BEJELENTKEZÉS

Quo Vadis – Journal of the Hungarian Society for Gerontology  -  Dr. Sandor Imre

My crooked way to and through gerontology.

Dr. L. Robert

Paris, France

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Born in 1924 in Budapest in a house built by my grand-parents and enlarged by my father, Müegyetemet végzett kulturmérnök, just opposite to an important hospital, ( Szeretetkorhaz, founded by the Hungarian jewish Community, a mai Egyetemi Idegklinika), with a (maternal) uncle, a gynecologist with also a large general practice, who married a midwife (catholic, Rozsi néni, this was the first mixed marriage in the family, many more came later as myself). I always wanted to become a “doctor” (physician). This orientation became more precise at about my 17th year, when my father offered me the famous book by Paul de Kruif, (a former microbiologist at the Rockefeller Institut in New York city): “Bacillus Vadaszok”. I became fascinated by medical research, an orientation further reinforced, when I was accepted in the biochemical laboratory of the neighboring hospital by its chief, Dr Hegedüs Andras (son of the architect who built the Gellért Szallo). I learned basic and medical biochemistry, mostly from german books. I was accepted a few years later in Bruno Staub’s Biochemistry Institute  at the Medical Faculty in Budapest where I hoped to remain for the rest of my carrier.

Our close family was lucky to survive the Nazi era but during the autumn of 1948 the communist overtake became unavoidable. Encouraged by my parents and even more by my brother Misi  who realized clearly the danger of this overtake for a “bourgeois” family, we left illegally Hungary with my brother early November 1948. After an adventurous and difficult (illegal) passage through the Russian army occupied large parts of Europe we arrived – on January 2, 1949 – in Paris from where we were supposed to join our father’s family established in Cleveland, Ohio, USA, since the early years of the last century. We were overwhelmed by the beauty of Paris, although still in post-war times, and as we experienced some difficulties with the American embassy,  we decided to stay in Paris and resume medical studies. We were accepted by Prof. Michel Polonovski , head of Biochemistry Department at the Paris Medical Faculty and resumed experimentation, first on enzymology, studying mainly xanthine-oxidase, an important enzyme of purine metabolism. My partner of early medical studies in Budapest, Klinger Borcsa joined us in June 1949 in Paris, and we finished together medicine – as well as our science-degree , PhD, got married and had our first child, Marianne in 1952 (who also became an MD), followed by two more girls later.

I kept however a strong inclination to what became to be known as connective tissue biochemistry. I learned about elastin from Balo and Banga at the Pathology Department  of the Budapest Medical Faculty and decided from the 1950-ies to work on this fascinating protein, considered as the main target of the atherogenic  process by the  Balo-Banga team who just isolated elastase from the pancreas. Paul Samuel, also from Budapest, joined us in this new adventure, he became later professor of cardiology in New York, specialized in lipid metabolism. Somewhat later, with Borcsa, we isolated the first elastase from the human aorta. These were unfortunately the last experiments she carried out, she unfortunately died in 1974 with an acute myeloid leukemia. This aorta elastase was shown to be closely involved in the degradation of elastic fibers. With a student, William Hornebeck (now at the Reims University in the Champagne county) we could show that this enzyme is upregulated with age and even more so in presence of increased levels of LDL, playing an important role in atherogenesis. Later we established the first Society for Connective Tissue Research, followed some years later by our Hungarian colleagues, on the  initiative of  Prof. Kadar Anna, later head of the 2nd Department of Pathology of the Semmelweis Medical University and with Bihari Magdi, then from Prof. Gerö’s  lab. Both ladies spent a year or more in our laboratory, followed by a number of young colleagues, mainly from the two Pathology Institutes of the Budapest Medical University, headed at that time by Prof. Karoly Lapis, the successor of Prof. Balo, and Prof. Harry Jellinek. We had thus a constant contact and collaboration with Hungarian scientists and Universities, not only from Budapest as shown by my longstanding friendship with Prof. Imre Zs. Nagy in Debrecen, also a former coworker of  Verzar.. We established progressively a relatively large department in University Paris XII (12) centered on connective tissue research with several pathological applications, essentially cardiovascular diseases.

Our approach to gerontology came unexpectedly although not quite by accident; I was invited during the 1970-ies to visit the director of the French National Institute for Medical Research (INSERM: Institut National pour la Santé et la Recherche Médicale), Prof. Constant Burg who wanted me to participate in a study section entrusted with an important budget  to encourage and finance grant-applications  in research on aging  and associated pathologies. This director, originally a biophysicist, understood, before I did, that connective tissues are first to suffer from aging. Cardio-vascular age-changes play an important role in the development of fatal atherosclerotic diseases, comprising strong involvement of extracellular matrix.

