Biogerontology (2005) 6:211–221 DOI 10.1007/s10522-005-7949-2
Ó Springer 2005
Interview
‘‘My involvement in aging research was just a series of coincidences’’ An interview with Kenichi Kitani Sataro Goto Faculty of Pharmaceutical Sciences, Department of Biochemistry, Toho University, Miyama 2-1-1, 274-8510, Chiba, Japan (e-mail:
[email protected])
I have known Dr. Ken Kitani closely since the first Congress of the International Association of Biomedical Gerontology (IABG) was organized by Denham and Helen Harman in New York in 1985, at the same time when the 13th World Congress of the International Association of Gerontology was held there. Coincidentally, at the IABG meeting, we were the only two participants from Japan. Since then I have been deeply impressed by Ken Kitani’s active involvement in domestic as well as international gerontological activities. I dare to say that he has not necessarily been very popular in Japan, simply and curiously because he has his own philosophy on aging research and life, and speaks up for what he believes regardless of whether it is welcomed by others or not as you can imagine from this interview. Ken has definitely been a maverick and this sort of attitude has not been very common in Japanese culture. Nevertheless, he was highly evaluated by leading scientists such as Professors Kunio Oota, and Kazutomo Imahori (the founding and second Director General of Tokyo Metropolitan Institute of Gerontology (TMIG), respectively), and more recently by Professor Akihiro Igata (Director of NILS hospital) who had recruited Ken as the founding Director of National Institute for Longevity Sciences (NILS), from the University of Tokyo. I believe that the readers of Biogerontology will enjoy learning how one of the leaders of modern aging research in Japan has struggled to establish himself as an internationally renowned gerontologist.
A new job at the Tokyo Metropolitan Institute of Gerontology Sataro Goto: Ken, I believe that you are the most appropriate person to tell us about the modern development of aging research in Japan, since you have been involved from the beginning of TMIG and also of NILS (which was reformed as a part of the National Center of Geriatrics and Gerontology as of March 2004) as a Section Chief and Director General, respectively. Let me ask you first about your own involvement in aging research. Why and how have you been involved in aging research as a clinical doctor of internal medicine? Kenichi Kitani: The answer to that question is very simple. I got a job in that institute (TMIG) which started in 1972 just by chance. Just before TMIG was opened, I had come back to Japan from the US after spending 2 years at UCLA, in
the Laboratory of Radiation Biology and Nuclear Medicine. Just by chance I got a job as the Chief of Laboratory of Clinical Physiology at TMIG, because I was simply a quick replacement of a senior scientist who declined to take the job at the last minute. At that time, I had no idea what gerontology was, nor did I even know the word of gerontology. So I did not have any active motivation toward gerontological research. But, just because I got a job there, I somehow started aging research in 1972. SG: What was the general atmosphere of aging research at TMIG when you started your work? KK: I have no clear idea about what kind of general atmosphere we had at that time. In that institute we had 35 laboratories including not only biomedical ones but also those of social gerontology. In 1977, 5 years later, 186 research
212 subjects were clearly registered in our annual report. So you can imagine how diverse our research activities at TMIG were, at least in the initial stage of our activities. But if I remember correctly, those who were really claiming that they were doing aging research were mostly scientists involved in the so-called Hayflick model of cellular senescence. That atmosphere continued for the first 5 or 6 years. Then there came a time of some kind of turning point from cellular senescence to organismic aging, although work on cellular senescence had been pretty strong. That is about all I can recall now. SG: I imagine that the late Professor Oota, the founding Director General of TMIG had a special idea about aging research and how it should be carried out in a country like Japan, which was one of the developing countries at that time. What was his idea? KK: I have never asked him directly what his idea on aging research was. So this is only my guess. Professor Oota was a cancer researcher and pathologist. I don’t really know what idea he had about aging. What is certain is that his enthusiasm for research on aging came mainly from his own past experience in cancer research. When he was young, cancer research was not a science. Those who had started to work on cancer had a hard time pursuing it, since they were not financially well supported. Nor could they see any bright prospects for their future careers in such a research field. That experience of Dr. Oota must have been a key reason why he was so enthusiastic about aging research, because there was also no sure prospect for a scientist in aging research and he couldn’t see any sure direction for aging research. I mean, we did not know which research direction to pursue. I think he loved the analogy between aging research at that time and cancer research in his own young days. So it means, emotionally he was very enthusiastic about establishing this new institute on aging, but I don’t think he had any clear idea about what we should do, just like all of the others at TMIG, including myself. I’m afraid that is all I can tell you. But of course, this is only my own feeling and totally my guess.
