New thesis provides insights into how we age
Lara Garcia Merino from the Integrative Cardiovascular, Cancer and Ageing Research Unit (ICCA) at the Department of Medicine, Huddinge (MedH), will defend her thesis entitled "Cell-type-specific dynamics of somatic mutation accumulation in age-related vascular and skeletal muscle dysfunction" on 23 October. Her supervisor is Maria Eriksson.
What is the main focus of your thesis?
Overall, I have focused on two main topics. One of them is progeria, a very rare disease in which the children show accelerated aging and die early due to cardiovascular disease. A part of the thesis has focused on understanding how the arteries of a mouse model of progeria change during disease development.
In addition, the thesis has also focused on studying mutations in the DNA that arise after conception, called somatic mutations. Somatic mutations are known to accumulate during natural aging in many organs, although their consequences for tissue function remain debated. We studied whether somatic mutations accumulated in the arteries of the progeria mice. In parallel, to assess potential consequences of having more somatic mutations, we assessed whether experimentally increasing the number of mutations in the muscle during muscle regeneration could negatively affect this process.
Which are the most important results?
We have observed that in the aortic arch from progeria mice, two different cell types, vascular smooth muscle cells (VSMCs) and fibroblasts, respond differently to the disease. VSMCs become progressively dysfunctional and die. By contrast, fibroblasts predominantly changed their phenotype without major signs of cellular stress. This heterogeneity is also observed in a specific type of molecules from the cells, lncRNAs, which showed a different profile in each cell type during disease. Furthermore, in the progeria mice, both VSMCs and fibroblasts accumulated more somatic mutations than normal mice. Remarkably, VSMCs accumulated the mutations faster than fibroblasts.
In parallel, increasing somatic mutation number in the muscle during regeneration after injury led to less efficient regeneration and reduced strength.
How can this new knowledge contribute to the improvement of people’s health?
The thesis can contribute to improving people ‘s health from different angles. On one hand our findings on somatic mutations accumulating in progeria, and on their effect on muscle regeneration, highlight the relevance of somatic mutations in the overall aging process, helping us understand more about how we age. Furthermore, this opens the door to exploring aging therapies that target somatic mutations.
Particularly for progeria, we see that therapies should be cell-type specific, and should be delivered early, before permanent cellular damage, like somatic mutations, accumulates in the cells. In addition, we hope that the described lncRNAs can be used in further research so that eventually they can be considered as potential therapeutic targets.
What are your future ambitions?
I would like to continue studying cellular and molecular mechanisms of disease, particularly in vascular diseases like aneurysm or atherosclerosis, or to switch to heart tissue.
Dissertation
Friday 23 October, 10:00, Gene in Neo, Blickagången 16, Flemingsberg