![\"\"](\"https:\/\/healthist.net\/en\/wp-content\/uploads\/sites\/3\/2026\/07\/297_en_feature01_02_fig01.png\")
<\/small><\/p>\nFigure 1. <\/span>The epigenome and aging<\/span><\/strong>Our epigenome changes as a result of acquired factors as we age, while the activity of the sirtuin genes that repair the epigenome declines. This makes it impossible to use the information required to maintain tissue function, like being unable to retrieve the things needed from a messy closet, resulting in such phenomena of aging as reduced muscle strength, cognitive function, and immunocompetence, as well as skin aging.<\/p>\n<\/div>\n We also know that epigenetic alterations are stored in cells and organs over the long term and are passed on through cell division. In other words, having an irregular lifestyle, such as eating and drinking to excess when young, will affect one’s aging in the future.<\/p>\n In addition, aside from epigenetic alterations, aging is also caused by mutations in which the gene sequence itself changes. Using our closet analogy, this is akin to the vacuum cleaner being replaced by a broom, and cancer is a typical disease that result from such changes.<\/p>\n In aging research today, 12 hallmarks of aging have been set out, and epigenetic alterations are positioned as one of them (Table 1). Crucially, these hallmarks of aging do not function in isolation; rather, they influence each other, with epigenetic alterations serving as an important key to shedding light on the mechanisms of aging.<\/p>\n Rather than having a single cause, aging progresses through the accumulation of multiple changes at the cellular level, as shown by the hallmarks of aging. Epigenetic alterations are regarded as one of the important hallmarks, so research efforts focused on them are gaining momentum worldwide.<\/p>\n<\/div>\n Aging research aimed at controlling lifespan has progressed worldwide since 1935, when, in a world first, an experiment on rats showed that limiting calories had a life-extending effect. In particular, various studies using mice and primates have demonstrated the basic mechanism behind the effect of calorie restriction in curbing the progression of aging; specifically, we know that it is down to the activation principally of the sirtuin gene SIRT1 by nicotinamide adenine dinucleotide (NAD+<\/sup>). As SIRT1 is a protein that controls the epigenome, attention has begun to focus on the epigenome. It has even been suggested that existing compounds such as metformin, which is a drug known for its use in treating type 2 diabetes, and the immunosuppressant rapamycin, could affect the epigenome and have anti-aging and life expectancy-extending effects. With research aimed at making cell rejuvenation possible even in elderly people also progressing right now, we are about to enter an age in which aging is regarded as a disease, where we can not only stem its progression, but potentially treat it.<\/p>\n In fact, until 2010 or so, the mainstream view was that while aging could be delayed, it could not be reversed. But is aging truly irreversible? At what point does aging occur and how does it progress? These questions provided the starting point for my development of ICE mice, in partnership with a team led by Dr. David Sinclair of Harvard University in the U.S. (Figure 2).<\/p>\n Figure 2. <\/span>Development of ICE mice<\/span><\/strong>When epigenetic alterations are induced in young mice, aging accelerates without changes in the DNA sequence. Epigenome improvements were observed as a result of restructuring this mouse’s epigenome, demonstrating the possibility that aging may be reversible.<\/p>\n<\/div>\n ICE mice are an accelerated aging model developed by performing procedures that induce epigenetic alterations in young mice by artificially damaging part of their DNA over a three-week period. In the process of the DNA damage being repaired, this resulted in reduced tissue function affecting memory, muscles, vision, and bone density, among others, as well as white hair and other phenomena of aging, without altering the DNA sequence. Additionally, we observed epigenetic alterations including DNA methylation, histone modification, and changes in chromatin structure in these ICE mice subject to accelerated aging. In particular, in mouse muscles, muscle-specific epigenetic information declined, while epigenetic modifications and gene expression in regions associated with immunity and inflammation increased.<\/p>\n From results such as these, we proved that, as described above, acquired stress (DNA damage) is stored in cells and organs as the epigenome, and that aging occurs when cell- or organ-specific epigenetic information is lost. It also became apparent that the epigenome determines the speed and timing of aging. Interestingly, we did not observe the progression of aging in mice when we reduced the period of DNA damage to two weeks. From this, we surmised that there is a threshold at which stress causes epigenetic information to be lost, and that aging progresses suddenly once that threshold is exceeded.