Summary: For decades, “neuroinflammaging”, the slow-burning inflammation that causes brain fog and memory decline, was considered an unavoidable part of getting older. However, a landmark study suggests the clock can be turned back.
Researchers developed a non-invasive nasal spray that uses microscopic “delivery parcels” to travel directly into the brain. With just two doses, the therapy dramatically reduced chronic inflammation, recharged cellular “power plants” (mitochondria), and restored memory and cognitive sharpness in aging models.
Key Facts
- Rapid & Lasting Results: Significant cognitive improvements were observed within weeks and, remarkably, persisted for months after only two doses.
- Universal Efficacy: Unlike many medical studies that show varying results by sex, this therapy proved equally effective in both males and females.
- Behavioral Recovery: Treated models showed a restored ability to recognize familiar objects and adapt to changes in their environment—key indicators of a healthy, functioning memory center.
- Future Applications: Beyond aging, researchers believe this approach could be adapted to help stroke survivors rebuild lost function or slow the progression of Alzheimer’s disease.
- Patent Pending: Texas A&M has already filed a U.S. patent for the therapy, signaling a major move toward real-world clinical application.
Source: Texas A&M
Picture this: your brain is a high-performance engine. Over decades, it doesn’t just wear down, it also starts to run hot.
Tiny “fires” of inflammation smolder deep within the brain’s memory center, creating a persistent brain fog that makes it harder to think, form new memories or even adapt to new environments, all the while increasing the risk to disorders like Alzheimer’s disease.
Scientists call this slow burn “neuroinflammaging,” and for decades it was thought to be the inevitable price of growing older.
Until now.
A landmark study from researchers at the Texas A&M University Naresh K. Vashisht College of Medicine suggests the inflammatory tide responsible for brain aging and brain fog might actually be reversible. And the solution doesn’t involve brain surgery, but a simple nasal spray.
Led by Dr. Ashok Shetty, university distinguished professor and associate director of the Institute for Regenerative Medicine, along with senior research scientists Dr. Madhu Leelavathi Narayana and Dr. Maheedhar Kodali, the team developed a nasal spray that, with just two doses, dramatically reduced brain inflammation, restored the brain’s cellular power plants and significantly improved memory.
The most surprising part? It all happened within weeks and lasted for months.
The findings, published in the Journal of Extracellular Vesicles, could reshape the future of neurodegenerative therapies and may even change how scientists think about brain aging itself.
“Brain age-related diseases like dementia are a major health concern worldwide,” Shetty said. “What we’re showing is brain aging can be reversed, to help people stay mentally sharp, socially engaged and free from age-related decline.”
Brain fog to brain focus, the future of cognitive therapy
The implications of this research could be nothing short of revolutionary.
“As we develop and scale this therapy, a simple, two-dose nasal spray could one day replace invasive, risky procedures or maybe even months of medication,” Shetty said.
The societal impact could be just as profound. In the United States alone, new dementia cases are projected to double over the next four decades, from about 514,000 in 2020 to about 1 million in 2060.
“The trend signals a pressing need for policies and innovative interventions that can minimize both the risk and severity of neurodegenerative disorders like dementia,” Shetty said.
The study also hints at broad applicability, working equally effectively across both genders — a rare outcome in biomedical research.
“It’s universal,” Shetty said. “Treatment outcomes were consistent and similar across both sexes.”
One day, the approach could even help stroke survivors rebuild lost brain function, or slow — even reverse — the effects of cognitive aging in humans.
“Our approach redefines what it means to grow old,” Shetty said. “We’re aiming for successful brain aging: keeping people engaged, alert and connected. Not just living longer, but living smarter and healthier,” Shetty said.
Rewiring the brain from the inside out
At the heart of this groundbreaking development are millions of microscopic biological parcels known as extracellular vesicles (EVs). They act like delivery vehicles, carrying powerful genetic cargo called microRNAs.
“MicroRNAs act like master regulators,” Narayana said. “They help modulate and regulate many gene and signaling pathways in the brain.”
But the delivery route is just as important as the cargo.
Packed into a nasal spray, the tiny EVs bypass the brain’s protective shield and travel directly into brain tissue, where they are absorbed.
“The mode of delivery is one of the most exciting aspects of our approach,” Kodali said. “Intranasal delivery allows us to reach, and treat, the brain directly without invasive procedures.”
Once absorbed into the brain’s resident immune cells, the microRNAs suppress systems, like NLRP3 inflammasome and the cGAS–STING signaling pathways, known to drive chronic inflammation in aging brains.
At a cellular level, the treatment recharged neuronal mitochondria, or the power plants that live inside the brain’s cells.
By recharging these cellular power plants, the therapy didn’t just clear brain fog, it physically improved the brain’s ability to process and store information.
“We are giving neurons their spark back by reducing oxidative stress and reactivating the brain’s mitochondria,” Narayana said.
