The Intestine as a Lifespan- and Proteostasis-Promoting Signaling Tissue

Abstract

In multicellular organisms such as Caenorhabditis elegans, cellular stress stimuli and responses are communicated between tissues to promote organismal health- and lifespan. The nervous system is the predominant regulator of cell nonautonomous proteostasis that orchestrates systemic stress responses to integrate both internal and external stimuli. This review highlights the role of the intestine in mediating cell nonautonomous stress responses and explores recent findings that suggest a central role for the intestine to regulate organismal proteostasis. As a tissue that receives and further transduces signals from the nervous system in response to dietary restriction, heat- and oxidative stress, and hypoxia, we explore evidence suggesting the intestine is a key regulatory organ itself. From the perspective of naturally occurring stressors such as dietary restriction and pathogen infection we highlight how the intestine can function as a key regulator of organismal proteostasis by integrating insulin/IGF-like signaling, miRNA-, neuropeptide- and metabolic signaling to alter distal tissue functions in promoting survival, health- and lifespan.

CUL-6/cullin ubiquitin ligase-mediated degradation of HSP-90 by intestinal lysosomes promotes thermotolerance

“…Studies of systemic signaling in stress responses have shown that RNAi knock-down of hsp-90 mRNA in either the intestine or in neurons triggers upregulation of hsp-70 mRNA expression in muscle cells to promote thermotolerance, a phenomenon named ‘transcellular chaperone signaling’. 20,42,43 These effects were recently found to be HSF-1-independent, as are the effects we see here with CUL-6. Therefore, some of the thermotolerance benefits from CUL-6-mediated loss of HSP-90 protein may be due to cell non-autonomous signaling to muscle.…”

Amyloid β Induces Hormetic-Like Effects Through Major Stress Pathways in aC. elegansModel of Alzheimer’s Disease

“…HSPs are associated with protein misfolding and molecular chaperones involved in the stress response, specifically heat stress, hypoxia, and oxidative stress (Kyriakou et al, 2022, Murshid et al, 2013). During stress, HSPs are typically upregulated in the neurons and intestine as a part of the stress response (Hodge et al, 2022). Aβ+ worms exhibited elevated levels of four HSPs under all conditions: hsp-16 .…”

“…Stress resistance in C. elegans is a cell nonautonomous response mediated by communication between several tissues, most commonly the intestine and neurons (Hodge et al, 2022, Miller et al 2020, Chen et al 2024, Dutta et al, 2022). Stress leads to upregulation of transcription factors like hif-1 in neurons, which can activate serotonin signaling and other pathways in a cell nonautonomous manner (Hodge et al, 2022, Kyriakou et al, 2022, Miller et al 2020, Chen et al 2024, Dutta et al, 2022).…”

“…stress, hypoxia, and oxidative stress(Kyriakou et al, 2022, Murshid et al, 2013. During stress, HSPs are typically upregulated in the neurons and intestine as a part of the stress response(Hodge et al, 2022). Aβ+ worms exhibited elevated levels of four HSPs under all conditions: hsp-16.1, hsp-16.2, hsp-16.49, and hsp-70 (Fig 4A-C).…”

Machine learning predicts lifespan and underlying causes of death in agingC. elegans

“…Notably, DAF-16 activity in the gut partially restores daf-2 mutant longevity in daf-16; daf-2 mutants. There is evidence that this involves paracrine action via both DAF-16-dependent and -independent responses, involving alteration of gene expression 40, 41, 42 and of various processes in other tissues 43, 44, 45 , reviewed by 46 . Thus, the intestine may regulate aging in the whole organism via paracrine (and also autocrine) signaling.…”