Leptin, Low Carb, and Alzheimer's

Abstract 

Accumulation of amyloid-β (Aβ) is a key event mediating the cognitive deficits in Alzheimer's disease (AD) as Aβ promotes synaptic dysfunction and triggers neuronal death. Recent evidence has linked the hormone leptin to AD as leptin levels are markedly attenuated in AD patients. Leptin is also a potential cognitive enhancer as it facilitates the cellular events underlying hippocampal learning and memory. Here we show that leptin prevents the detrimental effects of Aβ_1–42 on hippocampal long-term potentiation. Moreover leptin inhibits Aβ_1–42-driven facilitation of long-term depression and internalization of the 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (AMPA) receptor subunit, GluR1, via activation of PI3-kinase. Leptin also protects cortical neurons from Aβ_1–42-induced cell death by a signal transducer and activator of transcription-3 (STAT-3)-dependent mechanism. Furthermore, leptin inhibits Aβ_1–42-mediated upregulation of endophilin I and phosphorylated tau in vitro, whereas cortical levels of endophilin I and phosphorylated tau are enhanced in leptin-insensitive Zucker fa/fa rats. Thus leptin benefits the functional characteristics and viability of neurons that degenerate in AD. These novel findings establish that the leptin system is an important therapeutic target in neurodegenerative conditions.

http://www.neurobiologyofaging.org/article/S0197-4580(12)00425-3/abstract

I doubt the author's conclusion will lead anywhere.  It is well established that high levels of triglycerides  prevent leptin from crossing the blood brain barrier.  My conjecture - and admittedly this is way over my head but a plausible conjecture none the less - is that this is one of the ways that high carb diets negatively impact development of "AD".
First, high carb diets drive high triglyceride levels, and with subsequent development of insulin resistance, high insulin levels.  The high trigs mean that less leptin will interact in the brain, perhaps creating the effects described above which drive amyloid-B accumulation at faster rates.
High insulin levels means that the body's scavenger system for amyloid-B, insulin degrading enzyme, is busy with insulin and never has time to attend to amyloid-B.
Third, fasting results in the body finding and using as much protein in the body as possible, and there's some evidence that this "protein scavenging" reduces build of of AGEs (a protein damaged by glycation) and other "junk" proteins that wind up in the plaques associated with AD.
Lastly, high blood sugar levels drives higher levels of advanced glycation end products, which are also accelerants in the plaques that characterize AD.

The example of the diabetics is telling - they get AD at higher rates than everyone else.  It would be interesting to know - can AD develop in a person who maintains normal to low blood glucose across their entire lifespan?  Or, the same question stated differently:  has a person ever been diagnosed with AD who maintained optimal blood sugar levels across a lifetime (or most of a lifetime)?

Use It Or Lose It

Abstract

A contributing factor to the loss of muscle mass and strength with adult aging is the reduction in the number of functioning motor units (MUs). Recently, we reported that lifelong competitive runners (master runners = ∼66 yr) had greater numbers of MUs in a leg muscle (tibialis anterior) than age-matched recreationally active controls. This suggested that long-term exposure to high levels of physical activity may limit the loss of MU numbers with adult aging. However, it is unknown if this finding is the result of long-term activation of the specifically exercised motoneuron pool (i.e., tibialis anterior) or an overall systemic neuroprotective effect of high levels of physical activity.

Purpose: The purpose was to estimate the number of functioning MUs (MUNEs) in the biceps brachii (an upper body muscle not directly loaded by running) of nine young (27 ± 5 yr) and nine old (70 ± 5 yr) men and nine lifelong competitive master runners (67 ± 4 yr).

Methods: Decomposition-enhanced spike-triggered averaging was used to measure surface and intramuscular EMG signals during elbow flexion at 10% of maximum voluntary isometric contraction.

Results: Derived MUNEs were lower in the biceps brachii of runners (185 ± 69 MUs) and old men (133 ± 69 MUs) than the young (354 ± 113 MUs), but the old and master runners were similar.

