Could a nasal spray reverse brain aging?
Can brain aging be reversed? A recent article in Inc. mentions that this could be a reality, as researchers have created a therapy
that can target the inflammation that causes brain aging using nasal spray.
From a sensory research perspective, this offers an insight on how the olfactory system that controls the sense of smell can tie into cognitive health. For David Vumbaco, Ph.D., director of research at the North Texas Eye Research Institute, the results from this research offers insight into how sensory therapies might help lessen the impacts of cognitive impairment. This is also an area of interest for the Sensory Research Institute at UNT Health, as we continue to grow.
Dr. Vumbaco is working on several research opportunities investigating the link between eye and brain, specifically related to cognitive impairment. We asked Vumbaco to share more about his thoughts on this research and the importance of sensory and cognitive health.
How significant is this study from a sensory neuroscience perspective, and what does it suggest about the deeper relationship between the olfactory system and cognitive function?
It is true that the olfactory nerves offer transport to the brain not directly mediated by the blood, but the spray is also absorbed by the myriad capillary beds of the nose and still subject to the blood-brain barrier in that way. It is an advantageous route for drug delivery. If you can make something lipid soluble and small enough to be transported via the nerves, it is a solid advantage to having to go through full circulation and then find a way past the BBB. It has been known for a while that this route is a good one for targeted drug delivery, intranasal approaches to the brain were researched since the 50’s, the first clinical manifestation was in the 90’s. The route is gaining interest because of some of the advantages offered for small molecule drug delivery that I mentioned previously.
The olfactory-brain connection is one of the strongest and oldest we have. It is the sense of the fewest number of synapses away from the brain, with only one. Even more interesting to me from a life history and evolutionary biology perspective on the senses is that the eyes and olfactory system use a convergent piece of nerve cell biology. In a phrase, your eyes are organs evolved to smell light, substituting a bound rhodopsin molecule for previous odorants and light transduction for chemo-transduction. There is a deep relationship between olfaction and cognition, and it is true to say that smell can drive strong memory formation and retention. It is one of our oldest senses and deeply aligned to danger and comfort; being only a couple synapses away from the amygdala, which is in turn one of our oldest and most primitive brain structures, where a lot of these fight or flight decisions are made. Neuroscientists often say that babies are only born with two fears, loud noises and heights; I would anecdotally extend that claim to bad/dangerous smells.
Is it plausible that the same neuroinflammatory mechanisms driving cognitive decline are also behind sensory deterioration, and could a therapy like this one have broader sensory applications?
This is one of those ‘chicken or the egg’ questions, but the implication here is that decline happens independently across multiple systems and just follows a similar trajectory. The reality, unfortunately, is that decline happens to the whole brain with some of the most complex pieces of our biology taking a front row seat, the senses. Further, when there is dramatic sensory impairment, that cognitive decline accelerates. Recent studies have implicated sensory loss, i.e. presbycusis, presbyopia, to a much faster trajectory in declining cognitive functions and progression toward dementia and other related illnesses.
Neuroinflammation likely plays a role, but it’s currently impossible to narrow down all these changes to one etiology. It, like nearly all other neural diseases, will have many contributing factors. The good news is that sensory and engagement-based therapies will lessen the impact of cognitive impairment to a measurable degree. The Nun study from the NIA started back in the 1990’s comes to mind here in that engagement, sensory and otherwise, is strikingly preventative for the behavioral manifestations of cognitive decline.
Treated subjects showed marked improvement in detecting new objects and environmental changes — tasks that are fundamentally sensory-perceptual in nature. What does that tell us about where in the brain this therapy is acting, and could sensory perception metrics serve as reliable early indicators of treatment success in future human trials?
Perception and memory are inextricably linked. Everything you perceive is translated into lingering brain states and later into long-term storage. The argument for “where” novel object recognition is taking place is a hard one to make. It is likely several places in the brain with shared brain states involving memory and perceptual circuits i.e. perceptual loops for the all the involved senses, the prefrontal cortex to orchestrate the behavior, and the hippocampal circuits to store and organize the information. As a reminder, memory is a distributed process. “Sensory perception metrics” isn’t really that clear to me, and the controls would have to be fantastic for me to agree with new metrics based on perception. Behavioral tests are great indicators for success in human trials and have been for years.
The study positions microRNAs as master regulators of gene and signaling pathways in the brain. Are there known microRNA pathways that govern sensory cortex function specifically? Could this intranasal delivery mechanism eventually be adapted to target sensory-processing regions with precision?
MicroRNAs (miRNA) are spectacular tools for us to leverage. I’d argue that they are the most readily available way to manipulate gene and signaling pathways, not necessarily that they’re the master regulators themselves; the title belongs to methylation. miRNA are the messengers that carry out the instructions of the genes, the step before proteins and signaling and packaged in a more convenient way than traditional messenger RNA (mRNA). If mRNA codes for life, miRNA controls how the code is used. mRNA the simplified instructions from the blueprint, miRNA the actual on-off switch for production. Another way to look at this is that mRNA are the coding RNA (for proteins) where miRNA are the non-coding regulators of that transcription.
Sensory processing regions don’t have much to differentiate them selectively, a lot of the primary and secondary sensory cortices are made up of similar neurons doing similar things in a similar structure, just informed more by the incoming sensory neurons driving them. There would have to be some dramatic discoveries about selectivity to allow targeting of audition vs olfaction or similar. This work is ongoing, and there are some interesting developments around network selectivity, but I’ve yet to encounter a selective approach in the brain itself related to only one sensory modality. The discovery wouldn’t necessarily follow the intranasal approach, but from drug delivery and genetic targeting strategies. Arguably those new drugs could be given systemically and still be selective.