Associations with foreign collaborators SG: I understand that Professor Oota had an idea that aging research should be done not in a local or domestic but in an international framework. So actually, in that sense you yourself followed his idea, inviting many foreign scientists to your own laboratory. Can you tell me the history of your international collaborations? KK: We had a very good system, even from the start of TMIG, for inviting scientists from abroad, which was granted every year by the Tokyo Metropolitan Government. So it was not difficult financially for us to invite someone from abroad, but for a new institute with a new science, aging, it was not easy to invite foreign scientists, because no one outside my country knew about our institute. Even in the scientific communities of Japan, our institute was not well recognized for a long time. So in the first 5 or 6 years, there was no way for us to invite foreign scientists. The first foreign scientist who came to my own laboratory was from the Netherlands, where there existed a very good institute on aging, the TNO Institute on Experimental Gerontology in Rijswijk. As you know, I was originally from internal medicine and was specialized in gastroenterology, hepatology in particular. Hepatology is the study of the liver. So what I could do initially at TMIG was to find out the relationship between the liver and aging, primarily the effect of age on liver functions, first whether aging affects liver functions or not. If it did, I wanted to examine how aging affects liver functions. I found in the literature that a Dutch group was working on the liver and aging, so I communicated first of all with people in that institute. Also I wrote to them that we had a system of inviting foreign scientists, so that if someone was interested in coming to my laboratory, he or she would be welcome. I got one young scientist whose name was Kees van Bezooijen who spent 6 months in my lab in 1978. The second one was Imre Zs.-Nagy from Debrecen Hungary. The relationship between Imre and me is quite interesting and may probably still interest some scientists outside my country. You may know
213 that we have had some disagreement rather than agreements on his thesis of the Membrane Hypothesis of Aging (MHA), after working for more than 20 years together. SG: Yes I know, I have heard about it directly from him as well. KK: Our relationship started in 1977 in Giessen, Germany, where I was invited to ‘‘The Liver and Ageing Symposium’’ organized by Prof. Dieter Platt at Giessen University. Imre was also there. He was already advocating his ‘‘MHA’’. Every time he spoke about it, he was attacked by all the other participants. I could not understand what he was insisting. In fact, the discussions people were making were too difficult for me to understand. But anyway it was quite unusual and interesting for me to see and to hear one guy being attacked by all the other participants. So I remembered his name quite well. Two years later when I came back from my stay at the TNO institute in the Netherlands, I was getting more and more interested in cellular membranes, in my case the surface membranes of hepatocytes. Then I got interested in what this crazy guy was insisting in Giessen. I thought some may have been terribly wrong in Giessen. If Imre was right, all other participants in Giessen should be wrong, which is quite unusual. Of course, I could not judge whether Imre was right or wrong. I thought that the best way for me to judge whether he was right or wrong was to invite him and work together. That was the major reason why I decided to invite him to my laboratory in Tokyo. In 1981, in the International Congress of Gerontology (ICG) meeting held in Hamburg, we discussed more seriously and realistically what kind of research project we could plan. Then he proposed to work on the so-called FRAP, ‘‘Fluorescence Recovery after Photobleaching’’ technique. When I came back from Hamburg, I asked Professor Imahori, the second Director General of TMIG, to arrange a special budget of 6 million yen in the annual budget of the following fiscal year. Probably because Prof. Imahori was originally a ‘‘physicochemist’’, he was very interested in this particular project. In the fiscal year of 1982, Imre came to our institute and started to make the instrument and finished it in
2 months, an amazing job. That is the initiation of the relationship between us. He came to TMIG more than 10 times, to University of Tokyo and to NILS as well. He told me that he spent totally more than 2 years with me. For more than 20 years we have been collaborating as well as quarrelling and discussing. I will talk about Imre later and about the unsettled arguments between us. The next one should be Cristina (Maria-Cristina Carrillo) from Argentina. At first, she made an application for a grant from the Matsumae Foundation in Japan and she needed a Japanese scientist to support her. Although I had not known her name and work at all at that time, I agreed to be a supporting scientist, but it was not granted. Then in that particular fiscal year, there was one cancellation in our invitation system and we got three empty months. I wrote her a letter asking whether she was willing to come and she quickly agreed to come. So her stay was organized and realized very quickly. She spent 3 months in my institute and it was