HARVARD, DARWIN, OXYGEN AND ALZHEIMER’S DISEASE


March 26, 2015
From Harvard: Darwin, Mitochondria, and a completely different theory of Alzheimer’s Disease that has something to do with Oxygen


Although natural selection is often thought of as a force that determines the adaptation of replicating organisms to their environment, Harvard researchers have found that selection also occurs at the level of neurons, which are post-mitotic cells, and plays a critical role in the emergence of Alzheimer’s disease.

Using the principles of natural selection, Lloyd Demetrius, a researcher in population genetics at Harvard’s Museum of Comparative Zoology, and Jane Driver, an assistant professor of medicine at Harvard Medical School, have proposed a new model of Alzheimer’s that suggests mitochondria — cellular power plants — might be at the center of the disease. The study, which builds on earlier work by Demetrius and David Simon, an associate professor of neurology at HMS, was described in a recent paper in the Journal of the Royal Society Interface.

“We felt that, in order to explain the exponential increase in Alzheimer’s with age, we had to move away from the nuclear genome and look at what is going on with the energy-producing organelles,” Demetrius said. “That led us to a completely different model for the disease. We do not rule out the nuclear genes as playing a role … but, for the late-onset form of Alzheimer’s, we envision a mechanism based on the fact that mitochondrial DNA has a high mutation rate and that the organelles generate less energy with age.”

The prevalent model of Alzheimer’s is known as the amyloid cascade model. Proposed more than two decades ago, the amyloid hypothesis says that Alzheimer’s is primarily driven by the accumulation of beta amyloid in neurons. The accumulation is thought to be triggered by a mutation in the nuclear genome. A number of clinical trials have been conducted based on the model, but none have shown positive results. That prompted Demetrius and Driver to take a hard look at the fundamental underlying assumptions.

“A lot of people are realizing now that we have been focusing on the usual suspects — genetics and proteins ― and that’s brought us to a point where, despite billions of dollars in research, we are no closer to a disease-modifying therapy,” Driver said. “Of course, that’s not to suggest that genetics isn’t important, but I think what we haven’t done is to take the 20,000-foot view and ask if it is even logical to expect that changes to one protein could be responsible for an age-related disease. It just didn’t add up.”

“We felt that, in order to explain the exponential increase in Alzheimer’s with age, we had to move away from the nuclear genome and look at what is going on with the energy-producing organelles,” said Lloyd Demetrius, a researcher in population genetics at Harvard’s Museum of Comparative Zoology. Demetrius and Jane Driver, an assistant professor of medicine at Harvard Medical School, used the principles of natural selection in their research.

The genetic mutation model could explain early onset Alzheimer’s, but this form of the disease accounts for only about 5 percent of cases.


Are There Any Effective Drugs for Dementia or Alzheimer’s Diseasze from Majid Ali on Vimeo.

Below are suggestions that we have been publishing for years – including a spicy breakfast and spice enriched meals.


My Spice Omelettes for Memory Concerns and Alzheimer’s Disease – majidalimd.me from Majid Ali on Vimeo.


“The late-onset cases, however, are quite different,” Demetrius said. “They increase exponentially with age, and that is one of the most striking characteristics of the disease. As you age, the chances of getting it increase.”

In the model Demetrius and Driver describe, the disease’s first step is what they call “mitochondrial dysregulation.” The process is largely part of the natural course of aging.

As a person ages, the researchers say, the mitochondria in the cells generate energy less and less efficiently. Mitochondria, with their own DNA, are akin to the descendants of simple organisms that lived in a symbiotic relationship inside more complex ones. The mitochondria that produce cellular energy from nutrients such as glucose, in a process called oxidative phosphorylation, are incredibly efficient.

However, the process has the side effect of producing oxygen-free radicals, which can damage mitochondrial DNA and proteins. Random mutations can further damage mitochondrial structure and function. The accumulated harm leads to an energy deficit, triggering a compensatory event that Demetrius and Driver call “metabolic re-programming” — unaffected mitochondria increase output, by upregulating oxidative phosphorylation, to make up for the energy deficit.

The end result is two broad types of neurons ― relatively healthy, and impaired ― that must compete for nutrients. Impaired neurons, since they contain some mitochondria with upregulated activity, have an advantage in the competition. That competition, Demetrius said, plays out according to the principles of natural selection.

With normal aging, the two populations eventually reach equilibrium, typically with healthy neurons far outnumbering impaired neurons. As long as the balance is maintained, a person won’t slide into the grip of disease.

What can set a person on the path toward Alzheimer’s is the metabolic upheaval that accompanies both physical and emotional stress.

Ailments such as a stroke or a major depression disrupt the neuronal microenvironment and put additional stress on neurons. Some die, and others have to increase their energy production in order to survive. As a result, impaired neurons take up a larger share of the brain’s resources and begin to out-compete healthy neurons for nutrients.

