Juntendo Educational Corporation
Succeeded in identifying a clinically applicable senolytic agent – Possibility of therapeutic application to aging-related diseases such as Alzheimer’s disease –
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The research group led by Specially Appointed Assistant Professor Goro Katsumi of the Department of Internal Medicine and Cardiovascular Medicine, Juntendo University School of Medicine, and Professor Toru Minamino of the Department of Cardiovascular Medicine, Graduate School of Medicine, is supported by the Japan Agency for Medical Research and Development (AMED). We have identified a senescent cell
(*1)-eliminating drug that can be applied to age-related diseases among drugs that have already been used clinically, and clarified its mechanism of action. It has been gradually becoming clear that aging causes the accumulation of senescent cells in tissues and induces chronic inflammation (*2), which leads to the onset and progression of various age-related diseases. There has been no drug that removes senescent cells without major side effects and can be used clinically. This time, the research group has discovered that SGLT2 inhibitors (*3), which were developed as a treatment for diabetes, can help reduce metabolic abnormalities, arteriosclerosis, and age-related frailty by removing senescent cells that accumulate with aging and obesity stress. We confirmed that it not only improves (*4) but also extends the lifespan of progeria mice. This result suggests the possibility of application to the treatment of various age-related diseases, including Alzheimer’s disease.
■Points of this research result
SGLT2 inhibitor, a drug used to treat diabetes, acts as a senescent cell removal drug
lSGLT2 inhibitors improve pathological aging traits in various age-related diseases
lSGLT2 inhibitors promote the removal of senescent cells by the immune system by regulating immune checkpoint molecules
■Background
It is known that metabolic stress such as aging and obesity causes the onset and progression of lifestyle-related diseases and age-related diseases such as Alzheimer’s disease, but the mechanism is not well understood. For more than 30 years, our research group has been conducting research into the mechanisms underlying the onset of age-related diseases. We have made it clear that we are involved in progress. Furthermore, it has recently been shown that removing accumulated senescent cells (senolysis (*5)) can improve pathological aging traits associated with age-related diseases. However, most of the senolytic drugs that have been reported so far have been used as anticancer agents, and there have been concerns about side effects. Therefore, the research group conducted research with the aim of developing a treatment that acts more selectively on senescent cells and has fewer side effects.
■Contents
When chromosomal damage occurs due to age-related stress, cells age and stop dividing to prevent cancer. Senescent cells that accumulate in tissues in this way are programmed to secrete inflammatory molecules called SASP factors (*6), activate the immune system, and eliminate themselves. However, if this removal mechanism does not work for some reason, the accumulation of senescent cells will be prolonged, leading to chronic tissue inflammation and the associated onset and progression of age-related diseases. On the other hand, it has long been known that calorie restriction extends lifespan, and it was also known that the accumulation of senescent cells associated with aging is suppressed in individuals whose lifespan is extended by calorie restriction. The research group found that administering antidiabetic drugs (SGLT2 inhibitors) that lower blood sugar by promoting the excretion of sugar into the urine creates a state that mimics calorie restriction, inhibits the accumulation of senescent cells, and eliminates them. I thought that it would be promoted. First, when we administered a short-term SGLT2 inhibitor to mice made obese by eating a high-fat diet, we found that senescent cells accumulated in visceral fat were removed, inflammation in visceral fat was improved, and glucose metabolic abnormalities were observed. and improvement in insulin resistance. In contrast, we found that short-term insulin administration to improve hyperglycemia in obese mice did not remove senescent cells accumulated in visceral fat, nor did it improve inflammation in visceral fat. These results revealed that the senescent cell removal effect of SGLT2 inhibitors is a unique effect that is not related to blood sugar improvement. When we performed metabolomic analysis to clarify its mechanism of action, we found that administration of SGLT2 inhibitors increased the presence of AICAR, a metabolite that activates AMPK (*7). In fact, various experiments have shown that AMPK activation is important for the senescent cell removal effect of SGLT2 inhibitors. Furthermore, activation of AMPK suppresses the immune checkpoint molecule (PD-L1(*8)), whose expression level is particularly increased in highly malignant senescent cells, which helps the immune system, which is responsible for the removal of senescent cells. It has been shown that this drug activates the senescent cells and promotes the removal of senescent cells.
Similarly, administration of SGLT2 inhibitors promoted the shrinkage of atherosclerotic plaques by removing senescent cells from the atherosclerotic lesions that were promoted by hypercholesterolemia. Furthermore, by administering an SGLT2 inhibitor, we were able to observe improvements in age-related frailty and extension of the lifespan of progeria mice.
■Future developments
This time, the research group has identified a new senolytic agent and clarified its mechanism of action, with the aim of establishing new treatments for age-related diseases. Many of the conventional senolytic drugs have been used as anti-cancer drugs, and there were concerns about their side effects.However, SGLT2 inhibitors activate the immune system, which is responsible for removing senescent cells. It is a new class of senolytic agent in that it promotes the removal of senescent cells, and it is a therapeutic agent with fewer concerns about side effects. In this study, we confirmed the improvement effect on diabetes, arteriosclerosis, and frailty, as well as the life extension effect on premature aging.In the future, we will verify the effect on various age-related diseases including Alzheimer’s disease and apply it clinically to humans. is expected.