Conclusions: Although there were no significant differences in MUNE between both older groups in the biceps brachii muscle, with the number of subjects tested here, we cannot eliminate the possibility of some whole-body neuroprotective effect. However, when compared with the remote biceps muscle, a greater influence on age-related spinal motoneuron survival was found in a chronically activated MN pool specific to the exercised muscle.

http://mobile.journals.lww.com/acsm-msse/_layouts/oaks.journals.mobile/articleviewer.aspx?year=2012&issue=07000&article=00006

You already know that as you age you lose muscle, and you may know that an estimate is that you lose 6% per year of muscle unless you engage in strength training, which is estimated to slow the rate of muscle loss to 1%. 

As a side note, the fact that Louie Simmons is powerlifting in the neighborhood of 700 pounds in the deadlift, 800 pounds in the back squat, and 600 pounds in the bench press at age 60+ is ... well, I don't know what to say about that except that Louie is one incredible lifter.  I doubt he has any serious contenders for the title of "World's Strongest 60 Year Old." http://www.westsidebarbell.com/  Yes, I know powerlifters use funny lifting suits and they are not shy about their use of drugs which allow them to train harder, some of which are of questionable legality.  Still - that's a lot of hard work and determination and guts.

If I read this abstract right, the short version is that it appears you delay muscle loss for those muscle you put to work.  The authors hope there's a systemic benefit, but this test did not show that effect. 

In other words, common sense prevails - if you want to sustain your ability to move yourself around as you age, train all the functions of the body.  Run, jump, climb, push, pull, lift and press.  If you want to maintain the ability to generate power (speed and force), you must train with explosive elements (punching, kicking, throwing, oly lifting, jumping, sprinting).  This stuff isn't, as the old joke goes, rocket surgery.

Muscle Mass Is Cancer Prevention

Very interesting study, skip to conclusions below if you don't like (as I don't) reading geek-speak in studies.
Abstract

BACKGROUND: Several hypotheses proposed to explain the worse prognosis for older melanoma patients include different tumor biology and diminished host response. If the latter were true, then biologic frailty, and not age, should be an independent prognostic factor in melanoma.

METHODS: Our prospective institutional review board (IRB)-approved database was queried for stage III patients with computed tomography (CT) scans at time of lymph node dissection (LND). Psoas area (PA) and density (PD) were determined in semi-automated fashion. Kaplan-Meier (K-M) survival estimates and Cox proportional-hazard models were used to determine PA and PD impact on survival and surgical complications.

RESULTS: Among 101 stage III patients, PD was significantly associated with both disease-free survival (DFS) (P = 0.04) and distant disease-free survival (DDFS) (P = 0.0002). Cox multivariate modeling incorporating thickness, age, ulceration, and N stage showed highly significant association with PD and both DFS and DDFS. DDFS was significantly associated with Breslow thickness (P = 0.04), number of positive nodes (P = 0.001), ulceration (P = 0.04), and decreasing muscle density (P = 0.01), with hazard ratio of 0.55 [95% confidence interval (CI) 0.35-0.87]. PD also correlated with surgical complications, with odds ratio (OR) of 1.081 [95% CI 1.016-1.150, P = 0.01]. CONCLUSIONS: Decreased psoas muscle density on CT, an objective measure of frailty, was as important a predictor of outcome as tumor factors in a cohort of stage III melanoma patients. On multivariate analysis, frailty, not age, was associated with decreased disease-free survival and distant disease-free survival, and higher rate of surgical complications.

Read more here:
HT:  http://conditioningresearch.blogspot.com/2012/02/muscle-and-cancer-it-is-not-getting-old.html

It's difficult to know without reading the whole study how they separated causality - IOW, were the folks that were more frail more frail because their cancer was detected later?  They had already had more treatment?  These obviously would confound the result, it would be nice to think they were ahead of those issues.

