Journal Article

Ketone bodies: A double‐edged sword for mammalian life span

Chin‐Kanasaki, Masami, Kume, Shinji, Yamahara, Kosuke, Maegawa, Hiroshi, Tomita, Issei, Fujita, Yukihiro, Tanaka‐Sasaki, Yuki, Yasuda‐Yamahara, Mako, Kuwagata, Shogo, Nishi, Eiichiro, Tsuruta, Hiroaki, Katagiri, Hideki

2023

Overview

Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long‐term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole‐body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3‐butanediol, a precursor of β‐hydroxybutyrate. Furthermore, feeding the 1,3‐butanediol‐containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE‐deficient mice. By contrast, an ad libitum low‐carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double‐edged sword with respect to survival, depending on the method of administration and health status. The present study demonstrates that endogenous ketogenesis is essential for long‐term mammalian survival, which was revealed by a study using Hmgcs2−/− mice, and that dietary administration of 1,3‐butanediol (1,3‐BD), a precursor of β‐OHB, increases midlife mortality in normal mice, but extends life span in aged mice or atherosclerotic mice. By contrast, ad libitum low‐carbohydrate ketogenic diet increases mortality in any mouse models. Thus, ketone bodies represent a double‐edged sword for mammalian survival.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 3-Hydroxybutyric Acid / Animals / Apolipoprotein E / Arteriosclerosis / Butylene Glycols / Calories / Carbohydrates / Diet / Dietary supplements / Glucose / High fat diet / Hmgcs2 / Ketogenesis / Ketone Bodies / ketone body / Ketones / Life span / Longevity / Low carbohydrate diet / low‐carbohydrate ketogenic diet / Mammals / Metabolism / Mice / Middle age / Mortality / Nutrient deficiency / Proteins / Short Communication / Short Communications / Survival