Dr. Valery Krizhanovsky is a modern Juan Ponce de Leon, looking for a Fountain of Youth. The Weizmann Institute molecular biologist is not, however, seeking an anti-aging cure for wrinkles but a way to eliminate senescent cells in various organs of the body to delay or prevent age-related diseases.
Born in the southeastern part of the Ukraine as an only child, Krizhanovsky studied at pharmacy school in the Russian city of Kursk. Fortunately for science, he never completed his studies there due to technical reasons. His father, an aeronautics engineer, and his mother, a dentist, accompanied him at the age of 20 to Israel to settle.
“As Jews,” he recalled, “we felt the future is not in the former Soviet Union but in Israel.
The philosophy of life is better here,” he recalled.
Not interested in becoming a physician, he completed his first degree in nutrition at the Hebrew University’s Faculty of Agriculture, Food and Environment and then conducted research and earned his master’s degree. He then returned to HU for his doctoral study with developmental biology Prof. Nissim Ben- Arie on the genetics of the nervous system.
Krizanovsky did post-doctoral studies at the Cold Spring Harbor Lab in New York, an internationally renowned research institute whose researchers included Dr. James D. Watson, co-discoverer of DNA’s double helix, and seven other Nobel Prize laureates. Then he returned to Weizmann as a researcher and lecturer.
His wife works in on the administrative side of science in the field of grants for research.
Their two daughters, age 13 and 10, are too young to consider a career.
“We want them to do things that interest them and that they are the best in,” he said in very fluent, accented Hebrew that he learned almost completely in Israel.
“I have focused on the molecular cell biology of aging; it interested me from early on.
I am very satisfied here. There are excellent students and a good atmosphere. I have eight or nine people working in my lab,” he said in an interview with The Jerusalem Post. He will present his work at the MIXiii Biomed conference, May 23-25, in Tel Aviv, which is dedicated this year to aging and age related diseases.
Few laymen – or even scientists – know much about the multidisciplinary subject of cellular senescence; to some the term may bring to mind the obsolescence of smartphones.
Senescence comes from the Latin for “to grow old” and is a natural cellular response that can be trigged by damage to the DNA and other factors. Eventually, it will probably be dealt with in the future by stimulating the immune system to attack the unwanted cells.
In fact, cellular senescence is a programmed state in which the stable cell cycle is halted.
Cellular senescence is now considered a fundamental cell process playing important physiological roles in embryonic development, wound healing and tumor suppression, but ironically, it is also involved in pathophysiological conditions including age-related diseases, notably cancer and degenerative diseases such as sarcopenia, atherosclerosis, Parkinson’s disease and Alzheimer’s disease.
As such, research on therapeutic strategies in the field, said Krizhanovsky, has gained tremendous momentum. Last year, he organized a meeting of the Cell Senescence Association at Weizmann in Rehovot, and some 200 scientists attended. This year’s conference has just been held in Paris.
SOME LAYMEN have heard the simplistic idea that aging is the result of the shortening of telomeres, a kind of cap at the end of each chromosome that protects it deterioration or from fusion with neighboring chromosomes.
They are like the plastic tips at the end of shoelaces that, when the coating deteriorates and frays, they no longer function.
Without telomeres, the DNA strands become damaged and the cells can’t function properly.
“Telomeres getting shorter can be one of reasons for aging, but it is not the central one. The main cause of aging is a combination of a lot of factors that can happen simultaneously and at different levels – molecular, physical and physiological,” explained Krizhanovsky.
“The telomeres in mice are very long and don’t get shorter, but that doesn’t make them live any longer.”
Senescent cells, which stop dividing, accumulate in the tissue. I do all my research on mice or on human tissue in the lab. Just as senescent cells accumulate in the tissue of mice, they accumulate in the tissues of people.
We assess them quantitatively.”
Mice can live for about two and a half years, some maybe more. There is another rodent model that can live for 35 years underground.
They live in the north and are called naked mole rats.
“They don’t get cancer but rather die of old age. We don’t work on them, but I believe there is a lab at Haifa’s Technion-Israel Institute of Technology that study them.”
He doesn’t know about senescent cells in insects or birds, but they do exist in other mammals and in fish.
Senescent cells accumulate in mammalian organisms as they get older, he explained, and they are present in sites of age-related diseases.
While senescence aids embryonic development and limits the transformation of cells into cancer cells, the presence of senescent cells in tissues of the adult organism can also promote the appearance of tumors, a decline in tissue function and tissue aging.
