In a groundbreaking study that offers fresh insights into the battle against age-related cognitive decline, researchers have unveiled the potential of long-term atorvastatin treatment in enhancing brain function in naturally aging rats. This provocative new research, spearheaded by Xu, Cai, and Chen, reveals a sophisticated molecular mechanism by which atorvastatin exerts its neuroprotective effects, pinpointing the modulation of a critical post-translational modification pathway involving SIRT2-mediated transitions between crotonylation and ubiquitination at a specific lysine residue on neurofilament light chain (NFL). The findings, recently published in Cell Death Discovery, challenge traditional perceptions of statins and extend their scope far beyond cholesterol management, spotlighting them as intriguing candidates for tackling neurodegenerative processes.
Atorvastatin, widely known for its cholesterol-lowering properties, has garnered increasing attention for its pleiotropic effects in the central nervous system. Prior studies have hinted at its ability to modulate neuroinflammation and enhance cerebral blood flow, but the underlying molecular details had remained elusive. In this latest investigation, the authors employed a naturally aging rat model to closely mimic human aging, which is pivotal given the complexity and multifactorial nature of cognitive deterioration in elderly populations. Their strategic use of this model allowed for the observation of atorvastatin’s effects over an extended period, revealing sustained cognitive benefits that correlate with biochemical modifications in neuronal structures.
Central to the study’s findings is the dynamic interplay between lysine crotonylation and ubiquitination at position 272 on the NFL protein. NFL, a fundamental component of the neuronal cytoskeleton, is integral to maintaining axonal integrity and facilitating proper nerve signal conduction. Modifications at the lysine 272 residue appear to act as molecular switches that regulate NFL’s stability and turnover. The researchers discovered that atorvastatin increases SIRT2-mediated decrotonylation at this site, which subsequently promotes ubiquitination. This orchestrated transition facilitates the clearance of damaged NFL proteins, thereby preserving cytoskeletal architecture and enhancing neuronal resilience.
SIRT2, a member of the sirtuin family of NAD+-dependent deacylases, emerges in this study as a pivotal enzymatic regulator orchestrating this modification cascade. Previous literature has established SIRT2’s involvement in neurodegeneration and metabolic regulation, but this particular study delves deeper into its nuanced role in modulating post-translational modifications relevant to aging neurons. By enhancing SIRT2’s de-crotonylase activity, atorvastatin appears to fine-tune the balance between protein modification states, enabling more effective proteasomal degradation of damaged or dysfunctional NFL molecules.
What makes these findings particularly compelling is the link between molecular modulation and actual cognitive improvements observed in the aging rats. Behavioral assays conducted over the duration of the study documented significant enhancements in memory, learning, and spatial navigation among atorvastatin-treated subjects compared to controls. This provides strong evidence that targeting the SIRT2-NFL modification axis does not merely represent an abstract biochemical phenomenon but translates into tangible neurocognitive benefits with potential clinical significance.
Further biochemical analyses revealed that untreated aging rats exhibited elevated levels of lysine 272 crotonylation on NFL alongside diminished ubiquitination, correlating with increased accumulation of misfolded NFL aggregates. These aggregates are hypothesized to disrupt axonal transport and synaptic function, underpinning various cognitive deficits. Atorvastatin treatment reversed this pattern, amplifying ubiquitination and promoting clearance of these neurotoxic protein forms, emphasizing the drug’s role in maintaining protein homeostasis through post-translational modification dynamics.
The study also addressed the broader implications of SIRT2’s role in cellular aging. Beyond its well-established functions in metabolic sensing and gene expression regulation, SIRT2’s involvement in modulating the proteostasis network represents an exciting frontier. The ability of atorvastatin to upregulate this pathway hints at potential cross-talk between lipid metabolism modulators and epigenetic-like enzyme activities, opening avenues for novel polypharmacological strategies to mitigate aging-related neurodegeneration.
This intersection between lipid-lowering therapies and epigenetic regulation of neuronal proteins represents a paradigm shift in understanding how systemic pharmacological interventions can impact brain aging. It positions atorvastatin as a candidate drug for repurposing in neurodegenerative therapeutics, especially considering its known safety profile and extensive clinical use. However, important questions remain regarding dosage optimization, the precise timing of intervention, and long-term consequences on neuronal function that subsequent studies will need to address.
Intriguingly, the research team also speculated on the possibility that modulating post-translational modifications on NFL might influence the interaction dynamics with other neurofilament subunits and associated cytoskeletal components. Such changes could have ripple effects on axonal transport efficiency and synaptic connectivity, hallmarks that degenerate in multiple neurodegenerative diseases including Alzheimer’s and Parkinson’s disorders. Thus, refining our understanding of these molecular switches might yield broader implications for neurobiology and aging research.
Moreover, the utilization of cutting-edge mass spectrometry techniques allowed for precise quantification and localization of lysine crotonylation and ubiquitination marks, providing an unprecedented molecular resolution. The rigorous temporal characterization of these modifications throughout the treatment timeline adds a dynamic dimension, underscoring that the post-translational landscape is fluid and tightly regulated during pharmacological intervention.
The significance of this study extends beyond the immediate context of atorvastatin and aging rats. It adds to a growing body of evidence affirming the importance of reversible acylations, such as crotonylation, in regulating protein function in health and disease. Unlike more traditional post-translational modifications, crotonylation is just beginning to be explored, and its dynamic crosstalk with ubiquitination suggests an intricate regulatory network poised to be a fertile ground for novel therapeutic approaches.
As the global population ages, the quest to preserve cognitive vitality takes on increasing urgency. With this study, the prospect of using a widely available drug to harness endogenous enzymatic machinery for proteome maintenance could represent a major stride forward. It also underscores the critical role of fundamental research in revealing unexpected drug actions and biological pathways that may translate into impactful clinical interventions.
While the results are promising, the authors are cautious in their interpretation and emphasize the necessity for subsequent validation in primate models and eventually human clinical trials. They advocate for integrative studies combining molecular biology, neuroimaging, and cognitive assessment to fully unravel the mechanistic underpinnings and therapeutic potential of targeting the SIRT2-crotonylation-ubiquitination axis.
In conclusion, this innovative study bridges pharmacology, epigenetics, and neurobiology to illuminate a previously unrecognized mechanism by which atorvastatin may confer neurocognitive benefits during aging. The discovery that SIRT2-mediated modulation of NFL lysine 272 crotonylation to ubiquitination enhances cognitive function opens new vistas in the development of therapeutic strategies aimed at ameliorating age-associated cognitive decline. As such, it invites a reassessment of the broader potential of statins beyond cardiovascular health and stimulates enthusiasm for further investigation into the complex regulatory networks governing neuronal longevity and plasticity.
Subject of Research: The study investigates the molecular mechanisms underlying the cognitive improvement induced by long-term atorvastatin treatment, focusing on the modulation of SIRT2-mediated dynamic transitions between lysine 272 crotonylation and ubiquitination on neurofilament light chain (NFL) in naturally aging rats.
Article Title: Long-term atorvastatin improves cognitive function by modulating SIRT2-mediated dynamic transition of NFL lysine 272 crotonylation to ubiquitination in naturally aging rats.
Article References:
Xu, TC., Cai, JR. & Chen, HS. Long-term atorvastatin improves cognitive function by modulating SIRT2-mediated dynamic transition of NFL lysine 272 crotonylation to ubiquitination in naturally aging rats. Cell Death Discov. 11, 463 (2025). https://doi.org/10.1038/s41420-025-02764-7
Image Credits: AI Generated
