Periodic Reporting for period 1 - Arterial Aging (Age-related arterial dysfunction and gut dysbiosis in mice and cetaceans)
Reporting period: 2021-06-01 to 2023-05-31
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 (stiffening of large elastic arteries) and the development of vascular endothelial 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. 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 carried out two experimental studies: 1) mouse-to-mouse transplant of gut microbiota to investigate if gut microbiota alone transfers vascular phenotypes. 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.
On the other hand, 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 function. Thus, another main objective of this proposal is to explore if cetaceans, i.e. whales and dolphins, have developed an endothelium-protective mechanism to prevent arterial dysfunction with age and diving. To approach this objective, using a highly innovative research technique, we are testing the hypothesis that, in contrast to humans, the circulating blood (i.e. serum) of old dolphins does not impair endothelial function in the carotid arteries of young mice. If so, this would support the idea that, unlike in humans, aging in cetaceans does not induce adverse changes in the circulating blood that causes vascular dysfunction and disease.
On the other hand, 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 function. Thus, another main objective of this proposal is to explore if cetaceans, i.e. whales and dolphins, have developed an endothelium-protective mechanism to prevent arterial dysfunction with age and diving. To approach this objective, using a highly innovative research technique, we are testing the hypothesis that, in contrast to humans, the circulating blood (i.e. serum) of old dolphins does not impair endothelial function in the carotid arteries of young mice. If so, this would support the idea that, unlike in humans, aging in cetaceans does not induce adverse changes in the circulating blood that causes vascular dysfunction and disease.
We performed the mouse-to-mouse transplant of gut microbiota successfully, and the results confirmed our working hypothesis: the gut microbiome modulates arterial function. We are currently working on the publication of these results.
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.
Using an innovative technique, we have determined that when young, intervention-free, mouse carotids are incubated in serum from old mice or humans, we can measure a reduction in endothelial function. Currently, we are testing if the circulating milieu (i.e. serum) of old dolphins induces a similar decrease in endothelial function of young mouse carotids. Preliminary results confirmed the working hypothesis of cetaceans being a model of healthy vascular aging.
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.
Using an innovative technique, we have determined that when young, intervention-free, mouse carotids are incubated in serum from old mice or humans, we can measure a reduction in endothelial function. Currently, we are testing if the circulating milieu (i.e. serum) of old dolphins induces a similar decrease in endothelial function of young mouse carotids. Preliminary results confirmed the working hypothesis of cetaceans being a model of healthy vascular aging.
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.
Additionally, our preliminary results using dolphin serum of different ages suggest that cetaceans may be a model of vascular health aging. Using an innovative methodology, we have found this very novel result. We expect to confirm these results and provide some insight into the mechanism of “anti-aging” of dolphin serum.
Additionally, our preliminary results using dolphin serum of different ages suggest that cetaceans may be a model of vascular health aging. Using an innovative methodology, we have found this very novel result. We expect to confirm these results and provide some insight into the mechanism of “anti-aging” of dolphin serum.