The human brain doesn’t “break” overnight. Over years—typically decades—neurons quietly struggle to keep up with the relentless housekeeping that keeps thought and memory intact: turning the right genes on and off, making the right proteins, and clearing out the ones that become toxic.
When that molecular upkeep slips, the consequences can be catastrophic, with Alzheimer’s standing as the most common and devastating example.
Now, scientists have identified what appears to be a powerful molecular “master regulator” that sits unusually high in that control hierarchy of brain aging. In a study published in Genomic Psychiatry, researchers from the University of New Mexico report that a single protein, OTULIN, exerts sweeping influence over how neurons regulate gene expression, RNA stability, and one of the most important proteins implicated in brain aging: tau.
By manipulating OTULIN in human neurons, researchers were able to dramatically alter tau levels and reshape large portions of the neuronal transcriptome.
The findings suggest that targeting this master regulator could, in principle, help reset some of the molecular programs that drive brain aging and neurodegeneration, rather than merely treating their downstream consequences.
“Pathological tau is the main player for both brain aging and neurodegenerative disease,” lead author and professor at the UNM School of Medicine, Dr. Karthikeyan Tangavelou, explained in a press release. “If you stop tau synthesis by targeting OTULIN in neurons, you can restore a healthy brain and prevent brain aging.”
Tau has long been recognized as a central player in Alzheimer’s disease and related dementias. Under healthy conditions, tau helps stabilize the internal framework of neurons. However, with age and disease, tau becomes abnormally modified and begins to aggregate, forming the neurofibrillary tangles that are a pathological hallmark of Alzheimer’s brains.
Efforts to slow or reverse brain aging have often focused on clearing these tangles or preventing tau from clumping in the first place, with limited clinical success.
This new study takes a different approach. Instead of asking how to remove pathological tau once it appears, the researchers asked what controls tau expression and stability inside neurons over time?
The answer, they found, may lie with OTULIN, a protein previously known for its role in regulating ubiquitination—a system cells use to tag proteins for recycling or to trigger stress and immune responses.
OTULIN removes a specific class of molecular tags called linear, or M1-linked, ubiquitin chains. Until now, its function in neurons, particularly in the context of brain aging and neurodegeneration, has been poorly understood.
Researchers used human induced pluripotent stem cell–derived neurons generated from an individual with late-onset sporadic Alzheimer’s disease. These lab-grown neurons naturally accumulate abnormal tau, making them a powerful model for studying disease-relevant processes.
When the team compared these cells to neurons derived from healthy controls, they uncovered a striking pattern. Alzheimer’s neurons contained significantly higher levels of OTULIN protein, along with elevated levels of phosphorylated tau—the toxic form most closely linked to cognitive decline.
That association suggested that OTULIN might not simply be a bystander in aging neurons, but an active contributor to tau pathology.
The researchers then tested whether altering OTULIN could change tau levels. Using a small molecule inhibitor to partially block OTULIN’s enzymatic activity, they observed reductions in key phosphorylated forms of tau in Alzheimer’s-derived neurons.
While the effect was moderate, it suggested that dialing back OTULIN activity could push neurons toward a healthier molecular state.
The most revealing results came from gene-editing experiments. When researchers used CRISPR-Cas9 to delete the OTULIN gene, tau levels rapidly decreased. In some neuronal models, both total tau and pathological tau nearly vanished.
Significantly, this was not because the protein was being degraded more efficiently. Instead, the genetic instructions for tau production—the messenger RNA encoded by the MAPT gene—were effectively erased.
This discovery forces a major reinterpretation of OTULIN’s role. Rather than acting only as a regulator of protein cleanup, OTULIN appeared to govern gene expression itself. Large-scale RNA sequencing further confirmed this hypothesis.
Removing OTULIN triggered widespread disruption of RNA metabolism across the neuron, altering the expression of tens of thousands of transcripts. Genes involved in RNA stability, degradation, and transcriptional control were profoundly affected.
Tau was just one of many genes caught up in this global shift, but its disappearance underscored how deeply OTULIN is embedded in the neuron’s regulatory machinery.
“Together, our results suggest, for the first time, a noncanonical role for OTULIN in regulating the gene expression and RNAmetabolism, which may have a significant pathogenic role in exacerbating tau aggregation in neurons,” the researchers write. “Thus, OTULIN could be a novel potential therapeutic target for AD [Alzheimer’s disease] and ADRD [Alzheimer’s disease-related dementias].
When it comes to brain aging, this is enormous. Aging is increasingly understood not as the failure of a single protein or pathway, but as a gradual loss of coordination across gene networks. RNA metabolism, in particular, has emerged as a critical vulnerability in aging neurons.
If OTULIN functions as a master regulator of these processes, then modifying its activity could, in theory, help restore a more youthful balance of gene expression.
Researchers also highlight why brain aging is so difficult to treat. OTULIN does not regulate tau in isolation. Its influence extends to inflammatory signaling, protein quality control, autophagy, and transcriptional repression. Completely eliminating OTULIN caused massive transcriptomic changes, some of which may represent protective responses that prevent runaway inflammation or cellular stress.
That complexity means OTULIN is not a simple on-off switch. While partial inhibition reduced pathological tau, total loss of the protein produced sweeping effects that could be harmful if replicated in the human brain.
The researchers caution that any therapeutic strategy targeting OTULIN would need to be carefully tuned, aiming to modulate its activity rather than shut it down entirely.
Nevertheless, the conceptual advance is significant. By identifying a single molecule that can reshape tau biology and global RNA regulation, the findings reframe how scientists think about reversing brain aging.
Instead of chasing individual pathological proteins, future therapies might aim to recalibrate higher-level regulatory systems that govern neuronal identity and resilience over time.
The significance of that shift extends well beyond Alzheimer’s disease. As previously reported by The Debrief, researchers have already documented signs of accelerated brain aging in entirely different contexts, including a study showing that COVID-19 lockdowns were associated with premature structural brain aging in adolescents.
These findings underscore the scientific consensus that brain aging is not just a slow, inevitable march tied to late life, but a dynamic process that can be sped up—or potentially slowed down—by disruptions to underlying regulatory systems.
Discoveries that clarify how neurons maintain, lose, or restore those regulatory controls offer insight into how environmental stressors, disease, and molecular misfires converge on the same aging pathways in the brain.
Ultimately, OTULIN represents something more than another Alzheimer’s target. It may be a gateway into understanding how neurons lose—and potentially regain—control over their own genetic programs as the brain ages.
“We are developing a project to study the role of OTULIN in brain aging,” Dr. Tangavelou added. “This is a great opportunity to develop many projects for further research to reverse brain aging and have a healthy brain.”
Tim McMillan is a retired law enforcement executive, investigative reporter and co-founder of The Debrief. His writing typically focuses on defense, national security, the Intelligence Community and topics related to psychology. You can follow Tim on Twitter: @LtTimMcMillan. Tim can be reached by email: tim@thedebrief.org or through encrypted email: LtTimMcMillan@protonmail.com