<\/p>\n Next, we conducted an experiment in which we used Yamanaka factors to restructure (reprogram) the epigenome in these ICE mice. Discovered by Professor Shinya Yamanaka, who was awarded the Nobel Prize in Physiology or Medicine, the Yamanaka factors are a set of four genes that can reprogram cells to become induced pluripotent stem cells (iPS cells) capable of differentiating into the cells of all kinds of tissues. In this experiment, we used the three factors Oct3\/4, Sox2, and Klf4, omitting c-Myc because of the elevated risk of neoplastic transformation (tumor formation) arising from its powerful cell proliferation ability. We observed improvements in methylated DNA and parts of the epigenome as a result of inducing these Yamanaka factors, demonstrating the possibility that we might be able to treat aging.<\/p>\n Members of Dr. Sinclair’s laboratory subsequently succeeded in achieving vision recovery by rejuvenating optic nerve cells in a glaucoma model based on the application of ICE mice and reprogramming technology, with a clinical study on glaucoma patients scheduled to begin in 2026. Glaucoma is a disease in which damage to the optic nerve causes vision impairment and visual field defects, whose incidence rate increases with age. Given that there is currently no fundamental treatment to restore the optic nerve, we hope that this clinical study will produce positive outcomes.<\/p>\n Aging research aims not only to extend lifespan, but also to promote healthy longevity. In fact, extending healthy life expectancy requires the accurate, appropriate incorporation of a variety of approaches, including nutrition, exercise, and compounds such as supplements and medications. Particular attention should be paid to the intake of compounds thought to have a major impact on the body. In the case of the activation of the sirtuin gene by NAD+<\/sup> described above, for example, a nicotinamide mononucleotide supplement that increases NAD+<\/sup> has been developed. However, while taking it in the morning is effective, taking it in the evening could potentially accelerate aging. This is because the quantity of NAD+<\/sup> falls at night as part of the body’s circadian rhythm (an organism’s body clock, which fluctuates over a 24-hour cycle), and disrupting this rhythm causes metabolic disorders.<\/p>\n It is also very important to ascertain the degree to which aging has actually progressed, rather than looking at a person’s chronological age. This does not necessarily mean the time when an individual actually feels aging occurring. Some abnormalities occur at the molecular level well before phenomena of aging manifest themselves in a person’s appearance or body. Biological aging clocks are indicators used to visualize otherwise invisible aging.<\/p>\n A typical example used in aging research is called the epigenetic clock; this method measures epigenetic changes, such as methylation in the blood, which increase with advancing age. We ourselves used the epigenetic clock in the aforementioned ICE mice research. Also developed have been aging clocks that combine a variety of biomarkers, including proteins, metabolites, hormones, and immune function, whose use is progressing not only in aging research, but also in the provision of testing services, primarily overseas.<\/p>\n Understanding a person’s aging clock will enable us to provide an approach tailored to not simply an individual, but that individual’s organs and cells, rather than a uniform intervention method along the lines of “Your actual age is 30, but the biological age of your brain and heart is 50, so you should do this amount of this kind of exercise and consume this many grams of protein per day, and this supplement would be effective.” Another thing regarded as crucial is life design that takes an individual’s narrative as the starting point. Although everyone ought to understand the importance of improving their lifestyle for the sake of their health, many of us find it hard to start taking the practical steps required. However, life goals such as wanting to start a business at the age of 40 or wishing to go traveling with one’s grandchild next year are more powerful motivators for altering behavior than numerical changes. In order to design a biological aging clock tailored to each individual’s life design and extend their healthy life expectancy, I started up ASAGI Labs as both an incorporated foundation conducting basic research and a company promoting the commercialization of that research.<\/p>\n ASAGI Labs aims to develop a high-precision method of measuring biological age, using AI to analyze epigenetic changes and other biomarkers, data such as blood pressure and heart rate obtained via digital devices, and clinical data. In addition, we are building a list of drugs with the potential to extend healthy life expectancy, focusing on existing therapeutic drugs whose effectiveness and safety have already been demonstrated, as part of our research and development of foods and pharmaceuticals aimed at extending healthy life expectancy. Among them is ambroxol, the main component in expectorant drugs, which has antioxidant, anti-inflammatory, and autophagy-promoting effects, and is known to affect epigenetic alterations.