Behavioral tests confirmed the biology. Models treated with the nasal spray showed remarkable improvements in not only recognizing familiar objects but also detecting new objects and changes in their environment, a sharp contrast to the control.
“We are seeing the brain’s own repair systems switch on, healing inflammation and restoring itself,” Shetty said.
While further research is needed, Shetty and his team have already filed a U.S. patent for the therapy, marking a milestone in what could become a breakthrough for brain aging treatments.
Behind the breakthrough
Breakthroughs like the one led by Shetty highlight Texas A&M as a research powerhouse, where national and global research priorities help shape the next generation of innovative solutions.
“We aren’t just trying to understand the biological mechanisms, we are translating and developing our findings into real-world therapies that could make a difference,” Shetty said.
Backed by the National Institute on Aging (NIA), the Texas A&M team pooled collaborative knowledge, expertise and resources to turn a simple nasal spray into a therapy with the potential to reframe how scientists think about brain aging.
“Our partnership with the NIA is very important,” Shetty said. “This kind of work requires resources and the right people to tackle problems and develop solutions that could change lives.”
Ultimately, while the brain’s engine may sputter with age, scientists are now learning how to reignite it, sparking a new era of cognitive health and showing that the clock on brain aging might not just be paused, it can be turned back.
Key Questions Answered:
A: Most drugs are blocked by the “blood-brain barrier.” This spray uses extracellular vesicles—tiny, natural bubbles that the brain recognizes. Because they are delivered through the nose, they travel along the olfactory nerves directly into the brain’s memory center, bypassing the barrier entirely.
A: No, it actually improved performance. In behavioral tests, older models treated with the spray began to recognize and react to their environment with the sharpness of younger models. It’s a “reset” for the brain’s resident immune cells, turning off the “fire” of inflammation so neurons can work properly again.
A: While the results are revolutionary, it is currently in the research and patent stage. However, because it is non-invasive and works across both sexes, the path to clinical trials is highly anticipated. The researchers’ goal is “successful aging”—keeping people mentally sharp and connected for as long as they live.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain aging research news
Author: Zaid Elayyan
Source: Texas A&M
Contact: Zaid Elayyan – Texas A&M
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING Signalling, in Aged Hippocampus” by Leelavathi N. Madhu, Maheedhar Kodali, Shama Rao, Sahithi Attaluri, Raghavendra Upadhya, Goutham Shankar, Bing Shuai, Yogish Somayaji, Shruthi V. Ganesh, Vignesh S. Kumar, Jeswin E. James, Padmashri A. Shetty, Avery LeMaire, Xiaolan Rao, James J Cai, Ashok K. Shetty. Journal of Extracellular Vesicles
DOI:10.1002/jev2.70232
Abstract
Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING Signalling, in Aged Hippocampus
Neuroinflammaging, a moderate, chronic, and sterile inflammation in the hippocampus, contributes to age-related cognitive decline.
Neuroinflammaging comprises the activation of the nucleotide-binding domain, leucine-rich repeat family, and pyrin domain-containing 3 (NLRP3) inflammasomes, and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway that triggers type 1 interferon (IFN-1) signalling. Studies have shown that extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) contain therapeutic miRNAs that can alleviate neuroinflammation.
Therefore, this study examined the effects of late middle-aged (18-month-old) male and female C57BL6/J mice receiving two intranasal doses of hiPSC-NSC-EVs on neuroinflammaging in the hippocampus at 20.5 months of age.
Compared with animals receiving vehicle treatment, the hippocampus of animals receiving hiPSC-NSC-EVs exhibited reductions in astrocyte hypertrophy, microglial clusters, and oxidative stress, along with elevated expression of antioxidant proteins and genes that maintain mitochondrial respiratory chain integrity.
Moreover, hiPSC-NSC-EVs therapy decreased the levels of various proteins involved in the activation of the NLRP3 inflammasome, p38/mitogen-activated protein kinase, cGAS-STING-IFN-1, and Janus kinase and signal transducer and activator of transcription signalling pathways.
Furthermore, in vitro assays using genetically engineered RAW cells and hiPSC-NSC-EVs, with or without targeted depletion of specific miRNAs, demonstrated that miRNA-30e-3p and miRNA-181a-5p, both present in hiPSC-NSC-EVs, can significantly inhibit the activation of the NLRP3 inflammasome and the STING pathway, respectively.
Additionally, single-cell RNA sequencing conducted 7 days post-treatment revealed that hiPSC-NSC-EVs induce widespread transcriptomic changes in microglia, including increased expression of numerous genes that enhance oxidative phosphorylation and reduced expression of abundant genes that drive multiple proinflammatory signalling pathways.
These changes mediated by hiPSC-NSC-EVs were also associated with improved cognitive and memory function.
Thus, intranasal hiPSC-NSC-EVs therapy in late middle age can effectively diminish proinflammatory microglial transcriptome and signalling cascades that drive neuroinflammaging in the hippocampus, contributing to better brain function in old age.
