He talks about what happens during aging in the brain.
More and more as people get older, neurons age and die, predisposing us to Alzheimer's and other brain diseases. The mechanisms on how this happens are being shown and he discusses the different pathways.
Dietary energy restriction, exercise, cognitive enrichment promote neuroprotection (hormesis?) by reducing oxidative stress and inflammation.
Current trends in Alzheimer's showing it's a huge issue that's not being dealt with. We need a war on it like we have on cancer. Many people die from Alzheimer's and it's a tax on society.
He discusses amyloid plaques and neurofibrillary tangles (with tau) that is involved in AD pathogenesis.
There's a number of animal models for AD such as transgenic mice with overexpression of mutated amyloid-precursor protein. Also, PS1 mice.
Mattson manipulates diets of AD-prone mice to see how diet affects their cognitive function, memory, and amelioration of AD behavior.
Intermittent fasting and calorie restriction ameliorated AD behavior changes. He thinks that neurons can be stimulated by these diets to protect themselves against the amyloid protein. He shows us data on how CR reduced tau levels, but IF did not.
They also used "couch potato mice" model of AD: overfed, sedentary. Of course, these are great controls.
CR and IF showed gene expression in the brain (Martin et al, 2007, Endocrinology).
They wanted to show an effect in primates, so performed a study in rhesus monkeys. They took the monkeys and reduced their calories by 30 percent for 11 months. They tested their motor function, dopamine. They injected a toxin called MPTP.
Both the animals on the normal diet and CR diet had deficits in motor function, but CR had less seeming to have a protective effect from a functional endpoint. When measured for dopamine, there was major depletion in the striatum in both. When measured for BDNF, the CR had higher levels of BDNF.
In a stroke model, they took young, middle-aged, or old mice on either IF or normal diets. They then damaged the cerebral cortex and measured neurological deficit. There was significant benefit for the young and middle-aged mice on IF, but not in old.
"So start early," he says. Exercise, eat less when you're younger to prevent Alzheimer's in the future. IF reduced inflammation in the young and middle-aged, but not in old.
Mattson starts talking about type 2 diabetes now. The world prevalence of diabetes is rising. This disease leads to problems later on in the brain, as shown in more mice models (like leptin-receptor mutant mice), which he summarizes.
- reduced BDNF levels
- l wer neurogenesis
Diabetes reduces neurogenesis, but what about interactions with exercise or calorie restriction? Both exercise and CR increase BDNF levels.
Mattson talking about possibility of using drugs and phytochemicals now (Duen et al 2004; Nelson et al 2007).
Some drugs work by involving BDNF. There are also several fruits and vegetables, but he doesn't think they have an intrinsic factor as antioxidants. Instead, he said, they have toxins concentrated in the skin meant to repel insects. Lots of these plants have natural pesticides, so Mattson acquired many of these natural chemicals to see which produce resistance to neurogenerative disorders.
OK, back to talking about IF, this time about a study showing that IF improves cardiovascular risk factors under stress in animals.
-The body temperature is up on the feeding day, down low on the fasting day.
-Heart rate variability was measured too. Higher heart rate variability is a good thing, because it shows adaptability. IF improved heart rate variability.
-Higher levels of BDNF
Interesting thing, he notes, when they infused BDNF in mice, they showed better heart rate variability.
Human studies? Mattson talks of Jim Johnson's work on subjects with moderate asthma on alternate-day calorie restriction. The subjects adapted to the diet, lost bodyweight, their mood increased, but importantly their asthma improved.
Mattson begins discussing GLP1, a receptor that when stimulated reduces amyloid plaque accumulation, and drugs that stimulate it. GLP1 increases BDNF and insulin sensitivity.
He intends to conduct a 3-year double-blind, randomized trial on a drug (Exendin-4) to treat Alzheimer's disease, by testing CSF biomarkers. He is optimistic and says at least he knows the drug should help with blood glucose management.
Unfortunately, Mattson ran out of time, but the presentation was awesome! Good to know we have serious scientists like this working on AD.
Surprisingly, with all the talk about CR, IF and Alzheimer's, not a word was said about Sirtuin 1 activation, so I asked Dr. Mattson his opinion on the research, specifically Guarente's paper showing that SIRT1 activation inhibited two pathways in the progression of AD.
Mattson responded with a dose of skepticism about sirtuins and their potential, at least as a treatment in the diseased state when they'd use up a lot of NADPH at a time when the brain needs it.
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