Temporally Controlled Nervous System-to-Gut Signaling Bidirectionally Regulates Longevity in Caenorhabditis elegans

Core Concepts

The nervous system can both shorten and extend lifespan by differentially signaling the gut at early and mid-late life stages through the neurotransmitter acetylcholine and distinct gut receptors and transcription factors.

Abstract

This study in Caenorhabditis elegans reveals a temporal mechanism by which the nervous system bidirectionally regulates lifespan through nervous system-to-gut signaling.
The key findings are:

Cholinergic motor neurons in the nervous system can both shorten lifespan in early life and extend lifespan in mid-late life, depending on the temporal control of their output.

In early life, cholinergic motor neurons signal the gut via the neurotransmitter acetylcholine (ACh) acting through the nicotinic ACh receptor ACR-6 to regulate the FOXO transcription factor DAF-16 in the intestine, leading to shortened lifespan.

In mid-late life, cholinergic motor neurons signal the gut via the same neurotransmitter ACh but through a different muscarinic ACh receptor GAR-3 to regulate the heat shock transcription factor HSF-1 in the intestine, leading to extended lifespan.

The temporal switch in the intestinal expression of ACR-6 and GAR-3 provides a potential mechanism underlying the bidirectional regulation of lifespan by cholinergic motor neurons at different life stages.

These results highlight an exquisite role of the nervous system in orchestrating a body-wide aging process by temporally controlling nervous system-gut communications.

Stats

The 25% lifespan of worms with cholinergic motor neuron output inhibited was prolonged, while their 75% and maximal lifespan were slightly shortened.
Enhancing the output of cholinergic motor neurons throughout the entire worm life shortened lifespan.
Enhancing the output of cholinergic motor neurons during the larval stage only shortened lifespan.
Enhancing the output of cholinergic motor neurons after Day 5 adulthood extended lifespan.
The expression level of DAF-16 target genes sod-3 and mtl-1 was upregulated in worms deficient in releasing ACh from cholinergic motor neurons.
The expression level of HSF-1 target genes hsp-16.2 and pat-10 was upregulated in long-lived worms with enhanced cholinergic motor neuron output in mid-late life.

Quotes

"Cholinergic motor neurons regulate lifespan in early life through a neuroendocrine signaling circuit."
"Cholinergic motor neurons extend lifespan in mid-late life through a distinct neuroendocrine circuit."
"The temporal switch in the intestinal expression of ACR-6 and GAR-3 provides a potential mechanism underlying the bidirectional regulation of lifespan by cholinergic motor neurons at different life stages."

Key Insights Distilled From

Temporally controlled nervous system-to-gut signaling bidirectionally regulates longevity in C. elegans

by Xu,L., Han,C... at www.biorxiv.org 04-15-2024

https://www.biorxiv.org/content/10.1101/2024.04.12.589179v1

Deeper Inquiries

How do the temporal expression patterns of ACR-6 and GAR-3 in the intestine get established and regulated

The temporal expression patterns of ACR-6 and GAR-3 in the intestine are established and regulated through a complex interplay of genetic and environmental factors. The expression of these ACh receptors is likely controlled by a combination of transcriptional regulation, post-translational modifications, and signaling pathways.

Transcriptional Regulation: The expression of ACR-6 and GAR-3 genes is likely regulated by specific transcription factors that activate or repress their transcription at different life stages. Transcriptional regulators may respond to internal cues, external stimuli, or developmental signals to modulate the expression of these receptors.

Post-Translational Modifications: Post-translational modifications, such as phosphorylation, acetylation, or ubiquitination, can influence the stability, localization, and activity of ACR-6 and GAR-3 proteins. These modifications may be dynamically regulated in a stage-specific manner to control the availability and function of the receptors.

Signaling Pathways: Various signaling pathways, including those involved in neurotransmission, stress response, and developmental processes, may converge to regulate the expression of ACR-6 and GAR-3. These pathways could be activated or inhibited at different life stages to modulate the levels of the receptors in the intestine.

Environmental Factors: Environmental cues, such as temperature, nutrient availability, and stress conditions, may also impact the expression of ACR-6 and GAR-3. These factors could act as external signals that influence the temporal expression patterns of the receptors in response to changing environmental conditions.

The establishment and regulation of the temporal expression patterns of ACR-6 and GAR-3 in the intestine likely involve a sophisticated network of molecular mechanisms that integrate genetic, environmental, and physiological signals to finely tune the activity of these ACh receptors at different stages of worm life.

What other signaling components in the two neuroendocrine circuits may also undergo temporal regulation to contribute to the bidirectional control of lifespan

In addition to ACR-6 and GAR-3, several other signaling components in the two neuroendocrine circuits may undergo temporal regulation to contribute to the bidirectional control of lifespan. These components could include neurotransmitters, neuropeptides, receptors, transcription factors, and downstream effectors that are involved in the signaling pathways mediated by cholinergic motor neurons and the intestine.

Neurotransmitters and Neuropeptides: Other neurotransmitters and neuropeptides released by cholinergic motor neurons may exhibit stage-specific expression patterns and signaling activities. These molecules could interact with different receptors in the intestine to modulate downstream signaling pathways that impact lifespan regulation.

Receptors: Apart from ACR-6 and GAR-3, additional receptors in the intestine may also show temporal expression changes. These receptors could respond to different ligands or signaling molecules released by the nervous system to regulate diverse physiological processes associated with aging and longevity.

Transcription Factors: Transcription factors downstream of the ACh receptors, such as DAF-16 and HSF-1, may themselves be subject to temporal regulation. The activity and expression of these transcription factors could be modulated in a stage-specific manner to coordinate the cellular responses that influence lifespan.

Signaling Pathways: Various signaling pathways, including insulin/IGF-1 signaling, stress response pathways, and metabolic pathways, may exhibit temporal dynamics that impact the overall regulation of lifespan. These pathways could intersect with the neuroendocrine circuits to fine-tune the bidirectional control of longevity.

By considering the temporal regulation of multiple signaling components in the nervous system-gut communication pathways, a comprehensive understanding of how lifespan is bidirectionally controlled at different life stages can be achieved.

Could similar temporally controlled nervous system-gut communication mechanisms be found in other organisms, including humans, to regulate aging and longevity

The temporally controlled nervous system-gut communication mechanisms identified in C. elegans may have parallels in other organisms, including humans, to regulate aging and longevity. While the specific molecular details may vary, the fundamental principles of bidirectional control of lifespan through neuroendocrine signaling could be conserved across species.

Mammalian Systems: In mammals, the nervous system communicates with peripheral tissues, including the gut, through a complex network of neurotransmitters, neuropeptides, and hormones. Similar to C. elegans, temporal regulation of signaling components in these pathways may influence aging and longevity in mammals.

Human Aging: Studies in humans have highlighted the role of the nervous system in modulating aging processes, such as neuroendocrine regulation of metabolism, stress response, and immune function. Temporal control of signaling pathways that impact cellular senescence, inflammation, and tissue homeostasis could contribute to age-related changes in humans.

Therapeutic Implications: Understanding how temporal mechanisms regulate aging through nervous system-gut communication could have implications for age-related diseases and interventions to promote healthy aging. Targeting specific signaling components that are temporally regulated may offer novel strategies for extending healthspan and lifespan in humans.

By exploring the conservation of temporally controlled neuroendocrine signaling in different organisms, including humans, researchers can uncover new insights into the complex interplay between the nervous system and peripheral tissues in the regulation of aging and longevity.