyses also identified new molecular messengers, that may carry the signals of mitohormesis throughout the body. These discoveries open the door to therapies that could mimic or amplify these natural protective mechanisms.
The potential impact is wide-ranging. Scientifically, the project advances our understanding of how endothelial cells influence metabolism and ageing. Medically, it highlights a novel strategy to tackle two of the most urgent health problems of our time: obesity and age-related decline. Societally, it points to the possibility of healthier lives and reduced healthcare costs. And from an innovation perspective, it provides a foundation for intellectual property, translational development, and eventual clinical applications.
For these advances to be fully realised, several steps are needed. Future research should validate these findings in additional preclinical models and explore the role of candidate mediators. Studies will be essential to test the safety and effectiveness of targeting endothelial mitohormesis in humans. Support for intellectual property, commercialisation, and partnerships with industry and investors will be critical to move from discovery to therapy.
In summary, the project demonstrated that endothelial mitohormesis: a) protects against and reverses obesity and metabolic dysfunction; b) preserves physical, cognitive, and systemic functions during ageing; c) reveals new molecular mediators with therapeutic potential.
These results establish endothelial mitohormesis as a promising biological mechanism and a novel target for therapies addressing obesity, metabolic disease, and healthy ageing.