“When senescent cells gradually accumulate in tissues they promote a chronic ‘sterile’ inflammation, a hallmark of unhealthy aging. Several genetic studies in mice suggest that the elimination of senescent cells from the organism leads to extension of the mouse’s health span and lifespan. So, drugs allowing the efficient elimination of senescent cells in the mouse is a promising strategy for treatment of age-related diseases associated with accumulation of senescent cells.
“We eliminate senescent cells from mice using this pharmacological approach and study the effects of such elimination on the aging of the organism as a whole and on specific age-related diseases. A few age-related diseases account for most of the causes of death in old people. Senescent cells accumulate in premalignant lesions, sites of tissue damage and in normal tissues during aging.
We study the effect of the elimination of senescent cells in mouse models of these diseases.
One of these diseases, chronic obstructive pulmonary disease, mostly involves chronic lung inflammation and is one of the leading causes of death in humans,” he said.
HIS TEAM studies the positive link between epithelial cell senescence and progression of chronic lung diseases.
“Altogether, these studies focus on elimination of senescent cells as a promising strategy for extension of health span and lifespan as well as directed treatment of age-related diseases and to uncover the molecular mechanisms of the effect of senescent cells on these conditions.”
When the senescent cells stop dividing, they become pro-inflammatory, release cytokines, enzymes and other things that change the cells’ environment and are not good for the tissue. The immune system has to be called in to kill them off. The tissue cannot return to the state that existed before the damage was done.”
Until around 2005, when several articles published in Nature showed that senescent cells can prevent the development of malignant tumors, this field of research was very limited, recalled the Weizmann researcher.
“We don’t understand the process. Maybe when we do, we’ll be able to prevent the development of a premalignant growth into a cancerous tumor.”
THE FIRST description of senescent cells, said Krizhanovsky, was made by Prof. Leonard Hayflick, an expert in anatomy at the school of medicine of University of California at San Francisco who was a professor of medical microbiology at the Stanford University School of Medicine. Hayflick, who marked his 89th birthday yesterday (May 20), has studied the aging process for more than three decades. In 1961, he discovered that human cells divide for a limited number of times in a controlled environment outside a living being; his discovery became known as the “Hayflick limit.”
For a few decades, not many people were interested in the field of cellular senescence, and it was hard to get funding for research.
Those Israelis who do post-doctoral research usually do it in the US, and there was skepticism about senescent cells, so only a few labs there studied the subject. But there were a number of very good labs in Europe – in Germany, the Netherlands, Spain, England, and now at the Pasteur Institute in France that actively pursued it.” Their work piqued the interest of researchers in the US as well, and the field got a boost.
Although the Krizhanovsky lab does not conduct experiments on patients, “we cooperate with doctors, too, including some at Meir Medical Center in Kfar Saba and Hadassah University Medical Center in Jerusalem.”
Senescent cells “look different” than other cells that keep dividing. They are large and flat, as if they were eroded, like a yolk in an egg. As they accept blue tinted liquid, it looks like a blue fried egg, he said.
“They can be found in every type of tissue that divides naturally, such as the skin, digestive system, the lungs, kidneys, skin and hair.
But we know very little about their existence in the heart or the brain,” he went on.
“We want to understand why they don’t die on their own. There is an apparatus involving the amount of protein in them that prevents death of the cells [apoptosis]. When we reduce the amount of proteins, the cells die.
We could administer chemicals to kill them, but there are side effects that can cause more damage than benefit.”
Senescent cells accumulate in the skin. “If we kill them, there is a rise in the division of progenitor cells, thus this could cause more renewal of skin cells, he suggested. As for baldness, senescent cell research could contribute significantly, as it may be that if they are eliminated, hair grows. It has been done in mice in a lab in the Netherlands.”
He doesn’t know if the elimination of senescent cells in humans will make them look young.
“There are a lot of promises at this stage, but my lab is focusing on diseases connected to aging. This will make it possible to extend longevity and the number of years people are healthy. People live longer today than they did a century ago because nutrition is better, there are statins to reduce cholesterol in the blood, we have antibiotics to deal with bacteria and fewer people smoke. People’s telomeres are not longer today than they were in 1900, but humankind lives longer because there are better conditions.”
The Weizmann scientist predicts than in another five to 10 years, “the understanding of senescent cells will produce clinical treatment in patients – probably not in cancer patients, but in those suffering from diseases connecting to aging like osteoarthritis. Such medications – pills or injections – would have to be given once in a while, not daily.
“In the meantime, we have to understand more from basic research.”