<\/p>\n We plan to conduct a clinical study to evaluate improvements in such areas as cognition, muscle strength, and immune function in healthy individuals aged 50 or over to whom ambroxol has been administered. This clinical trial is participating in XPRIZE Healthspan, a global competition aimed at suppressing or improving aging in people aged 50–80 by at least 10 years. We are also developing a drug that controls specific epigenetic alterations in order to improve sarcopenia (muscle loss) arising from the use of GLP-1 receptor agonist drugs to treat diabetes and obesity.<\/p>\n Aging research centered on epigenetics, together with the social implementation of its findings, is expected to continue advancing worldwide. While the U.S. is currently the global leader in research and business focused on the regulation of aging, I believe Japan has strengths in this area, precisely because it is the most aged society in the world. At ASAGI Labs, too, we are undertaking joint research with the municipal governments of Shizuoka City, Fujinomiya City, and Fujieda City, in an effort to create products and services that support healthy life expectancy and thus promote the health of local citizens.<\/p>\n In the animal kingdom, Greenland sharks (Somniosus microcephalus<\/i>) show no signs of aging even when close to 400 years old, and Galapagos tortoises (Chelonoidis niger<\/i>) remain active and retain reproductive capacity even after the age of 100. The fact that living creatures do not necessarily age with the passage of years is a matter of endless interest to me as a biologist. With research into the genomes and epigenomes of long-lived creatures also progressing, we might one day reach a time when humans, too, live to be 250 years old.<\/p>\n Research into aging is progressing, amid a focus on anti-aging. While genetic factors are known to be involved in aging, acquired factors such as environment and lifestyle also have a major influence, with some scientists attributing more than half of aging to them. The main acquired factor is the epigenome, which controls gene function through DNA methylation, among others. As epigenetic alterations play a key role in shedding light on the mechanisms of aging, efforts to investigate the inhibition of aging and treatments that regard aging as a disease look set to advance worldwide.<\/p>\n","protected":false},"author":2,"featured_media":2677,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[14],"tags":[],"class_list":["post-2676","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicine"],"acf":{"author":"composition by Yumi Ohuchi Research into aging is progressing, amid a focus on anti-aging. While genetic factors are known to be involved in aging, acquired factors such as environment and lifestyle also have a major influence, with some scientists attributing more than half of aging to them. The main acquired factor is the epigenome, which controls gene function through DNA methylation, among others. As epigenetic alterations play a key role in shedding light on the mechanisms of aging, efforts to investigate the inhibition of aging and treatments that regard aging as a disease look set to advance worldwide.<\/p>","person":[{"acf_fc_layout":"personcontent","personimg":2680,"personsholder":"Associate Professor, Division of Aging Biology\r\nResearch Institute for Science and Technology, Tokyo University of Science","personname":"Motoshi Hayano","persondetail":"Graduated from Kumamoto University’s Faculty of Science in 2005. In 2011, he gained a Ph.D. in life sciences from the Department of Medical Genome Sciences at the University of Tokyo’s Graduate School of Frontier Sciences. After fellowships at Harvard Medical School in the U.S., including a Human Frontier Science Program (HFSP) Long-Term Fellowship, he was appointed an assistant professor at Keio University School of Medicine in 2017. He has held his current post since April 2025. He has also been involved in startups including Tsubota Laboratory, Inc. and One Genomics Inc., and has served as Chair of ASAGI Labs Foundation and CEO of ASAGI Labs Inc. since 2024. His research focuses on aging biology and epigenetics."}],"issue":2673,"custom_css":""},"_links":{"self":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts\/2676","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/comments?post=2676"}],"version-history":[{"count":0,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts\/2676\/revisions"}],"acf:post":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/issue\/2673"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/media\/2677"}],"wp:attachment":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/media?parent=2676"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/categories?post=2676"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/tags?post=2676"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}The 12 hallmarks of aging<\/h2>\n
![\"\"](\"https:\/\/healthist.net\/en\/wp-content\/uploads\/sites\/3\/2026\/06\/297_en_feature01_02_table01.png\")
Motoshi Hayano. Eijingu kakumei 250-sai made hito ga ikiru hi<\/i> [The Aging Revolution: The Day When People Will Live to Be 250]. p. 116–117, Asahi Shimbun Publications, 2024.<\/small><\/p>\nAging progresses suddenly once stress exceeds a certain threshold<\/h2>\n
![\"\"](\"https:\/\/healthist.net\/en\/wp-content\/uploads\/sites\/3\/2026\/06\/297_en_feature01_02_fig02.png\")
<\/small><\/p>\nDrugs with the potential to extend healthy life expectancy<\/h2>\n
illustration by Rokuhisa Chino","intro":"