The BL:  the more I learn about it, the less significance cardiorespiratory endurance seems to have to health.  Strength is a much more relevant measure of health (or muscle mass, a correlate of strength).  In some ways this seems like a blinding flash of the obvious - if you have the strength to get up and down from the floor, up and down stairs and hills, can push a lawn mower, and so forth - you'll be able to be independent, mobile and active.  The fewer the restraints on your activity, the more alive you are almost by definition.  Running, or jogging, is great, but leaves a lot on the table in terms of health.  By adding squats, pushups, pullups, or any degree of strength training, you can significantly improve you chances of aging well - and apparently, of surviving illness, too.

Healing Sick Mice

The mice that Dr. Tarnopolsky and his colleagues used lacked the primary mitochondrial repair mechanism, so they developed malfunctioning mitochondria early in their lives, as early as 3 months of age, the human equivalent of age 20. By the time they reached 8 months, or their early 60s in human terms, the animals were extremely frail and decrepit, with spindly muscles, shrunken brains, enlarged hearts, shriveled gonads and patchy, graying fur. Listless, they barely moved around their cages. All were dead before reaching a year of age.

Except the mice that exercised.

Half of the mice were allowed to run on a wheel for 45 minutes three times a week, beginning at 3 months. These rodent runners were required to maintain a fairly brisk pace, Dr. Tarnopolsky said: “It was about like a person running a 50- or 55-minute 10K.” (A 10K race is 6.2 miles.) The mice continued this regimen for five months.

At 8 months, when their sedentary lab mates were bald, frail and dying, the running rats remained youthful. They had full pelts of dark fur, no salt-and-pepper shadings. They also had maintained almost all of their muscle mass and brain volume. Their gonads were normal, as were their hearts. They could balance on narrow rods, the showoffs.

But perhaps most remarkable, although they still harbored the mutation that should have affected mitochondrial repair, they had more mitochondria over all and far fewer with mutations than the sedentary mice had. At 1 year, none of the exercising mice had died of natural causes. (Some were sacrificed to compare their cellular health to that of the unexercised mice, all of whom were, by that age, dead.)

http://well.blogs.nytimes.com/2011/03/02/can-exercise-keep-you-young/?src=me&ref=health

It would be interesting if the researchers could develop methodologies to allow them to compare the effect of high intensity exercise, strength training, and mixed modal activity, to see which modality would have the greatest effect in mouse-life-extension, even thought it wouldn't necessarily apply to humans.

Aging and Athletes

Do you want to live forever?  Do you want to avoid living in a worn out, useless, limiting body which makes a mockery of living?

Too me, these are two different questions but the yin/yang of aging.

In the long run, fitness is about living while being alive, and whatever your concept of living is should direct how you invest your training hours in 'fitness.'  While an old but tarnished concept of fitness involved endurance training, the newer and I think more relevant model requires that one attend to endurance, power, coordination and strength (and perhaps other trainable attributes like agility, flexibility, speed, stamina, accuracy and balance).  As the benefits of anaerobic training become more widely known, for example, we see more studies which document the "why."  Excerpts follow:

http://www.nytimes.com/2010/11/28/magazine/28athletes-t.html?_r=1

Exactly how exercise affects older people is complicated. On one level, exercise is a flat-out insult to the body. Downhill running tears quadriceps muscles as reliably as an injection of snake venom. All kinds of free radicals and other toxins are let loose. But the damage also triggers the production of antioxidants that boost the health of the body generally. So when you see a track athlete who looks as if that last 1,500-meter race damn near killed him, you’re right. It might have made him stronger in the deal.

