Summary of ICMS Seminar Club presentation on Friday, September 24, 2021.
Title: Research Institute at National Center for Geriatrics and Gerontology
Speaker: Dr. Akihiko Nishikimi, Chief of the Biosafety Division of the Research Institute at the National Center for Geriatrics and Gerontology, Obu, Aichi-ken
On Friday, September 24, by Zoom, Dr. Nishikimi gave a presentation to Fujita Health University. He gave an excellent talk in which he introduced the National Center for Geriatrics and Gerontology (NCGG) and described the features of old age in general and of cellular senescence. He also described his own recent findings on drug discovery for immunosenescence. However, for secrecy reasons, the latter is not included in the below descriptions.
This was the first time that all members of Fujita Health University were invited, and our usual crowd met several new faces. There were only 16 participants, but the talk was excellent and the discussion was enthusiastic and lively. I was slightly disappointed because I thought that more people would join, but hearing the positive comments afterward of the people whom I asked cheered me up again. Dr. Nishikimi stated: “I enjoyed the dense discussion with the participants. I am grateful for all the people who listened to my presentation and gave me a lot of valuable comments.” Prof. Shosuke Ito said that he had really enjoyed the meeting, and so did two newcomers, Prof. Zaliha Omar and Dr. Nursah Ertunc. The latter two additionally expressed that they were happy that there now was something like this in English at Fujita, and Dr. Ertunc specifically noted the happy atmosphere and that so many participants joined the discussion (for the questions of the audience see at the end of this post).
Professor Omar, who specializes in Rehabilitation Medicine, had a very interesting comment during the meeting about possible exercises for elderly people. She elaborated more on that comment when I contacted her later, and it is so interesting and insightful that I like to share it with you (see the end of this blog post).
In summary, I enjoyed the event a lot and feel privileged to have yet again learned to know a few nice people/scientists. Foremost, of course, Dr. Nishikimi, as we have had very pleasant contacts about the meeting and other science, before and after the meeting. I am grateful for his time and efforts to make this very nice presentation.
The contents of the presentation
The location of the NCGG
The NCGG in Obu is very close to Fujita (see the map on the cover image of this blog post). Many people with children may have seen it when visiting Aichi Kenko no Mori (Aichi Health Village Park) to which it is adjacent (Fig. 1). The building logo with the Japanese name of the NCGG, 国立長寿医療研究センター , is shown in Fig. 2.
The mission of the NCGG
In an NCGG pamphlet it is stated: The mission of our center is “We will contribute to establish health and longevity society by promoting mental and physical independence.”
Dr. Nishikimi explained that the goal of the NCGG is a general improvement of the quality of life of elderly people and that breaking longevity records is not a primary target.
History of the NCGG
For a full description of the history, starting in 1938, see the History page of the NCGG and at the bottom of this introduction page of the NCGG Research Institute.
In 1995, the National Institute for Longevity Sciences (NILS) was established.
In 2004, this was changed into the National Center for Geriatrics and Gerontology (NCGG).
The NCGG is one of the six National Centers for Advanced and Specialized Medical Care (NCs) set up nationwide in Japan (the others are: NCVC, National Cerebral and Cardiovascular Center; NCGM, National Center for Global Health and Medicine; NCNP, National Center for Neurology and Pathology; NCCHD, National Center for Child Health and Development; NCC, National Center for Cancer) (Fig. 3). Each of these institutes is composed of a research institute and a hospital. According to the Japan Health Research Promotion Bureau (JC) [https://www.japanhealth.jp/en/about/greeting.html], which has a function in the overview of the six NCs: “Each of the six NCs has its own research institute, where devoted efforts have been made to promote world-leading basic and translational research in its field of specialization. At the same time, the hospitals run by the NCs have been working on cutting-edge medical treatment and clinical research, thereby serving as an engine for the development of Japan’s healthcare industry.”
