Speaker 13: Mark Mattson - Meal Frequency and Health: Cellular and Molecular Mechanisms

Age is major risk factor for neurodegenerative disorders (alzheimers, parkinsons, huntingtons disease etc.).

Lots of bad things happen with aging. Crap builds up, like amyloid proteins in brain. Metabolic impairment (energy production drops). Calcium homeostasis impaired in brain with age - making nerve cells more likely to die.

Some people maintain good brain health to very old age.

Why do some people's brains age better than others?

Mattson thinks the biggest addiction in our country is food addiction.

Constant feeding CR vs intermittent fasting (IF)

IF = feed ad lib every other day.

In rats, IF leads to reduce calorie intake.

But in some strains of mice, IF leads to no reduction in weight - they make by eating 200% food on fed-day.

Fasting Insulin and glucose lowered in IF mice to at least the extent as seen in CRed animals fed every day.

But IGF-1 goes UP in IF group - could be bad, if IGF-1 is "bad guy" in aging, as many people seem to believe these days...

Resting heart rate and blood pressure reduced in IF rats relative to AL. But rats subjected to IF are CRed as well - since they don't eat as much as AL fed rats.

In IF fed rats, body temp drops on fasting day, but comes back up to normal on feeding day. Unlike daily feeding, where body temperature stays low. More evidence IF != CR?

IF leads to better handling of immobilization stress relative to AL in rats.

Heart rate variability in rats - The very short term variability in inter- beat interval of heart. High heart rate variability is good - predicts lower rate of heart failure.

Rats subject to IF show higher stress markers.

Now he's going to look specifically at brain effects:

IF rats results in resistance to these types of toxins.

And IF rodent performance on cognitive tasks (e.g. remembering location of platform in pool) is not impaired by brain toxin, unlike AL animals that can't remember where platform is.

Like with toxin, with age, this cognitive task also declines in AL fed animals. CR or IF attenuate this cognitive decline.

With respect to lifespan, macronutrients don't seem to matter.

But from cognitive perspective, high fat diet impairs rodents learning and memory. But study used saturated fat. Could depend on type of fat. Saturated seems bad. DHA and MUFA seem to improve escape time in water maze.

CR helps some neurogenerative diseases (alzheimers). But looks like CR might be bad for ALS. But rodent model of ALS may not be so good a model of human ALS.

How does CR and IF protect brain? - Neurotrophic Factors (NFs)

BDNF is one such NF.

NFs are expressed more as result of low level stresses, like CR and IF.

Heat shock protein like HSP-70 and GRP-78 (other protectors in brain) increased by CR and IF.

2-deoxyglucose restricts calories at level of cell by competing w/ glucose. Administering it seems to mimic neuroprotective effects of CR. But it is a toxin, unfortunately.

IF and CR increases neurogenesis via brain stem cells in hippocampus. In other words, neurons don't die as often, AND are born more often.

Reported on new study under review. In rhesus monkeys. Done in collaboration w/ Ingram.

Two groups or relatively young monkeys (8 in each group) - AL vs. 30% CR

Six months of CR (or AL).

Then measured dopamine cell activity prior to given neurotoxins.

Then gave neurotoxin that messes up dopamine neurons in half of brain where toxin is administered.

Then measured dopamine and motor function after toxin.

CR reduced impairment in motor performance as result of toxin - CR protective of brain in primates. Good news.

CRed animals had more dopamine than AL animals after toxin - more evidence of protection.

BDNF and GDNF (which protect dopamine neurons) appears higher in CR after toxin.

Huntington's disease (HD):

One side effect of HD is serious weight loss due to altered metabolism - HD results in depressed glucose utilization. So doctors typically encourage people with HD to eat a lot. Perhaps bad idea.

In mice models of HD, CR/IF animals lived longer, and didn't lose weight as fast as disease progressed. Brain degeneration slowed, and BDNF levels increased by CR/IF.

So CR appears to be beneficial in model of HD.

Paxil (anti-depressant) increases BDNF in brain, and helps in rodent model of HD. Might Paxil be considered mimic of CR protection in brain degenerative disease, any maybe even age-related cognitive decline?

Alzheimer's Disease (AD):

Neurons die as result of AD. Also crap (amyloids) builds up as AD progresses.

Amyloids damage cells through oxidative stress mechanism, eventually killing off nerve cells. Anti-oxidants seem to help - by reducing oxidative stress.

He's developed mice model of AD.

Early indications suggest CR/IF helps in the AD model mice. Less memory impairment in hidden platform finding task.

Paxil hurts normal mice, but helps AD model mice. Could be the normal mice are more mellow (less stressed) so don't care about finding platform quickly.

Learning and memory studies are hard to do in rodents.

Conducting new pilot study of humans

• 20 normal weight adults
• 10 subjects eat all food within three hours in early evening 10 subjects eat three meals per day.
• Meal size altered for all subjects to maintain constant body weight. To avoid confounding effect of CR.
• 2 months on respective diets, then off diet for two months, then cross-over.
• Compliance seems good - based on trigliceride levels pre-meal.
• Measuring couple hundred variables (via blood tests).

Some things being measured:

• weight, HR, BP, body temp
• heart rate variability
• Blood and urine draws
• OGTT and 24 hr HR monitor
• Reaction of blood lipids to "Big Mac feeding"
• Leptin etc.
• Doing cognitive testing - anxiety and depression

Warrior diet is like IF.

Benefits of IF could be seen to fit in with hormesis hypothesis. Going long time between meals is a mild stress.

Still open issue on whether IF really has same effects as "standard" CR (limited daily feeding). E.g. IGF-1 doesn't drop with IF. Even when effects are the same, is it result of animals not eating as much as AL due to not making up for missing calories on "down-days" when given free access to food on the "up-days". So what we might really be seeing is CR effect, not an effect of IF per se.

Masoro - U of Piza study showed CR works better than IF for lifespan and other.

Matson - IF may have some benefits via hormesis. CR may tickle hormesis, but may also be beneficial via another pathway. He suspects this may be the case.

MR - Nelson study and Masoro study showed meal frequency doesn't impact lifespan. Calories, calories, calories.

Matson doesn't think IF (without reducing calories) will have as much positive effect on lifespan as standard limited daily feeding form of CR.

But could help with disease, and that is purpose of pilot study - see if IF can help improve health.

What about kids who don't eat breakfast having poorer cognitive performance? Usually done very short term - skip one breakfast and measure kid's cognitive performance. Makes such studies suspect.

He's not sure of significance of slight increase in IGF-1 as a result of IF, which contrasts starkly with standard CR, which dramatically reduces IGF-1.

Interestingly, IGF-1 is generally good for the brain, but may be bad when it comes to aging.