C. elegans cognitive decline with age: more than just wiggling forward and backward

In this Outlook, Sengupta and Murphy discuss the lessons learned from C. elegans on the conserved mechanisms underlying complex behaviors like cognitive performance and memory. Model organisms used to study these mechanistic changes during aging could serve as a window into understanding the impact of cognitive aging and behavioral decline in humans and help illuminate how these effects might be countered.

Abstract

Caenorhabditis elegans has been at the forefront of research on mechanisms of age-related decline for the past 30 years. Despite its popularity in longevity research, C. elegans is underappreciated for its potential to study complex behaviors and the progressive decline in these functions with age. Using assays of learning and memory, we have identified genetic pathways that regulate these behaviors and identified new mechanisms to boost these functions with age in both worms and mice. Because C. elegans is so highly conserved, some of these recently described mechanisms may be good targets to prevent human cognitive decline with age.

Many of the molecular and cellular pathways that were first discovered to regulate longevity in Caenorhabditis elegans, such as insulin/IGF-1 signaling (IIS) (Kenyon et al. 1993), were later found to play the same longevity-regulating roles in other organisms (Kenyon 2010; Hedges et al. 2023). Although C. elegans has been used to study aging and longevity for decades, we would argue that the worms’ potential for understanding complex behaviors and their changes with age have been underappreciated. This is largely due to the mistaken notion that the worms’ behavior is limited to wiggling forward and backward and mating. Logically, any animal that survives in a complex, variable environment is likely to have evolved mechanisms to sense, interpret, learn, remember, and use cues from their surroundings to make important life history decisions: where to find food, when to reproduce and whom to mate with, and how to maximize the survival of their progeny. These decisions all require the ability not just to move or even sense odors but to learn associations with relevant environmental information (like food and pathogens) and how long it would make sense to remember that information.

As we presented at the Cold Spring Harbor Laboratory Symposium on Aging, not only can we measure C. elegans’ ability to learn and remember using Pavlovian pairings of food and odor (Kauffman et al. 2010; Stein and Murphy 2014; Lakhina et al. 2015; Kaletsky et al. 2016), we can also measure the declines in these behaviors with age and understand how the long-lived IIS mutant daf-2 extends these abilities in duration and with age (Weng et al. 2024). Studying complex behaviors (as opposed to simple stimulus–reflex type responses) has allowed us to investigate the contributions of basal states as well as emergent brain states, such as training-induced states, to behavior (Lakhina et al. 2015). Single-nucleus sequencing of adult neurons combined with learning and memory assays allowed us to identify key single-neuron differences between daf-2 and wild-type animals (Ange et al. 2024; Morillo et al. 2025) that underlie the improved cognitive performance of daf-2 mutants. Additionally, using the age-dependent behavioral paradigms and tissue-specific transcriptomic approaches that we developed, we also identified sex-specific cognitive aging trajectories (Weng and Murphy 2024; Weng et al. 2024). Because the molecular machinery that worm neurons require to carry out these behaviors are highly conserved with proteins in our own brains, there is great potential to use C. elegans to learn more about how we can maintain our own cognitive abilities as we age. In fact, we overexpressed one of the proteins that we first identified in C. elegans to improve memory, the Gaq protein ELG-30/Gnaq (Arey et al. 2018), and found that its hyperactivation also improves memory in aged mice using completely conserved mechanisms of CREB transcription factor activation in both species (Stevenson et al. 2023). The conserved molecular effectors underlying improved cognitive performance that we discover in C. elegans are therefore promising potential targets in our efforts to delay or reverse cognitive decline in humans.

Our work also highlighted the previously unappreciated ability of nonneuronal tissues to regulate C. elegans memory cell-nonautonomously. We found that insulin/FOXO signaling in the worms’ hypodermis controls Notch signaling to neurons, which in turn regulates CREB function in a broad set of neurons (Zhou et al. 2025). Our investigation of gene expression signatures at the single-cell level downstream from IIS and Notch signaling provided integrated molecular- and circuit-level characterizations of learning and memory engrams. We speculate that this hypodermal IIS–Notch–neuronal CREB signaling pathway may work on a slower timescale to control memory, perhaps allowing starving animals to preserve memories via CREB function additively with direct neuronal regulation. This regulation of memory in a highly metabolic, liver-like tissue is reminiscent of effects on the cognitive function of donor mice from liver-derived plasma proteins from exercised mice (Horowitz et al. 2020). Furthermore, CREB's role in memory and its regulation with age seem to be very well conserved, at least from worms to mice.

C. elegans’ success in being the first animal to have its whole connectome fully determined perhaps led to an early bias toward primarily examining the role of physical synaptic connections, often in simpler, nonassociative reflex behaviors. These behaviors were a major focus in early behavior studies in C. elegans, which may have contributed to the misconception that these constitute the entirety of C. elegans’ behavioral repertoire. Although the connectome has been invaluable in understanding how neurons function, it would be easy—but mistaken—to think that the physical connectome alone forms the neural basis of all behaviors. For fast, stimulus–response type behaviors, such as movement in response to a stimulus, the physical connectome is probably the most relevant network. However, similar to other organisms, neuromodulators in C. elegans play critical roles in long-range communication beyond immediate physical synaptic contacts (Leinwand and Chalasani 2013) and in generating long-lasting neural states (Flavell et al. 2013; Soden et al. 2023). Neuropeptide signaling from a sensory neuron class to an interneuron class underlies improved long-term memory performance in worms with hyperactive Gaq protein ELG-30/Gnaq (Arey et al. 2018). Recent work has elucidated the complete network of C. elegans neuropeptide–receptor pairs (Ripoll-Sánchez et al. 2023)—the peptidergic connectome—that may act on longer spatial scales and timescales than that of the physical connectome, perhaps overriding the physical connectome for longer-lasting neuronal interactions. As we and others have demonstrated, C. elegans can be used to interrogate complex behaviors such as associative learning and memory (Torayama et al. 2007; Kauffman et al. 2010; Chandra et al. 2023; Tang et al. 2023), which may rely heavily on slower and longer-range interactions that are best conveyed by neuropeptides or other types of signaling. Although our studies on the neural basis of associative learning and memory identified critical roles for long-range signaling, including neuron–neuron signaling mediated by neuropeptides and neuromodulators (Arey et al. 2018), our investigation of body-to-brain signaling revealed long-range signaling by the OSM-11 Notch ligand (Zhou et al. 2025). Neuropeptides and other neuromodulators in fact regulate some of the most conserved aspects of neural circuits and behavior, such as feedback mechanisms (Chalasani et al. 2010) and motivational states (Waggoner et al. 1998). Complex behaviors such as long- and short-term associative memory are also of major importance from a cognitive aging perspective, as these decline much more rapidly with age compared with simpler, motility-related behaviors in C. elegans (Kauffman et al. 2010), mirroring patterns of behavioral decline in other species.

We should not limit our imaginations to the worms’ ability to wiggle forward and backward but instead ask what other complex behaviors C. elegans might be able to perform; we can then study how these behaviors change with age. Understanding the molecular regulation of these behaviors may shed light on how our own brains work and how we might keep them functioning longer as we age. By modeling complex human behaviors that we care about in this simple model system, we have identified conserved pathways that act at diverse spatial and temporal scales to regulate the maintenance of cognitive performance, a critical component of health span.