The Director-General of the Research Institute of the NCGG, Dr. Shumpei Niida, states [https://www.ncgg.go.jp/research/aboutus/]—especially referring to the acquisition of genetic data and the establishment of biobanks for the use by other researchers in Japan and elsewhere: “It is no exaggeration to say that our institute is the research base of geriatrics research in Japan.”
Figure 3. The six NCs in Japan. This figure was used as a slide in Dr. Nishikimi’s presentation. The figure at the bottom is derived from the online site of the Japan Health Research Promotion Bureau (JH)
Organization of the Research Institute of the NCGG
The Research Institute of the NCGG is divided into six major units, as shown in Fig. 4. Dr. Nishikimi introduced them all individually. I think that his slides explaining these divisions (Figs. 5-10) are so informative that I do not need to add further textual information in this blog post. For more detailed information see the NCGG brochure.
Figure 4. The organization of the NCGG Research Institute into six units. This figure was used as a slide in Dr. Nishikimi’s presentation. The organization figure is from the introduction site of the Research Institute of the NCGG.
Figure 9. Medical Genome Center. This figure is a slight modification of a slide used in Dr. Nishikimi’s presentation. Most pictures are derived from promotion material of the NCGG.
Special facilities at the NCGG
Dr. Nishikimi highlighted several facilities at the NCGG because they should be interesting for our audience. These are the Biobank which is run by the Medical Genome Center and the Aging Farm which is run by the Core Facilities unit.
A major service of the NCGG to the research community is the storage of data and samples in a biobank system (Figs. 11 and 12). The NCGG biobank is a member of the National Center Biobank Network (NCBN), a collaboration of the six national centers (see above). The sample information collected in the NCGG biobank is enrolled in a catalogue database of NCBN central biobank and available for inspection by anyone via http://ncbiobank.org/. Dr. Nishikimi explained very kindly that members of our audience can personally approach the NCGG if they are interested in samples. Furthermore, he told us, without explaining details, that some agreements had been made between the NCGG and Fujita Health University in regard to biobanks.
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The Aging Farm is dedicated to continuously having mice and rats of the older life stages, as explained in Fig. 13. For enabling this, the farm regularly purchases four months old mice. Furthermore, they provide, in principle, mice that are 18 months or older.
Figure 13. The Aging Farm continuously has mice and rats of the older life stages. The figure on the left compares the life stages of mouse and human and is from the Jackson Laboratory homepage who adapted it from Flurkey K, Currer JM, Harrison DE. 2007. The Mouse in Aging Research. In The Mouse in Biomedical Research 2nd Edition. Fox JG, et al, editors. American College Laboratory Animal Medicine (Elsevier), Burlington, MA. pp. 637–672.
Old Age in General
Dr. Nishikimi discussed some general aspects of old age. In one of his slides (Fig. 14), he highlighted that for a very long time-period, maybe >1000 years, the average life expectancy was very low and an age of >40 was considered old. He gave a nice example by explaining that the “old” couple, depicted with gray hair, in the old Japanese story of Issunboshi (the one-inch tall boy) were only ~41 years old (Fig. 14).
Furthermore, Dr. Nishikimi explained that in Japan the life expectancy is among the highest in the world, with a higher life expectancy for men than for women (Fig. 15, compare with Fig. 14).
Cellular Senescence and Immunosenescence
The second part of Dr. Nishikimi’s presentation was mostly about cellular and molecular mechanisms of aging. Herein, he also described his recent findings on drug discovery for immunosenescence. Because details of the latter should remain secret for a wider audience, and because this blog post would become too lengthy, I here only describe two items of the cellular/molecular part of Dr. Nishikimi’s presentation.
The first item is about B and T lymphocytes, the cells that mediate adaptive immunity (specific immune memory) (Fig. 16). Young people—by a random mechanism—generate a large variety of naïve B an T cells, of which only a small proportion gets stimulated by specific antigens (e.g., a virus protein). These stimulated lymphocytes can proliferate and form effector and long-lived memory cells. Old people still have abundant memory B and T cells, but reduced numbers of naïve B and T cells. Thus, old people are not as capable to efficiently mount immune responses against new antigens. Furthermore, old people have more senescent B and T cells that can nonspecifically contribute to pathological inflammation.
