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Dr. Valery Krizhanovsky












We can see the external signs of aging – wrinkles and gray hair – but its central processes are hidden from sight within tissues and organs. One of these processes, called cellular senescence, occurs when cells keep functioning but stop reproducing. A better understanding of this senescence may in the future help keep the body's tissues “forever young,” so as to prevent cancer or degeneration of organs or treat aging-related diseases.

What is the natural purpose of senescence in the body? What causes senescent cells to accumulate with age? Is it possible to prevent aging or at least remove senescent cells from the tissues? These are some of the questions investigated in the laboratory of Dr. Valery Krizhanovsky of the Molecular Cell Biology Department at the Weizmann Institute of Science.

During the postdoctoral studies he conducted at Cold Spring Harbor Laboratory in New York before coming to Weizmann, Krizhanovsky and his colleagues revealed that cellular senescence plays a much more active role in fighting and preventing various diseases than previously thought. For example, tumors shrink during chemotherapy not only because cancer cells self-destruct, but also because a rising number of these cells becomes senescent.

Moreover, Krizhanovsky discovered that in the liver, cellular senescence is necessary to prevent disease. When liver cells are damaged by the hepatitis virus, fatty liver disease or alcohol abuse, cells called fibroblasts start dividing to repair the damaged tissue. Krizhanovsky found that when the fibroblasts undergo senescence and stop reproducing, the repair process stops and the tissue can return to the normal, pre-damage state. This senescence is needed to prevent a different kind of damage: It averts fibrosis, the overproduction of scar tissue by the fibroblasts, which in turn can lead to cirrhosis of the liver, a common cause of death in developed countries.  

Krizhanovsky then showed that yet another important phase in the healthy maintenance of tissues is the clearance of such senescent cells from the body. In the liver, the immune system’s “natural killers,” the NK cells, enter the picture, removing the senescent fibroblasts. If the removal is impaired or if the fibroblasts don’t become senescent, the result is continuous liver damage. “Cellular senescence provides first aid, like a clamp fastened on a torn artery to stop bleeding,” Krizhanovsky says. “But just as the clamp will cause harm if it’s not removed in time, so senescent cells that are not cleared properly from the body start releasing inflammatory substances, which in the long run cause damage to surrounding tissues.”
Senescent liver cells in culture
In more recent research conducted at the Weizmann Institute, Krizhanovsky uncovered the molecular mechanisms that underlie the clearance of senescent cells. He identified the receptors on their surface that help their identification by the NK cells; in addition, he found that the NKs kill the senescent cells by releasing a protein that perforates cellular membranes and lets a killer protein get into the cell.

With the help of drugs based on these mechanisms, it may be possible in the future to prevent fibrosis of the liver or other organs, or to treat aging-related diseases, such as certain forms of arthritis or atherosclerosis, in which senescent cells are involved. The drugs will help remove senescent cells that the body is not clearing properly.

Such drugs may also help prevent cancer. In the past few years, scientists have shown that cellular senescence is one of the body’s natural mechanisms for blocking cancer in its early stages. That is probably the reason many precancerous growths, such as moles that with time might turn into melanoma, contain a large proportion of senescent cells. An efficient removal of these cells from the body may help avert the transformation of precancerous lesions into full-blown cancer.

And in a more distant future, it may even be possible to remove senescent cells from tissues to delay aging and promote health over the years.

From Embryos to Aging Cells

During his doctoral research at the Hebrew University of Jerusalem, Dr. Valery Krizhanovsky studied the fate of cells in embryonic development. But his interest in cellular fate in more general terms ultimately led him to the other extreme of the cellular lifespan: senescence.

Krizhanovsky, born in Ukraine, had begun his studies at the University of Kursk in Russia, in the faculty of pharmacology. When he immigrated to Israel with his parents in 1991, he continued his studies at the Hebrew University. Starting in 2005, he went on to conduct postdoctoral research at Cold Spring Harbor Laboratory in New York, before joining the faculty of the Weizmann Institute in 2010.

Krizhanovsky lives in Rehovot with his wife Regina and their two daughters, Maya and Mika. In his spare time, he enjoys reading, particularly on theories and the psychology of economics.

Dr. Valery Krizhanovsky’s research is supported by the Simms / Mann Family Foundation; the Victor Pastor Fund for Cellular Disease Research; and Lord David Alliance, CBE. Dr. Krizhanovsky is the incumbent of the Carl and Frances Korn Career Development Chair in the Life Sciences.