quite successful in terms of our research achievements. Altogether she came to my lab 4 times and our achievements and our relationship have always been quite successful. Every time she came, we got new results, very publishable and it is amazing that all of the data she obtained in her stays of limited time have been published. After I moved to NILS, she came again to NILS and she did a very fine job. That was a long and very successful story of our collaboration. We published so many papers, first on glutathione S-transferase in the liver and aging (Carrillo et al. 1991) and later on deprenyl (and other propargylamines) and its effect on life span of rodents in relation to its effect of increasing antioxidant enzyme activities in brain dopaminergic tissues (Kitani et al. 2002). The fourth one who is also quite impressive is Gwen Ivy from Toronto, Canada. Of course, I did not know anything about her already very famous work or even her name when I met her for the first time at the San Francisco meeting of American Aging Association (AGE) in 1985. I remember that there was a very small audience present in a big room at the Sir Francis Drake Hotel, where I heard a very interesting story given by Gwen, later called the ‘‘Protease inhibitor model of aging’’. The data were first published in 1984 in the journal Science. Of course she was
214 and still is a neuroscientist and I was a liver physiologist, so I never thought that we could collaborate with each other. But we had a very good neuroscientist at TMIG who was working in a room next to my laboratory whose name was Yasu Ihara, now Professor and Director of the Neuroscience Institute at the University of Tokyo. He was very active at that time and was already a true pioneer in the research field of Alzheimer disease. My idea at that time was that may be I could invite Gwen and let her work together with Yasu. In 1986, I invited her to participate in the ‘‘Third Tokyo Symposium, Liver and Aging’’, the subtitle of the Symposium was ‘‘Liver and Brain’’, a rather peculiar one. She came to Tokyo to attend that meeting in 1986. Yasu was also a major speaker in the Symposium and Gwen and Yasu had a lot of time to talk together. That was the initiation of our relationship. Gwen came to our institute the following summer, 1987, and worked with Yasu. Since 1988, Gwen and I started to work together to develop lipofuscin-like pigments in internal organs, including the liver, by administering intraperitoneally (ip) several protease inhibitors including leupeptin. These experiments took a much longer time to succeed than we initially thought. Finally we found that we needed to administer more than a hundred-fold higher dose (ip) than was needed for the brain (intraventricular) per unit body weight to develop pigments (Kitani et al. 1990). She worked with us three summers at TMIG. We have some other people such as Lora Rikans from Oklahoma, the US and Gyorgy Lustyik from Debrecen, Hungary, both of whom came two times. So we do not have so many visiting scientists but almost all of them are repeaters. SG: I think during the period of your fruitful and beautiful international collaborations, the second Director General of TMIG was Prof. Imahori who was well aware of the importance of international collaboration. What was his general supportive idea on your research or researches at TMIG? KK: Yes, it is true that most of these collaborations started at the time of Prof. Imahori. He supported these collaborations very strongly. As I told you he really dared to grant the risky pro-
ject of FRAP. In the case of Gwen, it was a lucky coincidence that Professor Imahori was one of the main scientists who was involved in the development of leupeptin many years before. He was originally a physicochemist and had a long professional career as a protein biochemist, but had an extraordinarily broad knowledge in different disciplines. So actually, between Prof. Oota and Prof. Imahori there existed marked differences in methodology (pathology vs. protein biochemistry) and more importantly in philosophy, I mean a way of thinking, of course. In terms of leadership too, there was a big difference between the two. Professor Oota encouraged us to do any kind of research, on the condition that we were enthusiastic about it. So it was a sort of absolute ‘‘academic freedom’’. When Prof. Imahori came to our institute, taking over from Prof. Oota, he immediately thought that our research activities were too diverse and wanted to reorganize our institute in the direction of more subject-oriented research, primarily on aging or the health of the elderly. Right after he came, he organized several subject-oriented research projects. He, of course decided all these subjects by himself and then asked us to volunteer for the projects, for which he would grant us specific research funds. His idea was fantastic, but his method of organization was rather ‘‘physicochemical’’, I mean letting people volunteer to be on research teams devoted to a specific subject that he was interested in, regardless of the particular research interests, backgrounds, personalities, talents and human relationships that already existed among his staff. I think he really attempted to give us a kind of culture shock. When a research project turned out not to be working, he reorganized it again or replaced the project leader by another one. Partly because he appointed a leader of these research projects, in a physical–chemical way (in my wording), most of these projects really did not work well, with only a few exceptions. I myself served as a leader of a project called ‘‘Pharmacodynamics in the elderly’’. It is by this project that I started to dissect tissues other than the liver, primarily the brain, for the purpose of elucidating an alteration of pharmacodynamics of drugs affecting the central nervous system (CNS) with age. The final conclusions of this project were ‘‘the sensi-