“When that happens, you have a rapid shift toward Alzheimer’s — what I call pathological aging,” Demetrius said. “The two types of neurons are competing with each other, but the impaired neurons, in view of the particular environment of the aging brain, have a selective advantage.”

The healthy neurons die immediately because they are overwhelmed by the impaired neurons. The impaired neurons ultimately die because of the deleterious effects of the reactive oxygen species generated by their upregulated metabolic activity.

Warburg and Oxygen

Metabolic reprogramming, a cornerstone of the model, is called the Inverse Warburg Effect because it is analogous to the mode of metabolic alteration the Nobel laureate Otto Warburg proposed almost 100 years ago to explain the origin of late-onset forms of cancer. The metabolic shift in this case is the upregulation of glycolysis.

“The therapeutic implications are quite simple,” Demetrius said. “In order to prevent this shift from normal to pathological aging, all we need to do is ensure that the quasi-equilibrium between intact and impaired neurons remains stable, and we can do that through what we call metabolic interventions.”

The treatment involves interventions such as exercise, drugs, or nutrients that alter the neuronal microenviroment so that healthy neurons maintain their selective advantage and the brain doesn’t shift from normal to pathological aging. There is some evidence that increasing the availability of energy precursors such as lactate, ketones, and triglycerides may help neurons facing an energy crisis. Approaches that support the health and function of the astrocytes — the neuron’s metabolic support cells — could also act protectively.

“If you take good care of your blood pressure, if you exercise regularly and eat a lower-calorie diet ― all those things contribute to metabolic health,” Driver said. “The things we need to do to prevent Alzheimer’s, or at least make a dent in the incidence of the disease, are within our hands.”
Oxygen Model of Alzheimer’s Disease Validated

Medical models are proposed to reduce complexities in biology to workable simplicities and to predict clinical characteristics of diseases. In the context of genetics, The Oxygen Model of Alzheimer’s Disease predicts that the genes to be linked with the disease will be primarily involved with oxystatic, inflammatory, and detoxification pathways in the brain. This prediction was proven correct in April 2011 with the publications of two large studies in the journal, Nature Genetics. A gene analysis of more than 50,000 people in the United States and Europe doubled the number of genes—from five to ten— that increase the risk of Alzheimer’s disease. All ten are involved with inflammation and cholesterol metabolism. Cholesterol, of course is an antioxidant and, like other antioxidants in physiologic ranges in human biology, serves anti-inflammatory roles and favorably influences molecular traffic across cell membranes.

The Oxygen Models of Memory Disorders and Alzheimer’s Disease
Majid Ali MD
I put forth the oxygen models of memory disorders (dementia of various types and memory in the young) and Alzheimer’s disease to underscore the commonality of underlying energetic-molecular basis (add “and”???)a range of clinical, pathologic, and experimental observation concerning mental function. These unifying models meet the two essential characteristics of medical models mentioned above. In companion articles, I address problems of early and reversible memory loss in young people, memory loss associated with various forms of dementia, and AD to underscore the commonality of insults to brain cells and cellular dysfunction. Specifically, these models:

1.  Explains the scientific basis of memory lapses due to deranged oxygen signaling;
2.  Show how toxicities of foods, environments, and thoughts cause the loss of brain cells and plaques associated with clinical features of AD;
3. Reveal the mechanisms by which various direct and indirect oxygen therapies (including bowel and liver detox) work;
4. Compel clinicians to focus on all threats to oxygen homeostasis (balance) to restore the health of brain cells and mental functions;
5. Shed light on how all bodily functions improve when oxygen therapies are employed to improve the circulation and oxygen supply to the brain; and
6. Provide explanations of mechanisms by which time-honored natural remedies work to prevent or reduce the problems of memory and mentation.

Genetic Risks of Alzheimer’s

The main gene incriminated in AD is the gene for a protein called APO-E, which was discovered in 1995. It increases the risk for the disease by 400 percent if one copy is inherited from one parent and by 1,000 percent if from both parents. APO-E is involved with the metabolism of cholesterol. However, the genetic risk of a disease does not mean the presence of that disease. It is well established that genes respond to environmental changes (including the matters of foods and stress)—epigenomics, the field dealing with the phenomena is mushrooming—and we do not how many more genes carrying such risks will be discovered in the future.

In contrast, the newly discovered genes increase risk by about 10 to 15 percent. Researchers already believe it will not be reliable to use them to decide if a person is likely to develop Alzheimer’s. So, despite the front page story in The New York Times of April 4, 2011, the great jubilation about the recent discoveries do not signify much for people with AD.

While the new discoveries will undoubtedly open new venues for research in AD, they also underscore the importance of diligent and thoughtful examination of the issues of nutrition, environment, and stress that increase the risk of AD.


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