The second item of Dr. Nishikimi’s explanation on cellular/molecular senescence which I like to highlight is a transgenic system established at the NCGG for eliminating senescent cells in the lungs of mice (Figs. 17 and 18). This system was originally developed by Hashimoto et al. 2016. Most mammalian somatic cells eventually undergo permanent cell cycle arrest, called cellular senescence. Senescent cells accumulate in many tissues during aging and are considered to underlie aging-associated pathologies. The tumor suppressors p19ARF and p16INK4a, both of which are encoded in the CDKN2A locus (Fig. 17a), play critical roles in inducing and maintaining cellular senescence. Hashimoto et al. (2016) created PAC clones that contained the complete 19 kb of the mouse p19ARF genomic sequence plus additional flanking genomic regions, in which a p19ARF exon was replaced with sequences encoding diphtheria toxin receptor (DTR, conferring sensitivity to diphtheria toxin) and luciferase (enabling visualization by illuminescence) (Fig. 17b). Transgenic mice with multiple copies of this construct in their genome (at unknown insertion locations) expressed DTR and luciferase under conditions of CDKN2A activation, making senescent cells visible by illuminescence and sensitive to elimination by diphtheria toxin (DT). With this system, in older mice luminescence signals were observed in the lung, which together with the expression of the senescence markers p19ARF and p16INK4a were eliminated by intraperitoneal injection with DT. This DT-DTR mediated removal of senescent cells improved (“juvenated”) lung properties by, for example, increasing lung elasticity and decreasing alveolar size (Hashimoto et al. 2016).
The same NCGG research group then used this model to find that removing of senescent cells (“senolysis”) protects against pulmonary emphysema (Mikawa et al. 2018). Pulmonary emphysema is characterized by the destruction of alveolar walls, leading to permanent enlargement of the airspace in the lungs, and is a major component of chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide. Pulmonary emphysema is associated with the infiltration of inflammatory cells, which are believed to cause the accumulation of proteinases and lead to alveolar destruction. Mikawa et al. (2018) found that removal of senescent lung cells in their transgenic mice by DT protected against pulmonary emphysema induced by porcine pancreatic elastase (PPE), regarding both lung morphology and inflammation. They also found a partial protection against pulmonary emphysema by treatment with the senolytic drug ABT-263.
Questions and comments by the audience
(These are the questions and answers that I remember. They are modified for clarity)
Question 1.
The genetic data that the NCGG generates, are they publicly available, or do we need to establish specific collaborations to access them?
Answer: Those data are deposited in public databases.
Question 2.
In a graph, you compared the aging stages of mouse and rat with those of humans (see Fig. 13). However, that is an overall assessment. Are there some capacities or physiological systems that exhibit aging effects at relatively different rates in humans and rodents? As an imaginary example, maybe in humans the visual system shows deterioration signs of old age earlier than the olfactory system and in rodents it might be vice versa.
Answer: Rodents age much faster than humans and it would be difficult to pick up such points.
Comment from the audience: At the gene expression level, there are many similarities in the aging process (JMD: see, for example, de Magalhães et al. 2009). There are also good tools nowadays for making more detailed comparisons dedicated to gene expressions per organ or physiological system, as shown in Nakajima et al. 2021.
Question 3.
The gene “Klotho” has long been considered as playing a central role in aging. Is that still the case?
Answer: It is now generally thought that aging is a very complex process involving a large number of factors, not only Klotho.
Question 4.
Does the NCGG have aging mice models that form a good model for Parkinson’s disease (a brain disease affecting many old people)?
Answer: I am not aware that the NCGG has such models.
Question 5.
Why are Japanese people among the oldest in the world?
Answer, plus comments from the audience: It may be related to the type of food and the quantity of food. The current generation of old people in Japan grew up in a time with limited food supplies but had plenty of food later in life; this combination possibly increased their life expectancy. In animal models, it is known that food restriction can increase life expectancy.
Question 6.
