We live in a world that is surrounded by things that are directly perceptible by our five senses and others that are not. In physics, for example, the principles of Newtonian physics can be easily observed and thus quite understandable, by our senses in one way or another, however, this is not the case for quantum mechanics. This is probably because understanding the latter requires a greater accumulation of logic than does the former. When, I as a biology major, I was convinced that I had grasped a hold of a concept from physics-the Schroedinger's wave equation-I felt as if I were swimming in the middle of multi-dimensional space filled with a higher level of logic. A great deal of time has passed since then, and I probably would not understand it now without starting from the beginning.
Interestingly, the process of learning physics corresponds, for the most part, with its history. In the course of learning, we discover that an equation of Newtonian physics is, in reality, nothing more than an approximation that is applicable only under limited conditions when seen from a more universal view of physics. A lesson that can be learned from this experience is that truth often dwells in regions that are imperceptible to our five senses. This lesson has become one of the basic tenants of my style of research.
The same can be said of biological "time". The length of time we can perceive from the present into the past ranges from several seconds to several years to some tens of years at most, while from the present to the future, we can perceive time in seconds and years. Beyond these periods, time is hardly perceptible to our intuitions based solely on our senses. In the field of physiology, which laid the foundation for brain science today, measuring time in milliseconds is now possible and has revealed the essence of neurotransmission. While improving time resolution beyond our capacity can be achieved by technical advancement, widening the window of the time that can be experimentally observed is not easy. This is an intrinsic problem that always accompanies the research on life-long phenomena.
The time scale of human brain ageing, which is a major theme of our research, is anywhere from 60 to 100 years, making it impossible to study ageing as the subject of experimental science in a strict sense (not to mention the ethical issues such a study would confront). Therefore, we can only approach the question: "what is the essence of ageing in the brain?" by accumulating probable logic and experimental facts that support such logic. In this respect, the study of ageing differs from developmental studies. More than that, while the developmental process is likely partly the result of natural selection through evolution, factors such as the lengthening of the lifespan made possible by the progress of civilization are likely to influence ageing processes. Hence, in the study of ageing processes, the seemingly pertinent logic is often illogical in many cases. In the quest to discover the essence of human lifespan we are sailing without a chart. Also worth noting is that scientists involved in studying human ageing are themselves human beings whose research activities are constrained by age and time factors.
Furthermore, the ageing of the brain is fundamentally different from systemic ageing in other organs. This is because neurons are post-mitotic, meaning that they cannot cope with brain ageing by means of cell division. Therefore, recent findings demonstrating the role of telomeres in cell division affect the rate of ageing in mitotic cells are not very helpful in understanding brain ageing. Furthermore, since brain ageing is, apparently, the result of a longer lifespan, those factors that effect systemic ageing in the body cannot be regarded as specific factors in the ageing of the brain. In this sense, individual neurons require a proper quality control mechanism to live for several decades. It should however be pointed out that differentiation and growth of neuronal progenitor cells should not be disregarded in terms of neuroregeneration, as I discuss later.
One of the most orthodox methods employed in the study of human brain ageing involves comparing brain function and structure in the young with aged. Although an accumulation of a substantial amount of knowledge has been produced from these studies, this phenomenological method does not provide insight into the definite cause-and-effect relationships that lead to brain ageing. Another approach involves pinpointing the mechanisms of neurological disorders for which ageing is a risk factor. In fact, ageing is a risk factor for almost all diseases of the nervous system, so the greater the numbers of elderly patients, the more universal neurodegenerative diseases become. Among them, Alzheimer's disease is predominant and is often called "the image of the end-stage of brain ageing." Ageing is also a risk factor for Parkinson's disease and polyglutamine diseases although the number of patients although these diseases are less pervasive.
These approaches produced decisive progress in understanding brain ageing starting around 1990. Familial (genetic) origins for some of these diseases led to the identification of a number of mutations in causative genes related to these diseases. This made it possible to establish definite cause-and-effect relationships in the etiology of disease development (also attaching significance to pathological findings). It was also found that familial and sporadic cases shared many pathological aspects, suggesting that further analysis of these gene mutations might have universal significance. Briefly summerizing the results: the abnormal accumulation of protein in the brain, which often accelerates upon aging, results in neuronal dysfunctions that lead to neurodegeneration. Noticeably, abnormal amounts of proteins accumulate with ageing in virtually every human. Protein levels begin to accumulate in between 40 and 60 years of age. As a result, one human in two over the age of 85 may acquire Alzheimer's disease or a mild cognitive impairment, a likely prodrome of Alzheimer's disease.
- Elucidate the underling mechanisms that account for the ageing-dependent increase in the steady state level of the amyloid-β peptide, which results in a 1,000- to 10,000-fold accumulation over a period of tens of years.
- Elucidate the mechanisms through which the accumulation of amyloid-β peptide brings about neuronal dysfunction and degeneration.
- Establish preclinical diagnosis of Alzheimer's disease.
- Establish preventive therapy and improve symptomatic therapy.
