It was Responsiveness, What matters: Operation of Switch for Mortality
After considerable perusal, I had to shift my target for aging research. And I decided to focus on the growth responsiveness of those different states. Why cancer cell grows fast, normal cell grows slow but aged cell does not grow? There have been already many studies on cell cycling activation and growth factor response, but most of the works used to emphasize only the differences in amounts of ligands and receptors or their affinity without any conclusive explanation. At this stage, I set up a hypothesis that there must be some generally operating system in aging process for control of growth factor response. For the candidate, three dimensional regulation for growth factor responsiveness was conjectured, which must be not ligand-specific but more general in action. Through screening of differential expression of genes between young and senescent cells, the receptor mediated endocytosis system was finally selected for targeting, which is one of the general signal regulatory mechanisms. Thereby, caveolin-1 was identified to increase with aging and to suppress a variety of growth factor signaling in general. Moreover, by knock down of caveolin-1, the biosynthesis of nucleic acids was reactivated in the senescent cells and the morphological restoration to young cell like shape was induced though in partial. Therefore, the role of caveolin-1 as one of the general masters via adjusting tyrosine kinase-mediated signal activation was suggested as the mechanism for aging-related hypo-responsiveness to growth factors. Furthermore, the role of ampiphysin-1 in clathrinmediated endocytosis was also discovered to be associated with aging-related hypo-responsiveness as well. With these data of the low efficient growth factor response by aging related alteration of receptor-mediated endocytosis, Gate Theory of Aging was proposed, in which the extrinsic signals for growth are controlled at the membrane level and the efficiency of signaling to switch on/off is dependent on the level of caveolin-1 or ampiphysin-1, which are aging-dependently altered.
In middle of struggling for mechanism of aging, I actively joined the international aging conferences and there I met many aging research Gurus such as Professor Denham Harmon, Dr. Kenichi Kitani, Professor Sataro Goto, Professor Byung Pal Yu, Professor George Martin and Dr. Jan Vijg and so on. With them, I had many opportunities to discuss the aging issues and to be blessed with so many wonderful ideas by those Gurus. And the Korea-Japan aging research exchange program was organized through Japanese Biomedical Gerontology Society and Korean Society of Gerontology since 2002 until now continuously with a purpose of friendship and encouraging young scientists for their international relationship. Again I realized to my heart the importance of lessons from Gurus and friends and the truth that science cannot be achieved alone. Let me remember some of my dear friends in Japan, especially of my same age, born in 1949, which I named the Members of 49ers Club, including Professor Yasuyoshi Ouchi, Professor Nobuyoshi Hirose and Dr. Naoki Maruyama. Every time we met together, none of us hesitated to drink and chat, and we never forgot to encourage each other. Though met by coincidence, but we marched forward with destiny. Yes, it is true that science requires friendship!
Since aging related hypo-responsiveness toward growth factors was explained in terms of membrane function, I was curious about aging dependency of the responsiveness toward stress in the next step. Therefore, a series of experiments were carried out to test and compare the young and old cells with an idea that old cells might be more vulnerable to toxic stress than young cells. However, surprisingly, the old cells showed the resistance toward UV stress and many other apoptotic stress such as oxidative stress, ER stress and oncogene stress. Up to that time, the concept that aging would provide the more liable state to death was prevailed. And I myself had been also in agreement with the idolum that aging means a state close to death, as spoken by Dr. Martin Heidegger in his book of “Sein zum Tode ”. But the experimental data showed the opposite pattern to my preoccupied concept. The old cells are actually more resistant to toxic and apoptotic stress than young cells. This resistant character of old cells toward toxic stress was again confirmed by in vivo experiment.
Young and old animals were compared for apoptosis induction of liver tissues after peritoneal injection of MMS (methyl methane sulfonate), a DNA damaging agent, which resulted in high incidence of apoptosis in young organs but negligible incidence of apoptosis in old organs. These striking data that the senescent state is more resistant to toxic stress than young state in vitro and in vivo clearly elucidate the value of aging as survival strategy rather than death prone program.
Aging is not for death but for survival!! This new concept revolutionized all of my previous preoccupied prejudiced ideas on aging as the inevitable, irreversible and degenerate path to death and redirected me to the new and eye-opening idea of possibility for survival, control and restoration of aging.
Thereafter, I tried hard to bring a light on the nature of aging dependent hypo-responsiveness not only to growth factors but also to apoptotic factors. With many different models and tools, the common pattern of aging dependency toward extrinsic signals was identified as the peri-nuclear accumulation of down-stream signals. Why in aging, signals could not reach nuclei and be stocked in perinuclear zone? Through a variety of experiments, in the senescent cells, the reduced nucleocytoplasmic trafficking was confirmed as a general mode. In consequence, aging dependent formation of nuclear barrier was assumed and actually the general reduction in expression of nuclear pore complex genes was confirmed. Thereby, with these data, the Nuclear Barrier Hypothesis of Aging could be brought out to the world. In this hypothesis, the aging process would be initiated by formation of nuclear barrier, which was named as “Park and Lim’s Barrier”.
This barrier would limit not only the transport in and out of the nutrients and waste but also exchange of the essential components for life maintenance, resulting in restriction to living system and leading to the senescent state. This nuclear barrier together with membrane barrier in the senescent state are responsible for hypo-responsiveness not only toward growth factors but also apoptotic factors. In other words, the aging process is accompanied by reduced growth and enhanced survival at the same time. In summary, the cellular senescence has to tradeoff growth with survival. And this is the unique and clear molecular mechanism to explain the biological tradeoff phenomena. The biological significance of this TradeoffStrategy of Senescence prerequisite the sincere operation of payment or sacrifice in life economy.
Aging Revolution by Centenarians: Not Somebody But Everybody
In 1996, I was nominated as Director to Aging and Physical Culture Research Institute of SNUMC and in 2002, to Aging and Apoptosis Research Center of Ministry of Science and Technology. Thereby, my mission should not be confined to basic science of aging but extended to human aging with wide open eyes and ears. In study of human aging, it is out of question that the longitudinal study would be essential and fundamental. The first Korean longitudinal study on aging, named “Seoul Longitudinal Study on Aging (SLSA)” project was launched. In the middle of the project, all of sudden, a big and serious question turned up. That was: if the functional decline follows aging, what would be the minimal function of life to maintain the humanness and quality of life? For the study, I presumed the age of 100 as the ultimate age for monitoring the minimum status of life. In turn, I organized a multidisciplinary team for study of centenarians for the first time in Korea, inviting experts from medicine, psychiatry, nutrition, family, social welfare, ecology, economy and anthropology.
What I learned from our centenarian study can be summarized in a single phrase: “Centenarians are not so terribly degenerate but strong enough to maintain their life”. It was a thunder to me that the simple number of years could not determine the fate of human beings. How old a man may be, he could maintain his life! I had to change my prejudice that old man must be degenerate and obsolete. And I could be convinced that the longlive community might not be so gloomy as anticipated but there would be yet some sun light. Moreover, it becomes clear that the trend of population aging illustrates the generalization of centenarian phenomenon, implicating the coming world of centenarians not by somebody but by everybody. Longevity is now the common global issue for ordinary people in general.
It was a great and splendid success to work together with members from totally different training backgrounds for the same target of person and situation. Their respective own varying views on human longevity provided all of our members with the unexpected delights of knowledge on human aging. It was natural that our team, each in their own field, could initiate and lead the aging sciences and communities with new integrative and innovative ideas thereafter, which I am still proud of. And this collaborative works of multidisciplinary team led us to establish the Institute on Aging, SNU, which played a big role and contributed greatly to our aging society, thereafter.