Interestingly, the results of this study suggest that mild hunger pangs, and related hormonal pathways, may be as important to the much-discussed value of "caloric restriction" as actually eating less.
Caloric restriction is a regimen where an individual consumes fewer calories than average, but not so few that they become malnourished. Studies in many species have suggested that it could protect against neurodegenerative disorders and extend lifespans, but the effect has not been confirmed in human randomised clinical trials.
But researchers behind the new study argued that hormonal signals are the middlemen between an empty gut and the perception of hunger in the brain, and that manipulating them may effectively counter age-related cognitive decline in the same way as caloric restriction.
"This is the first paper, as far as we are aware, to show that the sensation of hunger can reduce Alzheimer's disease pathology in a mouse model of the disease," said Inga Kadish, Ph.D., assistant professor in the Department of Cell, Developmental and Integrative Biology (CDIB) within the School of Medicine at the University of Alabama at Birmingham.
"If the mechanisms are confirmed, hormonal hunger signaling may represent a new way to combat Alzheimer's disease, either by itself or combined with caloric restriction," Kadish noted.
The team theorizes that feeling hungry creates mild stress. That, in turn, fires up metabolic signaling pathways that counter plaque deposits known to destroy nerve cells in Alzheimer's patients. The idea is an example of hormesis theory, where damaging stressors like starvation are thought to be good for you when experienced to a lesser degree.
To study the sensation of hunger, the research team analysed the effects of the hormone ghrelin, which is known to make us feel hungry. They used a synthetic form of ghrelin in pill form, which let them control dosage such that the ghrelin-treated mice felt steadily, mildly hungry.
The study looked at whether or not the feeling of hunger, in the absence of caloric restriction, could counter Alzheimer's pathology in mice genetically engineered to have three genetic mutations known to cause the disease in humans.
Study mice were divided into three groups: one that received the 'synthetic ghrelin' (ghrelin agonist), a second that underwent caloric restriction (20 percent less food) and a third group that was fed normally. Study measures looked at each group's ability to remember, their degree of Alzheimer's pathology and their level of related, potentially harmful immune cell activation.
The first formal result of the study are that, in mice with the human Alzheimer's mutations, both the group treated with the ghrelin agonist LY444711 and the group that underwent caloric restriction performed significantly better in the a water maze than did than mice fed normally (p=0.023).
The second result was a measure of the buildup of a cholesterol-related protein called amyloid beta in the forebrain, an early step in the destruction of nerve cells that accompanies Alzheimer's disease. The formal amyloid beta results show that mice either treated with the ghrelin agonist or calorically restricted had significantly less buildup of amyloid beta in the dentate gyrus, the part of the brain that controls memory function, than mice fed normally.
Finally, the team examined the difference in immune responses related to Alzheimer's pathology in each of the three groups. Microglia are the immune cells of the brain, engulfing and removing invading pathogens and dead tissue. They have also been implicated in several diseases when their misplaced activation damages tissues.
The team found that mice receiving the ghrelin agonist treatment had both reduced levels of microglial activation compared to the control group, similar to the effect of caloric restriction.
The ghrelin agonist used in the study does not lend itself to clinical use and will not play a role in the future prevention of Alzheimer's disease, said Kadish.
It was meant instead to prove a principle that hormonal hunger signaling itself can counter Alzheimer's pathology in a mammal. The next step is to understand exactly how it achieved this as a prerequisite to future treatment design.
The study has been published in the journal PLOS ONE.