Lipoic acid rejuvenates aged intestinal stem cells by preventing age‐associated endosome reduction

Abstract

The age-associated decline of adult stem cell function is closely related to the decline in tissue function and age-related diseases. However, the underlying mechanisms that ultimately lead to the observed functional decline of stem cells still remain largely unexplored. This study investigated Drosophila midguts and found a continuous downregulation of lipoic acid synthase, which encodes the key enzyme for the endogenous synthesis of alpha-lipoic acid (ALA), upon aging. Importantly, orally administration of ALA significantly reversed the age-associated hyperproliferation of intestinal stem cells (ISCs) and the observed decline of intestinal function, thus extending the lifespan of Drosophila. This study reports that ALA reverses age-associated ISC dysfunction by promoting the activation of the endocytosis-autophagy network, which decreases in aged ISCs. Moreover, this study suggests that ALA may be used as a safe and effective anti-aging compound for the treatment of ISCdysfunction-related diseases and for the promotion of healthy aging in humans.

Neuroglian regulatesDrosophilaintestinal stem cell proliferation through enhanced signaling via the Epidermal Growth Factor Receptor

“…Intriguingly, recent research has identified age-related disruption of the endocytosis/autophagy pathway as one mechanism leading to an increase in EGFR and, consequently Erk signaling in aged ISCs via stabilization of ligand-activated EGFR (Du et al, 2020;Zhang et al, 2019). Our work suggests that an increase in Nrg-mediated potentiation of EGFR signaling may be additional mechanism that contributes to increases in ISC proliferation and intestinal dysplasia with age ( Figure 4, Supplementary Figure 4).…”

The early endosomal protein Rab21 is critical for enterocyte functions and intestinal homeostasis

“…Activated Ras phenocopied Rab21 depletion (Figure 5B-E and [55]), and interestingly, recent work has highlighted a role for autophagy in regulating EGFR signaling in Drosophila intestinal stem cells [56,57]. Therefore, we assessed if EGFR signaling was impaired upon Rab21 knockdown by immunostaining for diphosphorylated extracellular signal-regulated kinase ((dp)ERK).…”

“…Recently, an autophagy-endocytosis network was linked to the negative regulation of EGFR signaling in intestinal stem cells [56,57]. However, EGFR pathway regulation appears to be different in enterocytes, as inhibiting EGFR signaling did not rescue autophagy-induced increases in proliferation.…”

Lipoic acid and autophagy: new insights into stem cell aging

“…Although stem cell aging has been intensively explored, the mechanisms remain poorly understood. In this issue of EMBO Reports, Du et al report that alpha-lipoic acid (ALA) sustains an active endocytosis-autophagy network that effectively reverses agedependent ISC hyperplasia in Drosophila (Du et al, 2020). This work suggests a new strategy for treating aging-associated gastrointestinal diseases.…”

“…In this issue of EMBO Reports, Du et al screened ten endogenously synthesized chemicals, scoring their ability to repress age-dependent ISC over-proliferation in flies (Du et al, 2020). Among the compounds they examined, alpha-lipoic acid (ALA) showed the most potent effect on repressing ISC hyperplasia in aging flies.…”