The above assumptions might indicate that our lifespan its that period of time that precedes the onset of Alzheimer's disease, but we need not be pessimistic about this. On the contrary, by establishing the etiology of the sporadic form of Alzheimer's disease-by predicting its onset and by providing preventive treatment-a richer quality of life throughout the lifespan can be expected since a great deal of time lies before us. The basic research tasks are involved in overcoming this issue, and are shown in Table 1.
In the 1990s many researchers were involved in the study of how amyloid-β peptide (Aβ), the primary pathogenic agent of Alzheimer's disease, is generated in the brain. In order to play an original role in the research community, my colleagues and I focused on the other aspect of Aβ metabolism, Aβ degradation. Our research group was the first to tackle this problem head-on. We identified neprilysin as the major Aβ-degrading enzyme in the brain and found that neprilysin activity is reduced upon ageing, thereby causing the accumulation of Aβ in the brain. Moverover, the steady-state level of Aβ in the brain can be regulated by controlling neprilysin activity. Dr. Dennis Selkoe of Harvard University, a renowned Alzheimer's disease researcher, has recently produced a neprilysin-transgenic mouse that supports our findings. We have also established an experimental gene therapy, the indication of which could lead to the development of new medications for prevention and therapy of Alzheimer's disease that may be available for clinical trials in the next few years.
While the second task may appear easy to solved using ordinary cell biological procedures, the research community encountered more than a few difficulties stemming from differences in time course of events when compared with actual pathological conditions. It seems the time scale for cell biology is too different from that of brain ageing. Several candidate factors have been implicated such as: the intracellular calcium level, protein phosphorylation, stress response, and protein quality control disorders all of which are deeply associated with proteolytic enzymes. We are currently analyzing the role of intracelluar proteolytic enzymes using animal models. Considering our achievements in calpain, or intracellular calcium-activated neutral protease, we are confident that we will remain a leading research group in the field.
Incidentally, a similarity between Alzheimer's disease and certain forms of mental disorders may also provide deep insights into the mechanisms of Alzheimer's disease development. In depression, for example, memory and cognitive ability is lowered which is closely associated with stress responses. In addition, the finding that a fairly long period of time is required for antidepressants to become effective suggests an important role played by neuroregeneration in the disease development. Nerve growth factor is also presumed to be responsible for both depression and Alzheimer's disease; the reductions of a specific nerve growth factor, i.e. BDNF: brain-derived neurotrophic factor, have been described. Thus, the study of mental disorders presents numerous clues for comprehending the brain as a system and for elucidating the essence of brain ageing.
Developing a preclinical diagnosis of Alzheimer's disease, the third task, has also been elusive. Researchers throughout the world have spent costle resources on this study without having attained satisfactory results thus far. Two approaches that might be useful are a "logic-based" approach using results based on the accomplishments of the first two tasks and a "reductionistic" approach based on case control and longitudal studies. Using animal models is another potent approach, but animals manifesting all the major pathological conditions of Alzheimer's disease are not yet available. The successful development of one should provide powerful tools for obtaining adequate solutions to the first three tasks. In spite of the high risk involved in successfully generating an animal model, establishing such models by modifying mouse genes is the hope of the entire research community. The key to the success probably lies in relevent conversion of the "life time" of humans into the "biological time" of 1 to 2 years in a mouse.
The fourth task concerns the establishment of preventive therapy and the improvement of symptomatic therapies. We can obtain a great number of suggestions from epidemiological studies and from clinical medicine, an area beyond the reach of many experimental scientists. In this sense, it is quite important that closer cooperation between basic research and clinical practice develop to share information. I am fortunate to deliver lectures and teach at several medical schools, an experience from which I can profit greatly.
The results of investigations for these four tasks will be considered and reviewed. A coherent system will eventually emerge based on probable facts, which may not necessarily lead to illuminating the whole science of brain ageing, but will, without doubt, become the backbone of future research.
It was about the age of 40 years when I myself started thinking about the profound meanings of "life expressed as a length of time." It became apparent that, while middle-aged people could understand young people and the elderly could understand the middle aged, young people could only guess at what middle-aged people are experiencing and have in mind. This lesson, I suppose, is one of the merits of experiencing ageing. The same can be said of experiencing diseases. The realization that our lifespan is tantamount to something invisible to our senses brought me even more deeply to the study of ageing.
Lastly, looking back on the history of modern physics, we can see the outstanding roles played by the Royal Society of Great Britain, PTB of Germany and the Institute for Advanced Study of Princeton University in the U.S. The researchers here at RIKEN strive to achieve similar in their own fields. We are expected to produce results that will please and be understood by members of society (e.g. bureaucrats, taxpayers, and sometimes, editors of high profile journals), and yet pursue the truth that can be attained only by accumulating probable logic, even though it is complex. We probably should not distinguish between pure science (studying science solely from an interest in science) and accountability (conducting a study for the purpose of giving back time and money invested by achieving the results) as we do between real intention and stated intention (honne to tatemae). The two attitudes should coexist, and I believe that it is possible. This attitude is an eternal task in the study of every aspect of brain science including "protection of the brain".