Another Hungarian-born scientist, Prof. Verzar Frigyes, originally from the Debrecen  University, became also a good friend. We visited his lab in Basel, he came to our lab in Paris and offered the privilege to study age-changes in rat connective tissues. Verzar discovered the increased cross-linking of collagen fibers with age, known later to be the result of the Maillard reaction, non  enzymatic  glycation (see my review on this subject , written on the 120th anniversary of the birth of Verzar in “Magyar Tudomany” (the Journal of MTA, 2007, 3, 320 – 351). I consider Verzar as the founder of experimental gerontology.

The subject of aging was not quite unfamiliar to me, for several reasons. I spent my second year of medicine in Marosvasarhely in  Erdély. My father came from Kolozsvar, returned there in 1945 to explore the situation , and was immediately appointed  “varosi mérnök” in Marosvasarhely, where his brother Imre, as a “hero” of the first  world war (vitéz Robert Imre), he and his family did survive undisturbed the Nazi era, thanks to this distinction. During the first world war, my father was also seriously wounded as lieutenant on the Italian front, he was also decorated. His life with his close family could make the subject of a thriller movie, but we will not go in these details here.  The Medical Faculty of the Kolozsvari Bolyai Egyetem was arranged in the Katonai Akadémia in Marosvasarhely , where we registered  with my brother Misi for our second year of medicine. Most of our professors came from Hungary. They were of a superior niveau , we learned a great deal from them. The professor of biology was Haranghy Laszlo, endowed with an extraordinary amount and quality of knowledge. We learned a great deal from him. He established, after his return to Budapest, the first Institute for Experimental Gerontology, with Prof. Beregi Edit, with whom we got acquainted during our medical studies in Budapest  where I made the 3rd year of medicine. Some years later Haranghy came to Paris for a meeting, we were together at the banquet. This was just a short time before his tragic death. We continued however to visit and exchange with Prof. Beregi Edit who organized in Budapest  a remarkable congress of the World-Gerontology Association (IAGG).

I red and frequently cited Haranghy’s book on Hungarian centenarians published in 1965, the first of this kind of in-depth study of long-lived persons. I also cite regularly his publication on the autopsy of several centenarians which completely changed a paradigm of this long-lived individuals. Instead of claiming an exceptional health, possibly inherited, the real question had to be reformulated. The autopsy uncovered in each of these long-lived bodies several serious or even fatal diseases. So the question became: how could they manage to live so long instead of dying years ago of any of the discovered pathologies?  Somewhat later his pupil and successor, Prof. Beregi Edit published a second book on Hungarian centenarians with a large amount of detailed informations. I just want to cite one, a surprising result of her comparative study of male and female centenarians: women preferred an afterdinner drink of cognac, males opted for a “palinka”.

Over the years our laboratory converted its activity more and more to experimental gerontology, without however changing its designation as Connective Tissue Research Institute. This is easy to control by going through the list of our publications on the NIH – website. This reorientation was relatively easy: we just had to incorporate in our experiments the time-dimension. When my wife Jacqueline Labat-Robert started to be interested in fibronectin, an interface glycoprotein connecting cells to the extracellular matrix, one of the early experiments she performed with her team was to show that the biosynthesis of this protein is upregulated with age!  The same thing was shown concerning the level of production of proteolytic enzymes capable of degrading fibronectin. Several teams in France and in the USA showed that some of the proteolytic fragments of fibronectin have harmful  effects such as activation of malignant transformation, proinflammatory activity and most curiously some large peptides are endowed with proper proteolytic activity. These serial reactions and interactions of fibronectin represent  a feed-back loop with autoactivating harmful effects increasing with age! Several other matrix components were also shown to produce proteolytic fragments with unexpected biological activities as for instance elastin peptides. All these fragments are called “matricryptins” and opened a new and important field in medicine in general and in gerontological research also with potential clinical relevance.

Besides my friendship with Verzar, we became close friends with some of the most important scientists of experimental gerontology as for instance with Leonard Hayflick who discovered cell-aging, the limit of proliferative capacity of normal (non transformed) cells. We extensively used his method of “in vitro aging” for our experiments.

Finally I want to mention two unexpected results of our engagement in experimental gerontology. One resulted from our studies on skin-aging. The French and international cosmetic industry contacted us for collaboration. Their grants enabled us to stay active well after our official retirement from  the French National Research Center (CNRS) where I made most of my carrier. We were lucky to find not only money for this protracted activity but also lab-space, which was more difficult to find because of jealousy of colleagues. We had to close our lab only when I reached 85 years, quite exceptional for a carrier scientist.

The other, and similar surprising  result of our gerontological orientation is that both of us, with my wife Jacqueline, we are regularly invited to lecture and teach at several Universities. As if we would not have changed, got older over the years. Just last October (2011) we were invited to Krakov  in Poland to lecture on aging for a festivity organized for the 110 year anniversary of Helena Rubinstein whose Paris-based industry now belongs to L’Oreal. Let us hope that this trend will continue some more years at least.