Age-related arterial dysfunction and gut dysbiosis in mice and cetaceans

Informations projet

Arterial Aging

N° de convention de subvention: 892267

DOI

10.3030/892267

Projet clôturé

Date de signature de la CE 3 Avril 2020

Date de début 1 Juin 2021

Date de fin 31 Mai 2024

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 245 732,16

Contribution de l’UE

€ 245 732,16

Coordonné par

UNIVERSIDAD DE LAS PALMAS DE GRAN CANARIA
Spain

Periodic Reporting for period 2 - Arterial Aging (Age-related arterial dysfunction and gut dysbiosis in mice and cetaceans)

Période du rapport: 2023-06-01 au 2024-05-31

Résumé du contexte et des objectifs généraux du projet

Cardiovascular disease (CVD) is Europe's number one cause of death. Aging is the primary risk factor for CVD, which is partly attributable to increased arterial dysfunction. Advancing age can induce adverse changes in the gut microbiome, which in turn, can activate systemic pro-oxidant and pro-inflammatory signaling pathways with detrimental downstream consequences in the arteries.

One main objective of this project is to investigate the role of the gut microbiome in modulating arterial function with aging. To approach this objective, we have leveraged mouse-to-mouse fecal transplant of gut microbiota to investigate if the gut microbiota alone transfers vascular phenotypes with aging. This experiment has shown that the gut microbiota modulates arterial function with aging, and we are studying the mechanisms involved. However, this important proof-of-concept step in determining the role of the gut microbiome in modulating age-related arterial dysfunction lacks the necessary translational insight to prove that the gut microbiome of humans is directly involved. Thus, we also investigated the causal effects of the human gut microbiome on artery function using a “humanized” mouse model, in which we transplanted human microbiota into gut microbiota-depleted mice. Together, these experiments demonstrate that unfavorable changes in the gut microbiome with aging contribute to arterial dysfunction. As such, we have established that the gut microbiota is promising new therapeutic target to prevent or reverse age-related arterial dysfunction.

Another goal of this project is to explore if cetaceans (i.e. whales and dolphins) may be a model for studying healthy arterial aging. Cetaceans are long-lived mammals and excellent divers. They undergo constant cycles of tissue hypoxia-reoxygenation and shear stress caused by vascular adjustments while diving. In humans, these adjustments produce oxidative stress, inflammation, and impairment of endothelial cells. Thus, a working hypothesis of this project is that cetaceans may have arterial-protective mechanisms to prevent dysfunction with age and diving. To approach this objective, first we have studied the effect of the circulating milieu (i.e. serum) in the arteries of an experimental validated model: mouse. Using a highly innovative research technique, we tested the hypothesis that, in contrast to humans, the serum of old dolphins does not impair arterial function in the arteries of young mice. This result supports the working hypothesis that, unlike in humans, aging in cetaceans does not induce adverse changes in the circulating blood that causes vascular dysfunction and disease. As such, the dolphin circulating milieu is a promising setting to identify factors that may protect artery function with aging.

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

In relation with the first objective of this project, we performed the mouse-to-mouse transplant of gut microbiota successfully, and the results confirmed our working hypothesis: the gut microbiome modulates arterial function. The publication of these results is currently under review.

We also tested the human-to-mouse transplant of gut microbiota. Unfortunately, for reasons that have yet to be determined, the old mice used for this part of the project did not show a reduction of arterial function with aging. That is, our model organism of aging no longer produced the arterial dysfunction that is observed in humans with aging. As such, we could not continue these experiments, and thus, we were unable to test this working hypothesis.

With the accumulated knowledge of the gut microbiome, its changes with advancing age, and its effect on arterial function, we produced a mini-review in the American Journal of Physiology – Heart and Circulatory Physiology entitled “The gut microbiome as a modulator of arterial function and age-related arterial dysfunction”. Here, we discussed mechanisms by which the gut microbiome may contribute to age-related arterial dysfunction, with a focus on changes in various gut microbiome-related compounds in circulation.

Regarding the second goal of this project, first, we developed an innovative technique, that allows to isolate the effect of the bioactive factors in the blood serum directly on ex vivo arteries. This allows us to explain if changes in the serum due to aging can have a negative effect in the function of arteries. We determined that when young mouse arteries are incubated in serum from old mice or humans, their arterial function was impaired compared to those arteries incubated with serum from young mice or humans. Secondly, we tested arterial function following incubation with dolphin serum. Arterial function of young mouse was good (equivalent to young mice, young human or young dolphin serum) after incubation with old dolphin serum, confirming our working hypothesis that cetaceans are a model of healthy arterial aging. These results were presented at the American Physiology Summit (APS) and at the European Cetacean Society. The abstract received a distinction award from the APS. The award and the scientific results were disseminated in social media, European researchers night, in addition to several pitch events. Thes study has recently been accepted for publication in the American Journal of Physiology - Heart and Circulatory Physiology.

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)

We confirmed that the gut microbiome in mice, modulates arterial function with aging. This opens a new field of therapeutics to treat arterial dysfunction and thus prevent cardiovascular diseases, Europe’s number one cause of natural deaths. We hope to publish these results in a high-impact journal.

We have developed an innovative technique, that allows to isolate the effect of the bioactive factors in the blood serum directly in ex vivo arteries. We have shown that changes in the circulating milieu with advancing age may be a mechanism underlying age-related arterial dysfunction. This experimental approach allows to investigate the mechanisms of the circulating milieu mediating changes in arterial function, the efficacy of pharmacological treatments in treating arterial function, and the effect of the circulating milieu of other species (which might serve as a model of healthy aging or accelerated aging), to elucidate potential novel therapeutic strategies to improve age-related endothelial dysfunction in humans.

Mounting evidence suggests that cetaceans, long-lived mammals that dive continuously, show no signs of associated tissue or arterial damage. In this project, we have demonstrated that the circulating milieu of bottlenose dolphins is protective ex vivo in mouse arteries. Taken together, the diving adaptations of cetaceans may protect their endothelial cells from typical age-related insults of terrestrial mammals. Hence, cetaceans could serve as a model to investigate targets, mechanisms and potential therapies for preventing and/or treating adverse arterial aging and promoting CV health and longevity in humans.

CVD is the number one cause of death in Europe, and advancing age is the primary risk factor for CVD. CVDs cost €210 billion a year to the EU economy. Demographic trends of the EU population predict that the share of those aged 65 years or over will increase from 19.8 % in 2018 to 31.3 % in 2100, and the share of those aged 80 years or above will increase by 2.5 times for the same time period. Therefore the results of this project have the potential to impact the EU population health and economy.

Schematic representation of the goal of the study