QNAS
QNAS
QnAs with Mitsuhiro Yanagida Tinsley Davis, Science Writer
Profiling metabolites present in blood can reveal crucial information about health. Energy production and other cellular processes produce small molecules unique to specific reactions, such ATP production or muscle breakdown. Metabolomics can help provide a snapshot of such cellular activity. Mitsuhiro Yanagida, elected to the National Academy of Sciences in 2012, used human metabolomics to determine whether metabolite profiles differ between the young and the elderly. His team searched for variation in 126 metabolites identified by sensitive liquid chromatography-mass spectrometry assays of whole blood. The results, reported in Yanagida’s Inaugural Article (1), reflect a departure for a molecular biologist who has spent his career studying the mechanisms of chromosome segregation during cell division in the fission yeast Schizosaccharomyces pombe and investigating how fully differentiated cells, such as neurons, can live long without dividing. PNAS recently spoke with Yanagida, who is based at the Okinawa Institute of Science and Technology Graduate University in Japan, about his foray into the metabolomics of aging. PNAS: What prompted you to focus on a different field of research from your own for your Inaugural Article (1)? Yanagida: The reason why I was nominated was my study of chromosome biology, but I wanted to show my new research area, particularly because it is about public health. There are so many problems, like diabetes or cancer, and many of the problems actually come from blood. Blood represents everything, every symptom of health or disease, so chemical biology is my favorite research now. Blood has many compounds whose functions are completely unknown. Many of these compounds come from food or intestinal bacteria, etc. They are not made by the human body. The science is not simple, but they are directly related to human health and also human aging. Therefore, I am now very much interested to pursue this line of research and understand the role of these compounds, particularly in relation to human aging. I feel very lucky that I can conduct such research here in Okinawa. PNAS: In your Inaugural Article (1), you look for differences in metabolite distribution in 30 blood samples collected from young and elderly volunteers. Why did you
www.pnas.org/cgi/doi/10.1073/pnas.1607589113
choose to focus on blood samples as opposed to other tissues? Yanagida: If you look at an elderly person, you can immediately tell they are elderly by appearance, but if you take a sample, and the easiest sample to collect from humans is blood, you cannot tell. In fact, we are pretty much weak on these kinds of studies. There is no real authentic compound that is an indicator of aging. That is usually surprising to people because medicine has focused so much on why. Why can you tell from looking, but not from the blood? Mitsuhiro Yanagida. Image courtesy Okinawa
PNAS: Even though they lack Institute of Science and Technology. nuclei, red blood cells have an active metabolism and, in the article (1), you speculate that the cells’ longevity might reflect health or environmental stresses. What did the metabolite profiles reveal? Yanagida: Red blood cells need energy that is produced by ATP. This ATP is made by catalysis of blood sugar, glucose. The reactions produce a lot of oxidants so red blood cells also need abundant oxidant scavengers. The lifespan of [the] red blood cell requires proper energy sources and antioxidants. We succeeded in identifying 14 compounds that are related to human aging. Three of them were previously known [to be related to aging], so it’s consistent. Overall there are two major groups of compounds. One is increased in elderly people and one is decreased. The lifespan of the red blood cell itself might also depend on some of these metabolites. PNAS: Tell us more about the differences in samples from elderly subjects, who were typically in their early 80s. Yanagida: The compounds [that were] remarkably declined in older people are related to muscle strength and antioxidation. There are certain compounds required for muscle strength, such as the amino acid leucine or the other special amino acids, like carnosine.
PNAS | June 14, 2016 | vol. 113 | no. 24 | 6581–6582
These are very much declined in the blood of old people, which suggests that muscle maintenance is gradually declining in elderly people. The functions of these compounds are still at the level of hypothesis. A lot of future work is needed. There are other compounds much increased in elderly people’s blood. One type of compound is related to kidney function and urine, such as citrulline. These are known to be related to the excretion of metabolites in urine. Those compounds are remarkably abundant in elderly people so it looks like the efficiency of producing urine might be declined in elderly people. These compounds are usually made in the liver. The liver and kidney coordination might be declining in older people. PNAS: Did you find any relationships among the metabolites when you calculated the Pearson’s coefficient? Yanagida: If one compound is high in one particular person, and the second compound, which is functionally related, is also high, then we can say there is correlation. We found that related compounds behave similarly. This correlation of function analysis looked to confirm our conclusion. Overall, this kind of chemical
biology approach is beginning to measure the degree of human aging through collecting human blood. It’s a very small amount that we use, and without knowing any person’s history and without seeing any photo or picture and no knowledge, if we are looking at blood we might be able to say this person has a certain degree of aging. If we can correctly predict the age of blood donors then our research will enter a new era. PNAS: These volunteers were either in their late 20s or early 80s. What types of differences in blood metabolites would you expect if you looked at a 15-year-old versus a 50-year-old individual? Yanagida: We intentionally avoided youth or middleaged people so that we would have a big contrast. This is our way of eliminating “interferences” in the analysis of aging. We made a highly sensitive assay, collected samples, and obtained measurements with technical rigor, concentrating on a small number of elderly people. Our quantification data, reinforced by P value and correlation of function, were surprisingly consistent, which strongly indicates our conclusions are correct. However, the number of samples were still small. We try to pioneer. The rest can be done by our friends and colleagues in the same field.
1 Chaleckis R, Murakami I, Takada J, Kondoh H, Yanagida M (2016) Individual variability in human blood metabolites identifies agerelated differences. Proc Natl Acad Sci USA 113(16):4252–4259.