Exercise training helps stop muscle strength and endurance from slipping away. But it seems to also do something else, maintains Mark Tarnopolsky, a professor ofpediatrics and medicine at McMaster University in Hamilton, Ontario (who also happens to be a top-ranked trail runner). Resistance exercise in particular seems to activate a muscle stem cell called a satellite cell. With the infusion of these squeaky-clean cells into the system, the mitochondria seem to rejuvenate. (The phenomenon has been called “gene shifting.”) If Tarnopolsky is right, exercise in older adults can roll back the odometer. After six months of twice weekly strength exercise training, he has shown, the biochemical, physiological and genetic signature of older muscle is “turned back” nearly 15 or 20 years.

This article is a good read, and the conclusion matches the model of the paleolithic peoples:

This is the other story of the future of aging. When the efforts of medical science converge to simply prolong existence, you envision Updike’s golfer Farrell, poking his way “down the sloping dogleg of decrepitude.” But scientists like Taivassalo and Hepple have a different goal, and exercise — elixir not so much of extended life as extended youthfulness — may be the key to reaching it. James Fries, an emeritus professor at Stanford School of Medicine, coined the working buzz phrase: “compression of morbidity.” You simply erase chronic illness and infirmity from the first, say, 95 percent of your life. “So you’re healthy, healthy, healthy, and then at some point you kick the bucket,” Tarnopolsky says. “It’s like theNeil Young song: better to burn out than to rust.” You get a normal life span, but in Olga years. Who wouldn’t take it?

Heartscan on Glycation

A glycation rock and a hard place

Glycation is one of the most well known mechanisms of aging.  Cataracts, wrinkles, arthritis - all can be traced to a degree to glycated proteins gumming up the works.  In short - high blood sugars are making you old.

What to do?


There's nothing we can do about the low-level of glycation that occurs at low blood sugar levels of, say, 90 mg/dl or less. However, we can indeed do a lot to not allow glycation to proceed more rapidly, as it inevitably will at blood sugar levels higher than 90 mg/dl.

How do you keep blood sugars below 90 mg/dl to prevent excessive glycation? Avoid or minimize the foods that cause such rises in blood sugar: carbohydrates.

What food increases blood sugar higher than nearly all other known foods? Wheat.


But don't take Dr. Davis' word for it.  Get a glucose meter and figure out which foods make you older for yourself.

Bigger Bicepts, Bigger Bean

http://well.blogs.nytimes.com/2011/01/19/phys-ed-brains-and-brawn/

"... most of the science to date about activity and brain health has focused on the role of endurance exercise in improving our brain functioning. Aerobic exercise causes a steep spike in blood movement to the brain, an action that some researchers have speculated might be necessary for the creation of new brain cells, or neurogenesis. Running and other forms of aerobic exercise have been shown, in mice and men, to lead to neurogenesis in those portions of the brain associated with memory and thinking, providing another compelling reason to get out at lunchtime and run."

"In somewhat similar fashion, researchers from Japan recently found that loading the running wheels of animals improved their brain functioning. A loaded running wheel is not strictly analogous to weight lifting; it’s more similar in human terms to a stationary bicycle with the resistance dialed high — in this case, quite high, as the resistance equaled 30 percent of the rats’ body weights in the last week of the monthlong study. By then, the rats on the loaded wheels could run barely half as far as a separate group of rats on unloaded wheels, but the mice on the loaded wheels had packed on muscle mass, unlike the other rats. The animals that were assigned to the loaded wheels showed significantly increased levels of gene activity and B.D.N.F. levels within their brains. The higher the workload the animals managed to complete, the greater the genetic activity within their brains."

"Imagine what someone like Einstein might have accomplished if he had occasionally gone to the gym."


There you have it, proof positive that weightlifting is good for your brain.  Ok, not really, but here's where science has failed us in some respects.  Researchers have studied endurance athletes quite a bit more than other kinds, so extrapolation is required to estimate results for other types of exercise.  In my view, it would just be gravy if the high intensity, heavy weight training proves to be beneficial to the brain, because we know it's needed to age optimally.  Being more cognitively capable is grand, but so is a body that will do what the brains directs it to do.

