NOMIS scientist and board member Martin Hetzer and his colleagues at the Salk Institute for Biological Studies have discovered the ways cells from the human circulatory system change with age and age-related diseases.
LA JOLLA—Salk scientists have used skin cells called fibroblasts from young and old patients to successfully create blood vessels cells that retain their molecular markers of age. The team’s approach, described in the journal eLife on September 8, 2020, revealed clues as to why blood vessels tend to become leaky and hardened with aging, and lets researchers identify new molecular targets to potentially slow aging in vascular cells.
“The vasculature is extremely important for aging but its impact has been underestimated because it has been difficult to study how these cells age,” says Martin Hetzer, the paper’s senior author and Salk’s vice president and chief science officer.
Research into aging vasculature has been hampered by the fact that collecting blood vessel cells from patients is invasive, but when blood vessel cells are created from special stem cells called induced pluripotent stem cells, age-related molecular changes are wiped clean. So, most knowledge about how blood vessel cells age comes from observations of how the blood vessels themselves change over time: veins and arteries become less elastic, thickening and stiffening. These changes can contribute to blood pressure increases and a heightened risk of heart disease with age.
In 2015, Hetzer was part of the team led by Salk President Rusty Gage to show that fibroblasts could be directly reprogrammed into neurons, skipping the induced pluripotent stem cell stage that erased the cells’ aging signatures. The resulting brain cells retained their markers of age, letting researchers study how neurons change with age.
In the new work, Hetzer and his colleagues applied the same direct-conversion approach to create two types of vasculature cells: vascular endothelial cells, which make up the inner lining of blood vessels, and the smooth muscle cells that surround these endothelial cells.
“We are among the first to use this technique to study the aging of the vascular system,” says Roberta Schulte, the Hetzer lab coordinator and co-first author of the paper. “The idea of developing both of these cell types from fibroblasts was out there, but we tweaked the techniques to suit our needs.”
The researchers used skin cells collected from three young donors, aged 19 to 30 years old, three older donors, 62 to 87 years old, and 8 patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated, premature aging often used to study aging.
The resulting induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs) showed clear signatures of age. 21 genes were expressed at different levels in the iSMCs from old and young people, including genes related to the calcification of blood vessels. 9 genes were expressed differently according to age in the iVECs, including genes related to inflammation. In patients with HGPS, some genes reflected the same expression patterns usually seen in older people, while other patterns were unique. In particular, levels of BMP-4 protein, which is known to play a role in the calcification of blood vessel, were slightly higher in aged cells compared to younger cells, but more significantly higher in smooth muscle cells from progeria patients. This suggests that the protein is particularly important in accelerated aging.
Continue reading this Salk Institute release
Read the eLife publication
NOMIS Center for Immunobiology and Microbial Pathogenesis
Determining Biological Age in Humans
NOMIS RESEARCH PROJECT