215 tivity of the CNS to depressants is enhanced with age, while that to stimulants declines with age’’. Actually this was the confirmation of observations made by Fritz Verzar many many years ago, but we made it clear that this is not due to an alteration in kinetics, including hepatic drug metabolism. Further we found that while a CNS stimulant tends to be less effective with age, its lethal dose (and brain concentration) becomes lower, so that its therapeutic window becomes increasingly narrow with age (Nokubo and Kitani 1988). Dr. Imahori himself went to the US to establish a formal collaborative relationship between the National Institute on Aging (NIA) in the US and TMIG. We maintained, I don’t remember how long, but anyway, for more than 10 years, an official collaborative research program between the two institutes. We exchanged scientists and had symposia practically every year in one of the two institutes. Organizing liver and aging symposia SG: You have made great contributions by organizing international symposia especially on Liver and Aging. What was your idea of having such a symposium in Japan? KK: Well, Sataro, there were a couple of moments. First, in 1972, I attended the ‘‘Gstaad symposium’’ on the liver which was organized by my old liver friend, Gustav Paumgartner in Switzerland. I was very impressed with the organization, discussions in particular. I dreamed that some day in the future I could organize such a small, closed symposium in Japan so that young scientists could become very motivated without paying a huge sum of money to go abroad. Second, just because I was working on the liver and aging and realized that there was such a small number of scientists working in the field of liver and aging, but in broadly scattered disciplines such as gerontology, liver biochemistry, clinical hepatology, pharmacology and toxicology, liver drug metabolism etc., I really wanted to have all these people in the same room to discuss the liver and aging. In 1978, right after the ICG meeting in Tokyo, the First Tokyo Symposium, Liver and Aging
was held. I was enthusiastic about recording all the discussions, which I thought should also be published. The proceedings were published very quickly in the same year including all discussions (Kitani 1978). What I wanted to have as the title of the book was to have the year when the meeting was held, that is ‘‘Liver and Aging – 1978’’. The publisher did not like that idea because as soon as it was published, it would appear to be 1 year old, which might hamper a large sale of the book. But I insisted that we needed to have a record that such contributions and discussions were made in 1978, so that it would convey some historical value too, even many years later. At that time, however, I never thought that I could repeat this kind of meeting again, because I had terrible difficulty in raising funds for the meeting, but actually we could hold meetings with the same title of ‘‘Liver and Aging’’ until 1990, every 4 years, totaling 4 times. But, to me, the first one was most impressive because every experience was totally new to me. The primary forces which contributed to the continuation of this task were enthusiastic supportive responses from abroad. Domestically, however, I had no response at all.
Masoro and Kitani: two ‘‘stubborn’’ guys SG: I understand that because of your broad research activities on liver drug metabolism and pharmacodynamics affected by aging, you were once invited to a WHO meeting on Environmental Problems and Aging held in Geneva, Switzerland. What was your role in that task force? KK: WHO had maintained a project called the ‘‘Environmental International Program on Chemical Safety’’ co-sponsored by the International Labour Organization (ILO). They were publishing a series of booklets called ‘‘Environmental Health Criteria’’. When I was invited to co-chair the task force to discuss and publish a book from WHO in 1991, they were trying to make a booklet entitled ‘‘Principles for Evaluating Chemical Effects on the Aged Population’’ (International Programme on Chemical Safety 1993). While they were evaluating toxicologies of many different chemicals for many years, I think they started to wonder how age affects toxicities of these