A Million Plus Years of Survival of the Fittest Yields Amazing Capability

This is a summary of this post, which I also referenced here.

Low carb, or starvation metabolism, is the 'normal' metabolism.  Low carb intake, or starvation, presents the opposite challenge than what we neolithic humans usually face (how to dispose of excess blood sugar before it damages our nervous system), in that it has to generate enough glucose to feed glucose dependent tissues (primarily, the brain!).

A quote from the article:  "the metabolism of carb restriction = the metabolism of starvation. I would maintain, however, based on my study of the Paleolithic diet, that starvation and carb restriction are simply the polar ends of a continuum, and that carb restriction was the norm for most of our existence as upright walking beings on this planet, making the metabolism of what biochemistry textbook authors call starvation the ‘normal’ metabolism."

Where does the body come up with glucose when you are either starving or restricting carb intake?  First, from muscle tissue, protein from which is broken down in the liver to create glucose.  However, this isn't an ideal solution for the long term, for the obvious reason that you'll live better with more muscle, especially if you need to hunt and kill some food.  So keeping mind, as Dr. Eades reports that "normal blood sugar represents only about a teaspoon of sugar dissolved in the entire blood volume", you might assume that an "average person requires about 200 grams of sugar per day to meet all the needs of the glucose-dependent tissues".  So, how can a starving human spare glucose?  Easy, ketones, which are a fabulous glucose substitute, and are a by product of the break down of fats in the liver which is part of gluconeogenesis.  That's right - the machine is so incredibly efficient that it converts protein to sugar, a process powered by the body's really big energy storage tissue, fat, the by product of which (ketones) reduces the amount of gluconeogenesis required.

"Although ketones can’t totally replace all the sugar required by the brain, they can replace a pretty good chunk of it. By reducing the body’s need for sugar, less protein is required, allowing the muscle mass (the protein reservoir) to last a lot longer before it is depleted. And ketones are the preferred fuel for the heart, making that organ operate at about 28 percent greater efficiency."

As the Dr. says, "Fat is the perfect fuel."  This process is beautiful, man, just beautiful.  At least, it is if you are a *geek like me.*

Dr. Eades again:  "If, instead of starving, you’re following a low-carb diet, it gets even better. The protein you eat is converted to glucose instead of the protein in your muscles. If you keep the carbs low enough so that the liver still has to make some sugar, then you will be in fat-burning mode while maintaining your muscle mass, the best of all worlds. How low is low enough? Well, when the ketosis process is humming along nicely and the brain and other tissues have converted to ketones for fuel, the requirement for glucose drops to about 120-130 gm per day. If you keep your carbs below that at, say, 60 grams per day, you’re liver will have to produce at least 60-70 grams of glucose to make up the deficit, so you will generate ketones that entire time."

In the mean time, while you are making your own sugar and ketones from stored fat and ingested fat and protein, your body's systems are not fully engaged transforming and packing excess sugars into fat cells.  When not tied down by that emergency, your body will clean up AGEs (advanced glycation end products), amyloid plaques and such, while sustaining a low blood sugar level, meaning these things are not regenerated in as great a volume.  

Low blood sugar, fewer AGEs and decreased amyloid plaques is likely an all win scenario - unless you would like the challenge of rapid aging with atherosclerotic disease, loss of internal tissue pliability, loss of memory and cognition, and the other not-so-delicious results of metabolic syndrome. 
Edited 10 March, 2011