[Image 1: https://prtimes.jp/i/21495/643/resize/d21495-643-525381ddef09b16eac13-0.jpg&s3=21495-643-588acb06016bb851f5b99f0b0bd458dc-1927×685.jpg] Figure 1: Mechanism of SGLT2 inhibitors removing senescent cells SGLT2 inhibitors activate the immune system, which is responsible for eliminating senescent cells, and remove senescent cells, thereby improving chronic inflammation.
[Image 2: https://prtimes.jp/i/21495/643/resize/d21495-643-5a113939932a70d5f7a0-1.jpg&s3=21495-643-6e19a5392ae72c163d587a89cc4addad-826×305.jpg]
[Image 3: https://prtimes.jp/i/21495/643/resize/d21495-643-30e1803d850036eb32cd-2.jpg&s3=21495-643-aec8a85d1a00dcec9a66a40293124693-872×547.jpg] Figure 2: Effect of corridor cell removal drug
SGLT2 inhibitors removed senescent cells, improved obesity-related diabetes and arteriosclerosis, and age-related frailty, and extended the lifespan of progeria mice.
■Term explanation
*1 Senescent cells: Cells that irreversibly stop dividing due to damage to their chromosomes caused by various stresses. Cellular senescence is one of the mechanisms that suppress cancer development. *2 Chronic inflammation: Non-infectious inflammation caused by inflammatory cytokines secreted by senescent cells.
*3 SGLT2 inhibitor: SGLT2 is a sodium glucose cotransporter localized in the proximal tubule of the kidney. By inhibiting this, sugar is excreted into the urine, so it is used as a treatment for diabetes. *4 Frailty: A state in which physical function declines due to aging etc. *5 Senolysis: Selective removal of senescent cells.
*6 SASP factor: Cell aging-related secreted trait factor. Most are inflammatory cytokines.
*7 AMPK: Phosphoenzyme that is activated when there is a lack of intracellular energy. It is activated by AMP and its similar metabolite AICAR.
*8 PD-L1: A protein expressed on the surface of cells. It binds to a protein called PD-1 on the surface of T cells, which are immune cells, and suppresses the function of immune cells to prevent them from attacking. It plays a role in putting the brakes on the immune system. ■Original paper
This study was published online in the journal Nature Aging (dated May 30, 2024).
Title: SGLT2 eliminates inhibitions senescent cells and alleviates pathological aging
Title (Japanese translation): SGLT2 inhibition eliminates senescent cells and improves pathological aging
Author: Goro Katsuumi(１, Ippei Shimizu(２, Masayoshi Suda(１, Yohko Yoshida(１, Takaaki Furihata)(１, Yusuke Joki(１, Chieh-Lun Hsiao(１, Liang Jiaqi(１, Shinya Fujiki(３, Manabu) Abe(４, Masataka Sugimoto(５, Tomoyoshi Soga(６, and Tohru Minamino(1)
Author (in Japanese): Goro Katsumi1), Ippei Shimizu2), Masakichi Suda1), Yoko Yoshida1), Takaaki Furuhata1), Yusuke Ueki1), Chieh-Lun Hsiao1), Liang Jiaqi1), Fujiki Shinya 3), Manabu Abe 4), Masataka Sugimoto 5), Tomoyoshi Soga 6), Toru Minamino 1)
Author affiliation: 1) Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, 2) Department of
Cardiovascular Aging, National Cerebral and Cardiovascular Center. , 3) Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, 4) Niigata University Brain Research Institute, 5) Tokyo Metropolitan Health and Gerontology Center Research Institute, 6) Keio University Institute for Advanced Life Science
DOI: 10.1038/s43587-024-00642-y
This research is based on the AMED Moonshot Research and Development Project (21zf0127003), “Realization of medical treatment to extend healthy life expectancy to 100 years by removing inflammation-induced cells,” and the AMED-CREST (24gm1110012), “Individual functions targeting the entire life course. Supported by the Research and Development Area “Elucidation of the Decline Mechanism”, JSPS Scientific Research Fund (S) (JP 23H05487), Ministry of Education, Culture, Sports, Science and Technology Private Universities Strategic Research Infrastructure Formation Project, Academic Research Promotion Fund, and Vehicle Racing Public Interest Fund Memorial Foundation. , was conducted based on multi-institutional collaborative research. We would like to express our deepest gratitude to everyone who cooperated with this research.
AMED is striving to achieve Goal 7 of the moonshot R&D project: “By 2040, create a sustainable medical and nursing care system that prevents and overcomes major diseases and allows people to enjoy life without health concerns up to the age of 100.” We are promoting research and development.
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