Cutting edge Seminar

 

Speaker:  Yoshiro Maezawa (Lecturer, Department of Endocrinology, Hematology and Gerontology, Chiba
University Graduate School of Medicine)

Title:  Cellular Senescence and Individual Aging in Werner syndrome

 

 

※This seminar can also be attended through ZOOM. Please check the URL on “HIGO Cutting-Edge Seminar” at Moodle.

https://md.kumamoto-u.ac.jp/course/view.php?id=114380

 

Abstract:

Werner syndrome (WS) is an inherited premature aging disease characterized by the development of gray hair, bilateral cataracts, skin atrophy, and other signs of aging after puberty, and a high rate of diabetes, atherosclerosis and sarcopenia. Patients with WS usually die in the 50s due to malignancy and atherosclerosis. Currently, there is no fundamental treatment for WS. The elucidation of the pathogenesis of this rare genetic disease may provide insights not only into the development of new treatments for WS, but also into the understanding of general aging-related diseases such as sarcopenia, diabetes and atherosclerosis.

Clinically, Werner syndrome presents frequently show metabolic syndrome. Clinical index data from a patient registry showed that WS patients were small, with an average height of 153.6 cm and BMI of 18.4 kg/cm2. However, more than half of them have abnormal glucose and lipid metabolism and hypertension. In addition, grip strength, walking speed, and skeletal muscle mass were low, with a high rate of sarcopenia. Visceral fat area averaged 88 cm2, indicating a tendency toward visceral fat accumulation. In addition, 18.8% of patients have lower limb amputation due to intractable skin ulcers. On the other hand, patients with Werner’s syndrome show little cognitive decline and no central nervous system aging. Based on these findings, aging in Werner syndrome is termed segmental aging.

On the other hand, the pathogenesis of Werner syndrome has not been fully elucidated because KO mice of WRN do not show a premature senescence, and cultured cells also show early cellular senescence, making long-term culturing difficult. We have established iPS cells derived from WS patients, induced differentiation of vascular endothelial cells, macrophages, and myocytes, observed their phenotype, and reproduced signs of aging. We have found that the inflammation-inducing factors called SASP (senescence associated secretary phenotype) are increased in WS-iPSC-derived macrophages and that muscle differentiation is impaired. In addition, we found that mitochondrial dysfunction is one of the mechanisms of aging in WS and that this is ameliorated by supplementation with NAD, a cofactor for Sirtuin, at the cellular level. Then, we conducted the world’s first prospective crossover study of nicotinamide riboside in WS patients.

In this talk, I would be happy to share the results of WS studies and discuss the mechanisms of aging at the cellular and individual levels.