Wheat, Fake Wheat, Snickers and Blood Sugar

From the Heart Scan blog:
"Take a look at these glycemic indexes (GI):
White bread 69
Whole wheat bread 72
Sucrose 59
Mars bar 68
White rice 72
Brown rice 66"I've made issue in past of whole wheat's high GI--higher than white bread. Roughly in the same glycemic league as bread are shredded wheat cereal, brown rice, and a Mars candy bar.
"With few exceptions, wheat products have among the highest GIs compared to the majority of other foods. For instance:
Kidney beans 29
Chick peas 36
Apple 39
Ice cream 36
Snickers Bar 40
"Yes, by the crazy logic of glycemic index, Snickers is a low-glycemic index food.
"While I do not believe that low GI makes a food good or desirable, since low GI foods still provoke high blood sugars, small LDL particles, trigger glycation, and other abnormal phenomena, they are clearly less obnoxious than the items in the first list.
"Take a look at this list:
Cornflakes 80
Rice cakes 80
Rice Krispies 82
Rice pasta, 92
Instant potatoes 83
Tapioca 81


"Starches that are dried and/or pulverized, such as cornstarch, potato starch, rice starch, and tapioca starch (cassava root) will increase blood sugar even more than wheat. Foods with these starches have GI's of 80-100.
"Cornstarch, potato starch, rice starch, and tapioca starch: Sound familiar? These are the main starches used in "gluten-free" foods. A hint of the high GI behavior of these dried starches is seen in the GI for cornflakes of 80.
"So remember: Wheat-free is not the same as gluten-free. Gluten-free identifies junk carbohydrates masquerading as healthy because they don't contain one unhealthy ingredient, i.e. wheat."

Shi No Ubi's Picture Of Success

My friend has hit the 30 pound milestone!  Along the way, he's started to heal his damaged metabolism.  His system, no longer bombarded by wheat and other 'sugar bomb' foods, is regaining the capacity to regulate the levels of glucose he sustains.  Going from a waking glucose of 110, to a waking glucose of 99, is a significant shift in health in and of itself.  Why?  High glucose levels are associated with everything you don't want; high weight, a future of medications, accelerated aging, CVD, and a long, drawn out, decline in physical, and mental, fitness.  

The best measure of the health of your metabolism is called an A1c - it measures how much your hemoglobin has been 'glycated.'  Glycation is the process by which proteins are damaged by binding to sugars in a way that makes the proteins non-functional junk.  Glycation to some degree is inevitable, but above a certain level, it is associated with all the diseases of the West.  In other words, high glucose levels will generate too much glycation, and that will be reflected in the A1c number.  

Every day, my friend works to unload his metabolic systems (by eating meat, vegetables, nuts and seeds, some fruit, little starch and no sugar or wheat), allowing healing, which is reflected in his decreasing AM glucose readings.  He'll see the daily successes reflected in the A1c from his next visit to a doctor.

              

Introduction to AGE - Pleased to Meet You?!?

High HbA1c: You're getting older . . . faster

Dr. Davis on why you want to sustain low blood sugar levels by eating meat, vegetables, nuts and seeds.  Unless you dig looking and feeling older than you are!

"Over the years, we all accumulate Advanced Glycation End-products, or AGEs.

AGEs are part of aging; they are part of human disease. AGEs are the result of modification of proteins by glucose. AGEs form the basis for many disease conditions.

Accumulated AGEs have been associated with aging, dementia, cataracts, osteoporosis, deafness, cancer, and atherosclerosis. Most of the complications of diabetes have been attributable to AGEs.

There's one readily available method to assess your recent AGE status: HbA1c.

Hemoglobin is the oxygen-carrying protein of red blood cells. Like other proteins, hemoglobin becomes glycated in the presence of glucose. Hemoglobin glycation increases linearly with glucose: The higher the serum or tissue glucose level, the more glycation of hemoglobin develops. Glycated hemoglobin is available as the common test, HbA1c.

Ideal HbA1c is 4.5% or less, i.e., 4.5% of hemoglobin molecules are glycated. Diabetics typically have HbA1c 7.0% or greater, not uncommonly greater than 10%.

In other words, repetitive and sustained high blood glucose leads to greater hemoglobin glycation, higher HbA1c, and indicates greater glycation of proteins in nerve cells, the lens of your eye, proteins lining arteries, and apoprotein B in LDL cholesterol particles."