60-Year-Old Transformed to Youth-Like State… What Happened After a Nasal Spray Was Given to Aged Mice

Texas A&M University Develops Intranasal Treatment for Dementia
Spray-Based Therapy Shows Effects After Just Two Doses
Reduces Oxidative Stress and Restores Mitochondrial Function

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[Generative AI]

As aging progresses, chronic low-grade inflammation gradually accumulates deep within the brain. This phenomenon, known as “neuroinflammaging,” can impair memory and increase the risk of dementia. Long considered an unavoidable part of the natural aging process, new research suggests that it may be possible to reverse these changes using a nasal spray-based therapy.

A research team led by Prof. Ashok Shetty of the Texas A&M University School of Medicine has developed a cell-derived intranasal treatment designed to suppress inflammation in the aging brain at the molecular level and restore brain-cell function. The findings were published in the international journal Journal of Extracellular Vesicles.

The researchers conducted experiments in 18-month-old aged mice, roughly corresponding to about 60 years of age in humans. The experimental group received the treatment intranasally twice at two-week intervals. The researchers then monitored changes in hippocampal brain cells and recovery of cognitive function over several months.

The key therapeutic component consisted of extracellular vesicles (EVs) derived from neural stem cells generated from human induced pluripotent stem cells (hiPSC-NSCs). These vesicles carry potent molecular cargo, including microRNAs (miRNAs) that regulate gene activity in the brain.

When administered through the nose, the nanoscale vesicles can bypass the blood-brain barrier and, within approximately six hours, reach and be taken up by neural networks and immune cells in the hippocampus, a brain region critical for memory.

Once in the brain, the extracellular vesicles act on microglia, the brain’s primary immune cells. In younger brains, microglia help protect neural tissue, but with aging they can become chronically activated and release excessive inflammatory molecules that may damage otherwise healthy neurons.

Using single-cell RNA sequencing (scRNA-seq) to analyze the brains of treated mice, the researchers found that the therapy substantially suppressed the expression of multiple chronic inflammatory genes in microglia, including pathways associated with Toll-like receptors (TLRs) and tumor necrosis factor (TNF).

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[Unspalsh/Nikolett Emmert]

In particular, the treatment blocked two major signaling pathways strongly associated with age-related neuroinflammation: the NLRP3 inflammasome and cGAS–STING pathways.

According to the study, miR-30e-3p, a microRNA carried by the extracellular vesicles, suppressed the activity of NLRP3, an inflammation-associated protein complex, thereby helping prevent inflammatory damage to brain cells. At the same time, miR-181a-5p inhibited the STING pathway, reducing chronic interferon release triggered by cellular damage.

As inflammation subsided, the overall environment of the brain cells also improved. In hippocampal tissue, levels of oxidative stress markers associated with lipid peroxidation and protein oxidation—malondialdehyde (MDA) and protein carbonyls—fell sharply, while levels of the antioxidant enzyme superoxide dismutase (SOD) increased significantly. Expression of genes involved in the mitochondrial respiratory chain, Complexes I through V, also returned toward normal levels.

These molecular changes were reflected in the animals’ behavior. In cognitive assessments conducted one month after treatment, aged mice that received the therapy performed strongly in the Novel Object Recognition Test (NORT), which measures the ability to distinguish a new object, and the Object Location Test (OLT), which evaluates recognition of changes in an object’s location.

Unlike placebo-treated aged mice, which showed significant cognitive impairment, the treated animals responded to unfamiliar environments in a manner comparable to younger mice. The therapeutic effects were observed in both male and female animals, with no significant difference based on biological sex.

Prof. Shetty emphasized that “instead of risky and invasive brain surgery or medications that must be taken continuously for months, a simple two-dose nasal spray could potentially become a new approach to treating neurodegenerative brain disorders.”

He added, “The ultimate goal is not simply to extend lifespan, but to help people remain mentally clear and socially engaged as they age.”

The research team has recently filed a U.S. patent application covering the nasal spray-based therapeutic technology.