216 chemicals and how they needed to take the effect of age on toxicities of chemicals into account. They already had the second draft for this project. Later I heard that while they were collecting literature from all over the world which might be helpful for that particular subject, they found many papers related to this topic from my laboratory, more than 20, which was the largest number of references from a single laboratory among some 600 references they had already selected in their preliminary draft. I think that was the reason why I was recruited very suddenly. Our task force made the draft into the final one. Our group was called a task group. About half of us were from toxicology disciplines and the other half were from gerontology. I and Jan Vijg co-chaired the group. We had many complex discussions. One big issue was on the age of animals. How do you define young and aged rodents by the chronological age of animals? Toxicologists insisted very strongly that young adult rats should be 3 months old, not older. Gerontologists especially myself and Jan strongly disagreed. Anyway, all toxicologists firmly believed and insisted that 3-month old rats and mice are fully matured animals because they have a full reproductive capability but we disagreed that animals have to be 10–12 months old to be called young adults. We could never reach an agreement on this point and finally the draft had to say that the selection of animal age had to be carefully done, something like that. Another big discussion started when we came to a chapter on diets, husbandry conditions of animals. Dr. Edward Masoro from San Antonio declared that we should say that ‘‘a protein intake is hazardous’’ period. I was very upset because without eating proteins, we can’t survive. I asked him ‘‘Would you please add the word ‘excessive’?’’ That is ‘‘an excessive protein intake is hazardous’’. If we say simply in our book that ‘‘a protein intake is hazardous’’, it will create a terrible misunderstanding because all over the world, especially in developing or underdeveloped countries, so many people are suffering from the shortage of protein intake. They get a disease called ‘‘protein-calorie malnutrition’’ (PCM). Even in developed countries like Japan, PCM is one of the biggest problems in the elderly population. So I repeated again and again
‘‘please add ‘excessive’’’. However, he did not agree. He just said that ‘‘a protein intake is hazardous’’ should be described in the text. He totally ignored my discussion. So I thought that may be my English did not work with him, may be he simply couldn’t understand my English. Later it turned out that he could understand what I was insisting at that time. Many years later, my Korean friend, B. P. Yu, who had been with Dr. Masoro for many years, visited NILS. I told him my particular experience with Dr. Masoro and I was trying to find out one suitable adjective in English to express my feeling about him, which was very difficult, but finally I said ‘‘stubborn’’. Then B.P. showed me a funny face and told me, ‘‘He (Masoro) used the same word for you when he came back from Switzerland’’. So actually, he could understand my English and yet he tried to ignore my discussion. I checked that booklet this time to see how that issue was handled and found that a protein intake issue was very nicely edited including a discussion on PCM. Caloric restriction in humans: ‘‘I am rather sceptical’’ SG: Regarding nutrition and aging, many gerontologists including myself are working on caloric restriction that apparently retards aging. Do you have any opinion about it, Ken? KK: The ‘‘Caloric restriction paradigm’’, I am personally not so positive about that. I know Sataro, you have been working on caloric restriction in rodents for many years. But the primary question is whether it works on humans and if it does, how much. That is a big question which has never been answered. I know that in the US, they are now working on non-human primates. My friends at NIA, George Roth and Don Ingram, are very enthusiastic about it. They are showing preliminary data indicating that it improves the health status of monkeys exactly as has been observed in rodents. However, I still am not convinced how much it will work on humans. That is a big question and no one can determine the right answer now. My primary thesis is that if we define ourselves, we are not ad lib. animals. That is ‘‘our intake of foods is usually very self controlled’’.
217 Of course some of us, especially in the US, are not self restricted and may be close to ad lib. animals. For those ad lib. people, it is certain that dietary control is helpful for improving their health. In other words, the caloric restriction strategy may work for some Americans but not so much for the average Japanese, because we don’t have so many obese people in Japan now. Maybe in the future, obesity will become a big problem in Japan too, I agree. A more difficult question is how much we should reduce our food intake, if it works. Another big problem is that for those who may need caloric restriction, it becomes more difficult to do that. I mean to reduce ‘‘food intake’’. It is quite funny, however, that although I am not so positive about caloric restriction, I have been taking only two meals a day (a breakfast and a dinner) for more than 20 years. I started it just because I was always too busy with anesthetized animals at lunch time. I finally decided not to eat lunch and then my habit of not eating lunch started and continued for more than 20 years. As far as I know, the only gerontologist alive who believes that caloric restriction works on humans and is implementing it very strictly on himself is B. P. Yu. He is so skinny and he really does not eat so much, probably because he firmly believes it. I think he, himself, is under a kind of human experimentation by himself. I would like to see how long he will survive, but to do it I need to survive.