Is there a difference, within Japan, in life expectancy in cities versus the countryside?
Answer: I am not aware of such comparisons. However, within Japan, people in Okinawa get older than in the rest of Japan.
Question 7.
Researchers at the NCGG created a beautiful transgenic mouse system in which they can eliminate senescent cells in the lung (Fig. 17). Does the elimination of senescent lung cells reduce the susceptibility to coronavirus?
Answer: Everyone is asking that question. Unfortunately, mouse is not a good model for COVID-19. However, maybe our model could be optimized for such analysis, possibly by having these mice express human ACE2, the receptor for the COVID-19 virus.
Question 8.
The NCGG is a governmental organization researching physical and mental challenges that come with old age. In other countries, there must be similar organizations. Do those have similar focuses as the NCGG, or can you see a cultural difference in how old age is viewed and addressed?
Answer: I don’t know enough about such institutes in other countries for answering this question.
Question 9.
A famous rodent model for aging is naked mole-rat, as relative to their weight they become exceptionally old. Does the NCGG also investigate them?
Answer: No, but another group in Japan, under the leadership of Dr. Kyoko Miura at Kumamoto University does.
Question 10.
C. elegans is an animal model with a lifespan of only a few weeks. Is the NCGG also using this as a model?
Answer: As far as I know, the NCGG is not using this animal model.
(JMD: see this interesting paper in Nature on Lifespan-regulating genes in C. elegans)
Question 11.
You highlighted that old people have fewer naïve T cells, which means a poorer immune response against new antigens (because it reduces the chance of a good match between a new antigen and a naïve T cell). Nevertheless, the COVID-19 vaccines, for which old people are a priority group, are based on only a single protein of the COVID-19 virus. Do you think it would be good to make vaccines that include more different proteins of the virus, including also proteins (or peptide fragments) of the virus that are similar between the COVID-19 virus and other coronaviruses that cause the common cold (providing a larger set of potential targets to the naïve T cells and creating the possibility that memory T cells are stimulated).
Answer: Your reasoning is correct. It is thought indeed that previous infections with common cold coronaviruses have induced immune memory that, to some extent, can also recognize the COVID-19 virus.
Question 12.
The figure that you showed about social activity studies at the NCGG (Fig. 7) seems to be dedicated to very simple physical and mental exercises, as if for little children. However, some old people are very sportive, and even in our audience we have elderly people who use their brains at a top professional level. Does the NCGG check how different levels of physical and cognitive exercise (e.g., simple versus very hard and intense) might differentially benefit the elderly?
Answer: I am not aware that different levels of exercise are being tested.
Question 13.
It has been postulated that as a biological population of species it creates advantages to humans to also have old individuals, even if they can’t procreate anymore. For example, grandmothers without young children can help their daughters care for their children. It also creates a longer memory for rare catastrophic events, such as earthquakes. Moreover, our frequent election of old men as our leaders/presidents seems to indicate that we believe that old age creates some superior characteristics. Thus, maybe aging does not only represent a decline but also brings its unique superior characteristics. Can you elaborate on that?
Answer: The obvious advantage of old age is, indeed, that old people have more experience and can know more.
Comment by Professor Zaliha Omar
(my summary of her comment during and after the seminar)
Professor Omar specializes in Rehabilitation Medicine. In one of her studies in Japan, Prof. Omar organized gardening possibilities on the roof of an elderly home. She noticed that it made the elderly inhabitants very happy to be able to do this gardening, which she could scientifically verify by using software for recognizing facial expressions. She believes that when organizing activities for elderly people their experiences and characteristics should be considered. In this example case, many people in the current old generation enjoyed gardening when they were young, and this remembering gives the gardening activity extra layers of value. Prof. Omar believes that this extra value provides a stronger stimulation of the cognitive system. In addition, she believes in the additive values of experiencing space (e.g., being in the open air), emotion, and spirituality (e.g., being in contact with the divine through nature). I find her ideas very interesting, and they seem to match well with some of the ideas about architecture and music by Fujita-sensei, the founder of our University.
