Understanding Vascular Diseases: Lessons From Premature Aging Syndromes

Yuichi Ikeda, Hidetoshi Kumagai, Yoshihiro Motozawa, Jun ichi Suzuki, Hiroshi Akazawa, Issei Komuro

Research output: Contribution to journalReview article

5 Scopus citations

Abstract

Early human mummies examined recently by computed tomography demonstrated a high prevalence of vascular calcification, a pathognomonic sign of atherosclerosis, which was correlated with estimated age at death. Early populations had little exposure to modern-day metabolic risk factors: these observations thus suggest that humans have an inherent age-dependent predisposition to atherosclerosis. Premature aging syndromes are extremely rare genetic disorders that exhibit clinical phenotypes resembling accelerated aging, including severe atherosclerosis, but those phenotypes are usually segmental. Controversy persists, therefore, regarding the extent to which the molecular mechanisms underlying premature aging syndromes overlap with those of physiological aging. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome are well-characterized premature aging syndromes. HGPS is caused by gain-of-function mutations in the LMNA gene, which result in the accumulation of a mutant nuclear protein, called "progerin," at the nuclear rim. In contrast, loss-of-function mutations in Werner syndrome ATP-dependent helicase (WRN) lead to Werner syndrome. Mesenchymal stem cells (MSCs), which can differentiate into vascular cells to maintain vascular homeostasis in response to injury, are severely affected in these syndromes. Mechanistically, either aberrant expression of progerin or loss of WRN protein in MSCs alters heterochromatin structure, resulting in premature senescence and exhaustion of functional MSCs in premature aging syndromes. Surprisingly, vascular cells and MSCs in elderly healthy individuals have shown progerin expression and decreased expression levels of WRN, respectively. Studying these rare genetic disorders could thus provide valuable insights into age-related vascular diseases that occur in the general population.

Original languageEnglish (US)
Pages (from-to)650-658
Number of pages9
JournalCanadian Journal of Cardiology
Volume32
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Ikeda, Y., Kumagai, H., Motozawa, Y., Suzuki, J. I., Akazawa, H., & Komuro, I. (2016). Understanding Vascular Diseases: Lessons From Premature Aging Syndromes. Canadian Journal of Cardiology, 32(5), 650-658. https://doi.org/10.1016/j.cjca.2015.12.003