Pharmacological and nutritional interventions in aging SG: Ken, I know that you are very interested in interventions in aging. But you are more interested in chemicals such as deprenyl and more recently natural products such as curcumin. What is your idea of pursuing these types of possibilities rather than life style? KK: Of course, life style is quite important. No question about that. Life style has to be done by people themselves. Diets, not diet restriction, are quite important aspects of life style. However, scientists can recommend appropriate diets but
we can’t do anything for people if they don’t follow a diet by themselves. If we can get some other means which can keep people younger, or even if not younger but healthier, then we can provide such a strategy to everyone. Another reason why I have been pursuing the problem of deprenyl for more than 10 years is a question originally given to us by Professor Imahori. He raised a big question, actually as a research topic for one subject-oriented research project I mentioned earlier. That was ‘‘a pacemaker of aging’’. Somewhere in the body, there might be a pacemaker of aging, in other words, there might be some sort of hierarchy determining aging of the body. Some part of the body may be controlling the aging or life span of animals. That was my interpretation of his question of ‘‘a pacemaker of aging’’. We do not know what types of cells, tissues or organs are essential to maintain our lives. Nor do we know even whether such a pacemaker exists or not. Then I came across deprenyl. It has been shown by different investigators including our group that this drug can increase activities of some antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase (CAT) in selective brain regions of dopaminergic nature. Furthermore, starting from the original report by Knoll in Hungary in 1988, different groups including our group have reported the prolongation of life spans of animals of different species by the drug. We have found that a critical key factor is the existence of an optimal dose range for the drug. I mean, not only is too small a dose not effective but too large a dose is not effective or even may shorten the life span of animals. A similar inverse U shape effect has been more clearly shown for its effect on antioxidant enzyme activities. Available data so far suggest that these two dose efficacy relationships are overlapping or almost superimposed. Although this is only circumstantial evidence for the causal relationship between the two effects of deprenyl, there seems to be a good possibility that the protection against oxidative tissue damage by aging of dopaminergic regions in the brain has led to the prolongation of the life span of organisms. If it is true, then, dopaminergic tissues may reside at a higher position in the aging hierarchy, if not highest for regulating aging. By elucidating the
218 mechanisms of the effect of deprenyl on life spans of animals, we might be able to understand yet other mechanisms of organismic aging (Kitani et al. 2002). But recently, as you said earlier, I have started another approach, which may be a more practical approach for intervening in aging. That is a nutritional approach. We know that many plants, especially their fruits, seeds and leaves contain a lot of antioxidants and micronutrients, which are now called nutri(a)ceuticals. We now have a lot of evidence that many antioxidant nutrients can prevent experimentally induced age-associated disorders such as atherosclerosis and cancer in different organs, etc. I examined the effect of tetrahydrocurcumin, a biotransformed and more potent antioxidant of curcumin, contained in turmeric of Indian curry. When we fed mice with tetrahydrocurcum beginning at 13 months, we could significantly increase the average life span of male C57BL mice and even the 10% longest survival as well. Our new trial using green tea polyphenol also looks promising. As I told you earlier in this interview, I never disagree with the role of improvements of life style in achieving a healthy old life. On the contrary, nutrition is the most important aspect of life style. Further, I am walking a lot now, always carrying a step-counter on my belt. In fact, exercise and nutrition are the two key factors for a healthy old life. We should pay much more attention to our foods, not only in terms of quantity which is related to dietary restriction but also in terms of quality (Kitani 2005). In fact, I eat blueberries in yoghurt every morning. SG: The thesis of Jim Joseph? KK: Oh yes.
NILS Workshops on Longevity Sciences SG: I am very glad that you have been the founding DG of the NILS, because you are almost the only internationally well known basic gerontologist in Japan who is interested in both clinical and basic aspects of aging. I think it is quite important for the National Institute because all age-associated diseases have basic biological mechanisms of
aging behind them, so that the Institute should be involved not only in the clinical aspects, but also in the rather basic aspects of aging. So your appointment was very successful in that sense. You have been holding international meetings every year, inviting to the institute prominent scientists from abroad. KK: Actually since 1996, we have had five successive workshops entitled ‘‘International NILS Workshop(s) on Longevity Sciences’’. In addition in 1995, I had two meetings successively, the 6th Congress of IABG and 5th International Symposium on Lipofuscin and Ceroid Pigments, in Makuhari. I also organized two Symposia between Japan and Germany. It means that I have organized international meetings every two years in the past quarter of a century. Every year for the NILS Workshop we had a subtitle, different subtitles focusing on one particular aspect of Longevity Sciences, but again from different approaches and view points. But the last three workshops were on ‘‘Interventions in Aging and Age-associated Disorders’’. All of the proceedings of these workshops were published in special issues of Mechanisms of Ageing and Development. SG: Do you want to say something about these studies in experimental gerontology including your own studies in the past? KK: Since I came to TMIG, and started to work on rats and mice 30 years ago, I have always been thinking, wondering how our results obtained from aging rodents could be extrapolated to humans, probably because I was originally from the medical discipline. I am still wondering about this. I have a strong feeling that a true extrapolation from animal studies can’t easily be done. I have made a number of observations that many biological parameters, seemingly affected by aging in animal studies, are quite variable depending on the animal models used. Sex, strain and species differences are really enormous. In the word proposed by George Martin, ‘‘private’’ observations from one to another animal model differ very widely. In my view, the projection of animal studies to humans for hypotheses of aging should be based on
219 ‘‘public’’ observations which can be reproduced in different animal models, species, strains and sexes, etc. In my view, the practical objective of experimental gerontology is to keep human beings healthier until their old days. Of course, the basic science on aging has to be advanced but at the same time it has to contribute to the health of the elderly. That is the primary reason why I wanted to advance ‘‘interventions’’.
