title: Understanding Vascular Diseases: Lessons From Premature Aging Syndromes.
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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Advanced Clinical Science and Therapeutics, The University of Tokyo, Tokyo, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kumagai
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Motozawa
authors.affiliation: Department of Advanced Clinical Science and Therapeutics, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: komuro-tky@umin.ac.jp.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000375:Aging / Q000235:genetics; D019588:Aging, Premature / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D009106:Mummies; D009154:Mutation; D010641:Phenotype; D011371:Progeria / Q000150:complications / Q000235:genetics*; D014898:Werner Syndrome / Q000235:genetics*
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A