- A recent study using a mouse model of vascular cognitive impairment found that repetitive exposure to low levels of oxygen prevented memory loss.
- Under controlled conditions, oxygen deprivation can slow neurological degeneration and decline and promote increased cerebral blood flow.
- These seemingly paradoxical findings suggest that changing behaviors and environments may influence future therapies in treating Alzheimer’s disease and other neurocognitive diseases.
Vascular dementia is the second leading cause of dementia following Alzheimer’s. It occurs due to the interruption of blood and oxygen supply to the brain, which damages the blood vessels.
Low oxygen levels elsewhere in the body can also disrupt other critical organs and their functions. For instance, reduced blood supply to the heart can lead to cardiovascular disease and heart attacks.
Because low oxygen levels in the body can cause life threatening conditions, it seems paradoxical to deprive a tissue or organ of oxygen to confer benefits. However, a group of researchers is examining some potential benefits of exposure to low oxygen levels, also known as hypoxia.
The scientists recently carried out a study to address two hypotheses:
The results of the study appear in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Epigenetics explored
Although the genetic code we are born with remains constant throughout our lives, the way in which this code can be read, or translated, can change. This is called epigenetics. Our environment and behaviors can influence not what the DNA code “says,” but whether or not a gene is turned “on” or “off.”
For instance, methylation is one form of epigenetic change. Certain behaviors may cause sections of DNA to become methylated, meaning a methyl group is added to the DNA.
Once a gene is methylated, it is less likely to be expressed. So, although the gene is still present and functional, it is effectively switched off or dialed down.
Importantly, these epigenetic changes can pass from generation to generation without altering the genetic code.
In the current study, scientists put the experimental animals through repetitive hypoxic conditioning (RHC). The animals in the RHC condition experienced low levels of oxygen — similar to being at a high altitude — for 1 hour every other day over a 2-month period.
After this conditioning, the researchers subjected the mice to chronic cerebral hypoperfusion, which induces vascular dementia.
They assessed changes in memory and other brain functions 3 and 4 months later, respectively.
The research revealed that induced memory and brain function deficits caused by chronic cerebral hypoperfusion were reversed in the animals that had experienced RHC.
Similarly, the offspring of RHC-treated parents also showed strong resilience to dementia without experiencing RHC.
The authors write: “[N]either mice treated directly with 2 months of RHC or their adult offspring showed changes in white matter myelin density, neurocognitive function, or synaptic plasticity.”
How might this work?
Although there have been limited studies investigating the potential benefits of hypoxia on health, the authors outline some theories as to why it might work.
One such theory is that hypoxia induces angiogenesis, which is the development of new blood vessels. This, the authors explain, could enhance cerebral blood flow.
They also explain that “[r]esilience may also be afforded by direct pro-survival adaptations that RHC induces in cells of the neurovascular unit, rendering them more resistant to the pathological consequences of [vascular dementia].”
The paradoxical effect
Older studies have focused on an experimental procedure called remote limb ischemic conditioning (RLIC). In RLIC, brief, reversible periods of oxygen deprivation are followed by reperfusion of the area or resupplying it with oxygen. This gradual process renders the target tissues and organs resistant to damage from ischemia.
Medical News Today spoke with the study’s corresponding author, Jeff M. Gidday, Ph.D., a professor of ophthalmology, biochemistry, neuroscience, physiology, and molecular biology at the Louisiana State University Health Sciences Center in New Orleans.
“Dr. David Hess’s lab at Augusta University in Georgia had already shown that a different epigenetic stimulus — [RLIC] — protected against memory loss in the same animal model of vascular dementia,” he explained.
“RLIC is believed to be a nonharmful approach to inducing beneficial epigenetic responses in humans that may mimic what we triggered using intermittent hypoxia in mice or vice versa. The ideal ‘dose’ of RLIC may still require elucidation, based on an individual’s sex, age, and other comorbidities, but in principle, it is an ‘adaptive epigenetics’ therapeutic approach that many feel still holds great clinical promise.”
“Such [intragenerational] (single generation) or transgenerational (multiple generations) epigenetic effects are not new, but 99% of studies in these disciplines […] focus on how repetitive adverse stress causes or contributes to the cause of disease in future generations,” Dr. Gidday continued.
According to the authors of the new study, the vast majority of research into epigenetics so far has focused on “negative” outcomes. In other words, they have tried to identify epigenetic changes that produce negative consequences in offspring. The authors write:
“[O]ur findings are the first to document the inheritance of an epigenetically induced phenotype that is protective against disease.”
“We believe the germ cell modifications (again, plasticity) is really a 50-50 scenario, meaning both adverse and beneficial outcomes may result depending on the nature of the epigenetic stimulus — we simply showed that was indeed possible,” Dr. Gidday told MNT.
Limitations of the study
Speaking about the study’s limitations, Dr. Gidday said: “As for our intergenerational findings, those are not suitable for clinical testing per se, which would take decades, but they do suggest that all manner of healthy living behaviors prior to conception may promote disease resilience in our children and grandchildren that we may not even be aware of. Of course, the converse is also true.”
“While our treatment was efficacious,” he continued, “we did not use old mice, or mice with common comorbidities like hypertension, that would reflect better the human population that develops dementia.”
“It would also be wise for other labs to repeat our studies with an expanded testing battery to get a better handle on the different types of memory — and learning, and other cognitive functions — that our treatment may abrogate in the setting of vascular dementia and in other preclinical models of dementia, including, most obviously, Alzheimer’s.”
Takeaway
MNT also spoke with Dr. Davey Smith, M.S., FACP, vice chairman of the Department of Medicine at the University of California San Diego in La Jolla. He concluded:
“I think this is a fascinating study further showing that epigenetic changes can be inherited and influence health. In this mouse model, the investigators show the link between epigenetic changes and resilience to dementia. These new data may open the way for new therapies aimed at epigenetics for treating dementia. Of course, mice are not people, so human studies will be needed.”
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