The free radical theory of aging and Denham Harman SG: OK, Ken, finally, let me ask you about recent trends of people working in gerontology in terms of oxidative stress and aging. Everyone now speaks about the ‘‘free radical theory of aging’’ (FRTA), and roles of reactive oxygen species in aging. I am quite sure that Denham Harman is really the pioneer in this thesis. He is still very active by organizing the 9th Congress of IABG in Vancouver in 2001, and by participating in the 10th Congress of IABG in Cambridge, UK in 2003, to see the development of his theory at the age of 88. KK: Yes, he is still so active. He is 20 years older than I am. It is really amazing! SG: It is really impressive that he is still quite active. He is a true symbol of our aging research. KK: He certainly is. In fact, for example almost all topics that have been discussed in the past three NILS symposia on ‘‘Interventions in Aging and Age-associated Disorders’’ are more or less based on antioxidant strategies by means of administering so-called antioxidants or by creating an upregulation of some antioxidant machinery endogenous to the body. In that sense I do believe that free radicals are heavily involved in aging itself, and especially in age-associated disorders too. However, I have something in my mind which does not fit perfectly into the idea that aging is also the same mitochondrial disease as cancer, as is claimed by some people. I think many people now discuss aging and other ageassociated diseases as coming from the same mechanism of mitochondrial oxidative damage. My personal concern about such a simple way of
thinking regards the pathological relationship between cancer and aging, because some people even say that both aging and cancer are caused by oxygen induced tissue damage, presumably initiated by mitochondrial damage. However, as we become older, some people contract cancer but others do not. They die of diseases other than cancer or of senescence itself. Such different outcomes caused by the same mechanism of mitochondrial aging are not easy for me to understand. The particular reason why this question is hanging around in my brain is that we know that if we get older, for example, than 90 years, even if we get cancer, cancer does not kill us so quickly. At that old age, cancer does not grow so quickly, so that we neither suffer from nor die of cancer. Many people die of senescence or of disorders other than cancer even if they have cancer at the oldest age, simply because cancer grows more and more slowly as we get older. In fact, in most developed countries in the world, the death rate per population by cancer drops after 90 years. We know that as the organism gets older, the cell proliferation rate in general tends to be retarded. Polyploidy observed in hepatocytes, brains cells and in others is evidence for that. At the same time, free radical damage is thought to induce cancer at all three phases of cancer development including initiation, promotion and progression. To me, it looks like aging of the body or organism is controlling the growth of cancer cells exactly as it is controlling that of normal cells, thus retarding the proliferation of even cancer cells and thus, the progression of cancer. If aging is caused simply by mitochondrial damage as many people argue, how can the same mitochondrial damage possibly accelerate the cancer cell proliferation, while it causes deceleration of the proliferation of normal cells? Maybe other people could explain this more easily but I am not convinced with such an explanation totally. It still bothers me why organismic aging appears to retard the progression of cancer. So I still keep this question in my mind, hoping that some one can give me a convincing answer to my question. Of course, I don’t have any other theory of aging than the FRTA. Especially for many age-associated disorders, there is ample experimental evidence that oxygen-induced tissue damages are heavily
220 involved in the pathogenesis of these disorders. Furthermore, there is much experimental as well as epidemiological evidence available showing that so-called antioxidant strategies are effective in preventing these disorders (Kitani, 2005). So we need to know whether antioxidant strategies work on aging per se.
dependent enzymes) stay unchanged with age as long as the subjects remain healthy (Kitani 1991, 1999). P-450 dependent enzymes are not the exception. I have also worked on activities of glutathione S-transferase, a cytosolic and antioxidant enzyme. These stay quite stable after maturity and don’t show a general decline with age (Carrillo et al. 1991; Kitani 1991, 1999).
