Model Organisms in Aging Research: Caenorhabditis elegans

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Cover image for research topic "Model Organisms in Aging Research: Caenorhabditis elegans"
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Maria Olivia Casanueva
European Molecular Biology Laboratory
Kim A. Caldwell
University of Alabama
Cindy Voisine
Northeastern Illinois University
Carmen Nussbaum-Krammer
Ludwig Maximilian University of Munich
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Original Research
19 August 2022
Age-dependent accumulation of tau aggregation in Caenorhabditis elegans
Wendy Aquino Nunez
, 2 more and 
Brian D. Ackley
Pan-neuronal model of tau aggregation. (A) Schematic representation of the 2N4R tau isoform (hTau40) and the mutations used in this report. (B) A schematic representation of the DNA constructs injected (created with BioRender.com). (C) A transmitted light and (C′) fluorescent image of a day one adult animal expressing hTau40GFP. Magnified confocal images of the (D) ventral nerve cord and (E) tail regions of the animals in the wild-type hTau40, 3PO (D’,E’) and P301S (D”, E”) expressing animals. Note, the images are taken from regions indicated by the hashed boxes in (C). (D) We found that in the ventral nerve hTau40 was evenly concentrated throughout axons, in contrast to (D′) 3POtau which was concentrated in the cell bodies. (D”) P301S was similar to the wild-type tau. (E,E’,E”) In the tail we observed similar results, with tau present through the cell bodies.

Aging is the primary risk factor for Alzheimer’s disease (AD) and related disorders (ADRDs). Tau aggregation is a hallmark of AD and other tauopathies. Even in normal aging, tau aggregation is found in brains, but in disease states, significantly more aggregated tau is present in brain regions demonstrating synaptic degeneration and neuronal loss. It is unclear how tau aggregation and aging interact to give rise to the phenotypes observed in disease states. Most AD/ADRD animal models have focused on late stages, after significant tau aggregation has occurred. There are fewer where we can observe the early aggregation events and progression during aging. In an attempt to address this gap, we created C. elegans models expressing a GFP-tagged version of the human tau protein. Here we examined how tau-gfp behaved during aging, comparing wild-type tau (hTau40), a disease-associated mutation (P301S), and an aggregation-prone variant (3PO). We measured age-dependent changes in GFP intensity and correlated those changes to normal aging in the nematode. We found differences in tau stability and accumulation depending on the tau variant expressed. hTau40GFP and P301SGFP were localized to axons and cell bodies, while 3POGFP was more concentrated within cell bodies. Expression of 3POGFP resulted in decreased lifespan and variations in locomotor rate, consistent with a pathological effect. Finally, we found that the human tau interacted genetically with the C. elegans ortholog of human tau, ptl-1, where the loss of ptl-1 significantly accelerated the time to death in animals expressing 3PO.

6,188 views
11 citations
Review
02 June 2022
The Intestine as a Lifespan- and Proteostasis-Promoting Signaling Tissue
Francesca Hodge
, 1 more and 
Patricija van Oosten-Hawle

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.

4,039 views
22 citations
The mitochondrial unfolded protein response. (A) ATFS-1 is a unique protein that can serve as a sensor for mitochondrial health and fitness. It contains both a nuclear localization signal (NLS) and a mitochondrial localization signal (MLS). Under basal, unstressed conditions, ATFS-1 is imported into the mitochondria where it is degraded by LON protease. Under conditions of mitochondrial stress or damage, mitochondrial import decreases, allowing ATFS-1 to instead accumulate in the mitochondria where it can activate UPRMT with additional transcriptional regulators including DVE-1 and chromatin regulator JMJD-1.2. (B) Similar to the HSR, UPRMT can also be communicated in a nonautonomous manner. Neurons that experience mitochondrial stress can signal to the peripheral tissue, including the intestine, through serotonin and WNT signaling to result in systemic activation of UPRMT, increased stress resilience, and increased lifespan.
Review
24 March 2022
Hijacking Cellular Stress Responses to Promote Lifespan
Naibedya Dutta
, 1 more and 
Ryo Higuchi-Sanabria

Organisms are constantly exposed to stress both from the external environment and internally within the cell. To maintain cellular homeostasis under different environmental and physiological conditions, cell have adapted various stress response signaling pathways, such as the heat shock response (HSR), unfolded protein responses of the mitochondria (UPRMT), and the unfolded protein response of the endoplasmic reticulum (UPRER). As cells grow older, all cellular stress responses have been shown to deteriorate, which is a major cause for the physiological consequences of aging and the development of numerous age-associated diseases. In contrast, elevated stress responses are often associated with lifespan extension and amelioration of degenerative diseases in different model organisms, including C. elegans. Activating cellular stress response pathways could be considered as an effective intervention to alleviate the burden of aging by restoring function of essential damage-clearing machinery, including the ubiquitin-proteosome system, chaperones, and autophagy. Here, we provide an overview of newly emerging concepts of these stress response pathways in healthy aging and longevity with a focus on the model organism, C. elegans.

7,612 views
23 citations
Post-translational modifications (PTMs). Distinct PTMs such as phosphorylation, acetylation, ubiquitination, and SUMOylation modulate the activity, intracellular localization and degradation of numerous proteins, determining cellular function and organismal longevity. (A) The ATP-consuming process of phosphorylation is required for the activity of many proteins, either through providing a functional chemical moiety, or by allowing the protein to translocate to the required cellular compartment. (B) Acetylation is also required for the function of various proteins, and is particularly important for correct chromatin function. In this instance, histone acetylation is required for chromatin opening and access to DNA by the cell. (C) The ubiquitination of unwanted proteins marks them for recognition and degradation by the UPS. This often requires repeated units of ubiquitin to be successively added to a growing polyubiquitin chain. The balance between ubiquitination and deubiquitination can thus control and regulate the composition of the proteome. (D) SUMOylation can both activate or deactivate modified proteins. SUMOylation can trigger conformational changes that allow proteins to interact with their biological substrates, block binding sites to prevent substrate interaction, or act as a component of a structural motif to enable recognition of the modified protein.
Review
18 March 2022
Insights Into the Links Between Proteostasis and Aging From C. elegans
William Hongyu Zhang
, 1 more and 
David Vilchez

Protein homeostasis (proteostasis) is maintained by a tightly regulated and interconnected network of biological pathways, preventing the accumulation and aggregation of damaged or misfolded proteins. Thus, the proteostasis network is essential to ensure organism longevity and health, while proteostasis failure contributes to the development of aging and age-related diseases that involve protein aggregation. The model organism Caenorhabditis elegans has proved invaluable for the study of proteostasis in the context of aging, longevity and disease, with a number of pivotal discoveries attributable to the use of this organism. In this review, we discuss prominent findings from C. elegans across the many key aspects of the proteostasis network, within the context of aging and disease. These studies collectively highlight numerous promising therapeutic targets, which may 1 day facilitate the development of interventions to delay aging and prevent age-associated diseases.

5,962 views
17 citations