6582 | www.pnas.org/cgi/doi/10.1073/pnas.1607589113
Davis
QNAS
QnAs with Mitsuhiro Yanagida Tinsley Davis, Science Writer
Profiling metabolites present in blood can reveal crucial information about health. Energy production and other cellular processes produce small molecules unique to specific reactions, such ATP production or muscle breakdown. Metabolomics can help provide a snapshot of such cellular activity. Mitsuhiro Yanagida, elected to the National Academy of Sciences in 2012, used human metabolomics to determine whether metabolite profiles differ between the young and the elderly. His team searched for variation in 126 metabolites identified by sensitive liquid chromatography-mass spectrometry assays of whole blood. The results, reported in Yanagida’s Inaugural Article (1), reflect a departure for a molecular biologist who has spent his career studying the mechanisms of chromosome segregation during cell division in the fission yeast Schizosaccharomyces pombe and investigating how fully differentiated cells, such as neurons, can live long without dividing. PNAS recently spoke with Yanagida, who is based at the Okinawa Institute of Science and Technology Graduate University in Japan, about his foray into the metabolomics of aging. PNAS: What prompted you to focus on a different field of research from your own for your Inaugural Article (1)? Yanagida: The reason why I was nominated was my study of chromosome biology, but I wanted to show my new research area, particularly because it is about public health. There are so many problems, like diabetes or cancer, and many of the problems actually come from blood. Blood represents everything, every symptom of health or disease, so chemical biology is my favorite research now. Blood has many compounds whose functions are completely unknown. Many of these compounds come from food or intestinal bacteria, etc. They are not made by the human body. The science is not simple, but they are directly related to human health and also human aging. Therefore, I am now very much interested to pursue this line of research and understand the role of these compounds, particularly in relation to human aging. I feel very lucky that I can conduct such research here in Okinawa. PNAS: In your Inaugural Article (1), you look for differences in metabolite distribution in 30 blood samples collected from young and elderly volunteers. Why did you
www.pnas.org/cgi/doi/10.1073/pnas.1607589113
choose to focus on blood samples as opposed to other tissues? Yanagida: If you look at an elderly person, you can immediately tell they are elderly by appearance, but if you take a sample, and the easiest sample to collect from humans is blood, you cannot tell. In fact, we are pretty much weak on these kinds of studies. There is no real authentic compound that is an indicator of aging. That is usually surprising to people because medicine has focused so much on why. Why can you tell from looking, but not from the blood? Mitsuhiro Yanagida. Image courtesy Okinawa
PNAS: Even though they lack Institute of Science and Technology. nuclei, red blood cells have an active metabolism and, in the article (1), you speculate that the cells’ longevity might reflect health or environmental stresses. What did the metabolite profiles reveal? Yanagida: Red blood cells need energy that is produced by ATP. This ATP is made by catalysis of blood sugar, glucose. The reactions produce a lot of oxidants so red blood cells also need abundant oxidant scavengers. The lifespan of [the] red blood cell requires proper energy sources and antioxidants. We succeeded in identifying 14 compounds that are related to human aging. Three of them were previously known [to be related to aging], so it’s consistent. Overall there are two major groups of compounds. One is increased in elderly people and one is decreased. The lifespan of the red blood cell itself might also depend on some of these metabolites. PNAS: Tell us more about the differences in samples from elderly subjects, who were typically in their early 80s. Yanagida: The compounds [that were] remarkably declined in older people are related to muscle strength and antioxidation. There are certain compounds required for muscle strength, such as the amino acid leucine or the other special amino acids, like carnosine.
PNAS | June 14, 2016 | vol. 113 | no. 24 | 6581–6582
These are very much declined in the blood of old people, which suggests that muscle maintenance is gradually declining in elderly people. The functions of these compounds are still at the level of hypothesis. A lot of future work is needed. There are other compounds much increased in elderly people’s blood. One type of compound is related to kidney function and urine, such as citrulline. These are known to be related to the excretion of metabolites in urine. Those compounds are remarkably abundant in elderly people so it looks like the efficiency of producing urine might be declined in elderly people. These compounds are usually made in the liver. The liver and kidney coordination might be declining in older people. PNAS: Did you find any relationships among the metabolites when you calculated the Pearson’s coefficient? Yanagida: If one compound is high in one particular person, and the second compound, which is functionally related, is also high, then we can say there is correlation. We found that related compounds behave similarly. This correlation of function analysis looked to confirm our conclusion. Overall, this kind of chemical
biology approach is beginning to measure the degree of human aging through collecting human blood. It’s a very small amount that we use, and without knowing any person’s history and without seeing any photo or picture and no knowledge, if we are looking at blood we might be able to say this person has a certain degree of aging. If we can correctly predict the age of blood donors then our research will enter a new era. PNAS: These volunteers were either in their late 20s or early 80s. What types of differences in blood metabolites would you expect if you looked at a 15-year-old versus a 50-year-old individual? Yanagida: We intentionally avoided youth or middleaged people so that we would have a big contrast. This is our way of eliminating “interferences” in the analysis of aging. We made a highly sensitive assay, collected samples, and obtained measurements with technical rigor, concentrating on a small number of elderly people. Our quantification data, reinforced by P value and correlation of function, were surprisingly consistent, which strongly indicates our conclusions are correct. However, the number of samples were still small. We try to pioneer. The rest can be done by our friends and colleagues in the same field.
1 Chaleckis R, Murakami I, Takada J, Kondoh H, Yanagida M (2016) Individual variability in human blood metabolites identifies agerelated differences. Proc Natl Acad Sci USA 113(16):4252–4259.
6582 | www.pnas.org/cgi/doi/10.1073/pnas.1607589113
Davis