Imre Zs.-Nagy and membrane theory of aging A series of combinations of coincidences in my life SG: Thank you very much. Well, would you like to make any more comments in this interview?
SG: Ken, would you like to say anything else?
KK: I want to add some more comments about the ‘‘Membrane Hypothesis of Aging’’ of Imre Zs.-Nagy. I think many people now know that Imre and I have worked together for more than 20 years but that we still have some disagreement. Our major observation made by the FRAP technique is that the protein lateral diffusion constant in the cellular surface membranes steadily declines in a linear fashion with age, which still holds. However, this does not prove his ‘‘MHA’’. I have a different interpretation of this observation in terms of its physiological roles (Kitani 1999). His ‘‘MHA’’ attempts to explain a general decline in intracellular enzyme activities with aging by an intracellular dehydration, which is caused by the physical–chemical alteration of cellular surface membranes that steadily increases with age (Zs.-Nagy 2001). As I have discussed repeatedly (Kitani 1991, 1999), there is no evidence that intracellular enzyme activities decline with aging in general terms. He has never shown it by himself either. I listed so many examples of no decline, or even up-regulation of enzyme activities, but Imre does not accept these (Zs.-Nagy, 2001), because if he admits this point then his thesis loses its objective and becomes meaningless. He is always complaining that I don’t understand his hypothesis. But my complaint about him is that he does not accept the facts. From my studies in the liver as well as in the brain, I am convinced that many enzyme activities remain unchanged after maturity and during aging. Now there is ample evidence experimentally and clinically that hepatic drug metabolizing enzyme activities (e.g. P-450
KK: I would like to introduce one more story of an unexpected coincidence of events which happened to me that had a great impact on my professional life. This is related to the first Liver and Ageing Symposium I mentioned earlier that was organized by Dieter Platt in Giessen, Germany in 1977. In an airplane in the fall of 1976, on my way back from Europe, the idea came to me that I might be able to organize a small international workshop with the title of ‘‘Liver and Aging’’ in 1978, when the ICG was scheduled to be held in Tokyo. Upon coming back to Tokyo, I was surprised to find that a German professor was actually organizing a symposium with the title of ‘‘Liver and Ageing’’ in April 1977, a few months ahead. I quickly wrote a letter to Dieter (of course I did not know him at all) asking him to allow me to attend his symposium as an observer at my own expense. His letter which came quickly to me was a real surprise. He said that he would invite me as a guest speaker with business class airfare with the condition that I serve as an introductory speaker on ‘‘Functional aspects of ageing liver’’ for 30 min, followed by a chairmanship in the plenary session on the first day until 2.00 p.m. At first, I did not understand what happened to me. Thirty minutes later I figured out from his letter that Professor Hans Popper at Mount Sinai, New York, originally from Vienna, was scheduled to do this major job with the lecture title of ‘‘Morphological aspects of ageing liver’’. He was a super-hepatologist and liver pathologist well recognized all over the world in the field of hepatology. The coincidence was that just because Mr. Carter
221 unexpectedly won the US presidential election, he and his top administration staff were scheduled to do an oath on April 12th, 1977, which was the first day of the symposium. Professor Popper was invited to the oath because he was appointed as the top Scientific Adviser for the Carter Administration. Accordingly his attendance to the Symposium was cancelled. My letter to Dieter reached him right after this unexpected abrupt cancellation. Apparently the only choice for Dieter was to replace Popper by this unknown Japanese fellow with no name, since the symposium was only 2 months ahead. It was by this unpredicted invitation that Prof. Kunio Oota, the founding DG of TMIG changed his mind about me to some extent. He, as a pathologist, was well aware of the prestigious name of Hans Popper. From that time, he began listening to my idea of Liver and Aging in 1978, and helped me a lot in raising funds. Without his assistance, I would have never been able to organize the first symposium and eventually later ones as well. It means that without any one of these four single events, four books on Liver and Aging would not have existed. Of course, I am still very grateful to Dieter for his decision to have me in place of Popper. I feel that almost all the important events in my professional life beginning with my job at TMIG to DG of NILS were determined only by chance and that my life has been directed by a combination of coincidences. Probably, however, I may have actively taken a chance in a rather positive way, every time it came to me.
Acknowledgements SG and KK express their sincere gratitude to Dr. GO Ivy for the careful reading of the manuscript
and linguistic advice she kindly provided for them. Thanks are also due to Ms. T. Ohara for her excellent secretarial work.
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