A New Possibility for Anti-Aging: Senescence Inhibition of Vascular Endothelial Cell Prevents Atherosclerosis

  • Read in Japanese
  • 2014/03/25

Dr. Toshio Hayashi at the graduate school of medicine, Nagoya University, and his co-researchers have discovered that the liver X receptor (LXR) prevents cellular senescence and consequentially, atherosclerosis and diabetes. In addition, they elucidated that in combination with metformin, an antidiabetic, an adverse effect of the LXR, such as fatty liver, can be avoided. Their paper was published in Proceedings of the National Academy of Sciences of the United States of Americaon January 21, 2014.

Japan is aging at an unprecedentedly rapid pace. For medicine and research, the accumulated data of various patients is essential. However, the collection of data concerning elderly people over 75 years old, whose population constitutes up to 10% of the total population, and who concurrently represent up to a 40% of the total number of patients in Japan, has just started. To provide an optical clinical treatment for seniors and to forestall aging, geriatrics is one of the most urgently required branches of medicine in Japan. Vascular conditions play an important role in the health of the aged. As is well expressed in the words of Sir William Osler, "A man is as old as his arteries." Preventing cellular senescence can lead to the prevention of geriatric conditions because many disorders are triggered by atherosclerosis. Blood vessels have a cell layer, the endothelium, which excretes nitric oxide (NO). NO has antioxidant effect, inhibits oxidization and deposition of Low density lipoprotein into sub-endothelial spaces, and evokes vasodilatation. Endothelial cellular senescence diminishes the secretion of NO causing narrow blood vessel. As a result, atherosclerosis and diabetes are more likely to be manifested. Previously, medicines like nitroglycerin were used to artificially increase NO and maintain vascular enlargement in atherosclerotic patients (especially patients with angina pectolis); however, the vessels soon acquire drug tolerance unsuited for chronic therapy. Therefore, new approaches to activate endothelium rather than new medicines are currently in great demand.

Dr. Hayashi, Professor Louis Ignarro at University of California, Los Angeles (a Nobel laureate in physiology or medicine 1998), and their co-researchers previously discovered that high glucose-level in nutritive fluid, just like diabetes status in people, accelerate endothelial cellular senescence. To determine a substance able to prevent the endothelium and vascular aging, Dr. Hayashi examined various potential molecules by dusting over human umbilical venous endothelial cells cultured for 72 h under a high glucose condition at 3-4 times its normal rate. As a result, he elucidated that LXR, which is also involved in the metabolism of carbohydrates and fats in the liver, has an antiendothelial cells aging action and consequentially promotes NO excretion, therefore preventing atherosclerosis.LXR has attracted broad attention; however, because it triggers fatty liver it was believed that its practical applications were limited. To solve this problem, Dr. Hayashi investigated the interaction between LXR and existing medications discovering that when metformin, a diabetic medicine used universally in the world (and more frequently in USA), is administered with LXR, it can prevent fatty liver. The result was demonstrated by animal experiments. It is widely expected that a combination therapy using LXR and metformin could be applied clinically.Dr. Hayashi, through his research on citrulline, also actively contributes to the development of anti-aging products in cooperation with the industry.

Dr. Toshio Hayashi

When Dr. Hayashi was a doctor in practice at a hospital, the department of internal medicine was divided into many disciplines. He experienced working in various departments and met many elderly patients who he examined in various disciplines, and many of the symptoms were caused by vessel disorders such as myocardial infarction and stroke. He was motivated to comprehensively examine elderly patients through his knowledge on underlying disorders like arterial sclerosis and chose Nagoya University Community Healthcare and Geriatrics, which was established at the fourth place among Japanese national universities. He aims to provide an optical clinical treatment for seniors, and contribute to the progress of medicine in support of a rapidly aging society.

Outlook for the Future

"Elderly people of at least 75 years old constitute approximately 40% of all the patients in Japan and many of the elderly patients suffer from multiple diseases. To overcome the current situation and to allow the elderly to play an active role in the society is a main goal not only for Japan but also for the rest of the world. Research on geriatric conditions has just started. I would like to advance geriatric, diabetic and vascular endocrinological medicine so that everyone can take a positive approach to aging and to the diseases related to aging."

Message to Young Students

"Japan is well on the way to become a super-aging society, but other countries must also cope with the same phenomena in the future. To squarely learn and prepare for an aging society not only contributes to medicine but also to broader fields. If we succeed in coping with the problems of an aging society, our case can offer a guide to others in the world. In dealing with illness I take much notice on the fact that lifestyle diseases like diabetes are significantly involved in aging. Why shouldn't we explore these topics with the highest interest?"


Research Information
Dr. Toshio Hayashi Information