Anti-Aging Effect of the Ketone Metabolite β-Hydroxybutyrate in Drosophila Intestinal Stem Cells.

Joung-Sun Park,Yung-Jin Kim

doi:10.3390/ijms21103497

Joung-Sun Park, Yung-Jin Kim

Open Access

https://doi.org/10.3390/ijms21103497

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Abstract

Age-related changes in tissue-resident adult stem cells may be closely linked to tissue aging and age-related diseases, such as cancer. β-Hydroxybutyrate is emerging as an important molecule for exhibiting the anti-aging effects of caloric restriction and fasting, which are generally considered to be beneficial for stem cell maintenance and tissue regeneration. The effects of β-hydroxybutyrate on adult stem cells remain largely unknown. Therefore, this study was undertaken to investigate whether β-hydroxybutyrate supplementation exerts beneficial effects on age-related changes in intestinal stem cells that were derived from the Drosophila midgut. Our results indicate that β-hydroxybutyrate inhibits age- and oxidative stress-induced changes in midgut intestinal stem cells, including centrosome amplification (a hallmark of cancers), hyperproliferation, and DNA damage accumulation. Additionally, β-hydroxybutyrate inhibits age- and oxidative stress-induced heterochromatin instability in enterocytes, an intestinal stem cells niche cells. Our results suggest that β-hydroxybutyrate exerts both intrinsic as well as extrinsic influence in order to maintain stem cell homeostasis.

Highlights

Adult stem cells play a key role in tissue homeostasis and regeneration based on their ability to sustain self-renewal and produce differentiated cells [1,2,3,4]
We report that β-HB, a key molecule that is involved in ketone body signaling, has an inhibitory effect on adult stem cell aging in the Drosophila midgut
The key results of this study are: (1) β-HB inhibits age- and oxidative stress-induced increases of centrosome amplification in midgut Intestinal stem cell (ISC), (2) β-HB inhibits age- and oxidative stress-induced DNA damage accumulation in midgut ISCs and progenitors, and (3) β-HB inhibits age- and oxidative stress-induced increases of heterochromatin instability in midgut ECs, ISC niche cells

Summary

Introduction

Adult stem cells play a key role in tissue homeostasis and regeneration based on their ability to sustain self-renewal and produce differentiated cells [1,2,3,4]. Age-related changes in adult stem cells are closely involved with tissue aging and age-related diseases, including cancer [5,6,7,8,9]. Studies need to focus on stem cells and their microenvironments in order to elucidate the mechanisms that slow down or recover age-related changes in adult stem cells. Organismal diet is emerging as an important regulator of adult stem cell function [11]. Caloric restriction and fasting are commonly associated with extended lifespan, delayed onset of age-related diseases, and reduced cancer incidence, and they are generally beneficial for stem cell maintenance and tissue regeneration [12,13]. The ketone body β-hydroxybutyrate (β-HB) has emerged as an important molecule for imparting the anti-aging effects of caloric restriction and fasting [14]

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