1: Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency.

J Clin Invest

2020 Aug 3; 30(8):4152–4166. DOI: org/10.1172/JCI134431

Wakako Kawarazaki, Risuke Mizuno, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Daigoro Hirohama, Kohei Ueda, Fumiko Kawakami-Mori, Shigeyoshi Oba, Takeshi Marumo, Toshiro Fujita.

It was known that elderly people are prone to hypertension, but the causes and mechanisms were unclear. A research group led by Toshiro Fujita (Professor Emeritus, The University of Tokyo), a Guest Professor at our School of Medicine, has elucidated the pathogenic mechanism of hypertension in the elderly. Using elderly mice, the research group demonstrated a series of processes where, with aging, the anti-aging factor Klotho protein in the blood decreases. Consequently, high salt intake activates the vascular contraction pathway (Wnt5a-RhoA non-canonical pathway), which was previously suppressed by Klotho, leading to an increase in blood pressure. Furthermore, to support this, they showed that when Klotho protein was supplemented to restore blood levels to those of young mice beforehand, blood pressure did not rise even when salt was administered. This study proposes the potential of Klotho supplementation and Wnt inhibitors as new treatments for hypertension in the elderly. It also emphasizes the importance of salt reduction for preventing the onset of hypertension.

(Toshiro Fujita, 51st class, Guest Professor, School of Medicine; Professor Emeritus, The University of Tokyo)

The Lancet Diabetes & Endocrinology,

01 Jul 2020, 8(7):606-615, DOI: 10.1016/s2213-8587(20)30130-3

Kohsaka S, Lam CSP, Kim DJ, Cavender MA, Norhammar A, Jørgensen ME, Birkeland KI, Holl RW, Franch-Nadal J, Tangri N, Shaw JE, Ilomäki J, Karasik A, Goh SY, Chiang CE, Thuresson M, Chen H, Wittbrodt E, Bodegård J, CVD-REAL 2 Investigators and Study Group

Thank you very much for featuring this paper. For a long time, the goal of diabetes treatment was considered to be lowering blood glucose levels and HbA1c, and it was believed that this "legacy effect" would lead to the long-term prevention of cardiovascular complications such as myocardial infarction and stroke, and by extension, an increase in healthy life expectancy. However, the results of the large-scale RCT of SGLT2 inhibitors (the EMPA-REG trial) published in 2016 surprised the world. This was because it was shown to suppress cardiovascular complications, especially heart failure-related events, very early after initiation (2–3 years). While this was welcome news, it contradicted the long-held conventional wisdom in diabetes treatment, sparking widespread debate about "Is this really true?" (It is often experienced in the cardiovascular field that RCT results cannot be replicated depending on the region or patient population). In response to this debate, this paper conducted a comparative verification using patient data from a cohort of 380,000 cases in 13 countries, mainly in Asia, comparing a group that initiated SGLT2 inhibitors with a group that initiated DPP-4 inhibitors, which were approved around the same time. For this verification, it was necessary to ensure the consistency of data from each country, standardize outcome definitions, and apply state-of-the-art statistical processing. As a result, we were able to show that the RCT results were reproducible across a wide range of patient populations. While the "use" of big data is attracting global attention, I believe this study was recognized for its international collaborative approach to a global research question (RQ).

(Shun Kohsaka, 76th class, Department of Cardiology)

Nature Communications

2020; 11(3820). https://doi.org/10.1038/s41467-020-17636-0

Takumi Hirata, Yasumichi Arai, Shinsuke Yuasa, Yukiko Abe, Michiyo Takayama, Takashi Sasaki, Akira Kunitomi, Hiroki Inagaki, Motoyoshi Endo, Jun Morinaga, Kimio Yoshimura, Tetsuo Adachi, Yuichi Oike, Toru Takebayashi, Hideyuki Okano & Nobuyoshi Hirose

Against the backdrop of global longevity, the population of supercentenarians is rapidly increasing, but supercentenarians (SCs) over 110 years old are extremely rare and are considered a special group approaching the limits of human lifespan. In this paper, we followed 1,427 long-lived individuals (aged 85 and over), including 36 SCs, for more than 10 years and examined the association between nine biomarkers and life expectancy. The results showed that five blood molecules (figure), including NT-proBNP, an indicator of heart failure, were associated with the life expectancy of long-lived individuals. NT-proBNP was strongly associated with life expectancy, especially after age 105, and we discovered that the lower the blood concentration of this molecule, the higher the probability of reaching age 110 or older. In addition, albumin (nutrition, liver function) was associated with life expectancy across all age groups. Since NT-proBNP increases with age and correlates with renal function, we presumed that slow aging of the cardiorenal circulatory system is a biological characteristic of SCs. It is hoped that this will lead to future research on the prevention of cardiovascular disease in the elderly and the development of new treatments.

(Hideyuki Okano, 62nd class, Department of Physiology / Center for Supercentenarian Medical Research; Yasumichi Arai, 70th class, Center for Supercentenarian Medical Research)

Ocul Surf.

2020 Jul 28;S1542-0124(20)30107-5. doi: 10.1016/j.jtos.2020.06.010

Daisuke Tomida, Yukari Yagi-Yaguchi, Kazunari Higa, Yoshiyuki Satake, Jun Shimazaki, Takefumi Yamaguchi