Take a look at the long protein that stretches through the entire sarcomere that is called the giant protein TITIN. It is a sensor of stretch and contraction and passes through the M-band and the Z-band and affects muscle gene expression powerfully. In this post, I explore the research and theory behind the new form of exercise I have been using now that I am to be 76 this August. It is a combination of standard exercises in some sense, so it is not wholly new and could not be because exercise is simply muscle contraction or stretch. After looking over the research and using my self-experiment, I have come to a tentative conclusion that targeting TITIN and another sensor in the muscle cell is a useful model of effective exercise. It is a model that can help you and has helped me to design an exercise routine and think about the purpose of exercise.

My basic goals are to

1. stave off sarcopenia (wasting of lean muscle),
2. limit inflammation (but use it as an acute signal),
3. preserve the alpha-motor neurons (they fire the FT fibers) and their signals
4. produce acute signals of BDNF (brain derived neuronal growth factor),
5. preserve mitochondrial density and function, and
6. stimulate (acutely, not chronically) protein synthesis,
7. maintain high anabolic and sex hormone production.

That sounds like a big challenge, but it is not so hard to do since I have spent a lifetime doing that in following Evolutionary Fitness, which I developed in the 1980s and summarized in my book, The New Evolution Diet. The challenge now is to do this without loading my joints or over-loading my adaptive capacity. I find it extraordinary that older people are often put on the same old exercise technology used by body builders and recommended by exercise physiologists --- 3 sets of 10 reps with 80% of the one-repetition maximum, three times a week. The experiments that I have read that track response and stress almost always show that the old-timers experience a rise in stress hormones such as cortisol (so do lots of people who overdo it in the gym) and often experience a rise in inflammation. That they still manage to gain strength and muscle mass is a very strong endorsement of weight lifting, but it could be done much more efficiently in my view. The rise in cortisol and inflammation limit and may even prevent the gains that are sought.

The easiest things to temper the pace of aging are to eat as detailed in my previous post.

In developing my new approach to exercise, I was concerned about the slow rate of force development that occurs with aging, which is attributable to the degeneration of the alpha motor neurons in the spine, and with the imbalance between agonist and antagonist muscles that lead to stiffness, poor balance, and the impaired movement shown in the aged. The muscle cells of the aged take on a disorganized state, with a mixing of fiber types, diffuse signaling of the motor neurons as they diminish in size and signaling strength, intrusion of connective tissue, and lessened density of mitochondria. As the motor neurons diminish in number and firing strength, they fire more broadly over the muscle cells and they become less coordinated. FT fibers are lost and the remaining fibers look like a mass of disorganized, undifferentiated fibers.

The inability of aged muscles to absorb force (such as in landing from a jump) imposes a higher load on the joints and connective tissues. This is partly due to the inability of the agonist muscles to lengthen under load and also due to the excess tone or stiffness of the antagonist muscles. A summary of what follows would be this:

1. Point number one of my exercise is to increase the ability of the agonist muscle to lengthen under load and diminish the resistance from the antagonist muscle.
2. Point number two is to increase the signaling to the FT fibers, which has the side benefit of improving the alpha motor neuron connection, firing, and signal conductance.
3. Point number three is to increase the rate at which I can develop force --- rapid force production is the key.
4. Point number four, and this is a key, is to improve the integrity of the muscle cell to prevent its fall into a disorganized state. I think the alpha motor neuron activation and measures of muscle cell size and stress such as the giant elastic protein titin and dystrophin are big factors here.
5. Point 5, keep the mitochondria in the muscle dense and active, when you lose enough of them the cell goes into a death program.
6. Point 6, hang on to the nuclei of your muscle cells. Lose them and you lose muscle cell size.
   

The muscle cells diminish through a loss of cell number or a loss of cell size. Disorganized cells may actually be larger than organized ones, but they are lost because disorganized cells are removed. The aging must contend with cell atrophy, which is an active process under genetic control. These atrogenes (atrophy producing genes) promote the activity of the ubiquitin-proteasome pathways that actively destroy the muscle cell. Diabetes, cancer cachexia, renal failure, fasting, and denervation (loss of motor neurons) lead to cell death through activation of the atrogene pathways (atrogin-1/MFb1 and MuFR1 have been identified as the primary atrogenes). The atrogenes seem to be the master genes for muscle wasting.

Insulin, acute insulin, not chronic insulin, and IGF-1 induce Akt action. So, rather than making muscle grow, Akt action primarily works by turning down the muscle-wasting atrogenes. It is simple to activate the Akt (and downstream the mTOR) pathway --- exercise induces muscle-produced IGF-1 and eating protein or consuming BCAAs induces an acute release of insulin. Both activate Akt. Carbohydrates release insulin, which up regulates Akt, but the activation is long-lasting and quickly becomes chronic if excess carbohydrate intake leads to insulin resistance. Note, that diabetics suffer muscle wasting at least partly because they become insulin resistant and fail to activate Akt.

Akt-1 is the important pathway for muscle growth and it is activated by exercise. Passive stretch strongly activates Akt signaling and FT fiber development. Akt expression also up regulates mTOR expression and muscle growth. Protein consumption also increases mTOR expression, which seems to be an energy sensor or nutrient sensor.

Interestingly, blocking myostatin, a limiter of muscle size, seems to produce larger but less effective muscles. The FTb fibers, the ones I prize most, form disorganized tubular structures that do not correlate with force production when myostatin is blocked. A myostatin blocker, the holy grail of body builders, leads to bigger, less functional muscles, a price they may be willing to pay.

The inflammatory pathways, through increased levels of TNF-alpha, the cytokine IL-6, and myostatin, are involved in upregulating the atrogenes that cause muscle atrophy. PGC-1alpha is the master regulatory gene for mitochondrial biogenesis, which is crucial for muscle preservation. A loss of mitochondrial density in muscle not only reduces its effective energy and strength, it leads to either the death of the cell or its atrophy. BCAAs improve PGC-1alpha function and expression so that mitochondrial biogenesis is activated. So does intermittent fasting.

Atrophy is the enemy of aging muscle, more so than a lack of anabolic or growth factors. Aging muscle can grow, but only if the balance of atrophy versus anabolism moves to a positive balance acutely. Chronic expression of an anabolic state, paradoxically to a homeostatic point of view, leads to muscle atrophy. But, unfortunately for the homeostatic model, cell size is not a homeostatic variable under genetic control of the muscle cell. Thus, acute changes in atrophy versus anabolism seem to be essential to preserving or growing muscle cell size. Inhibiting cell turnover does not seem to influence protein breakdown, which primarily occurs in the cell to reduce its size.

Conclusion: sarcopenia, at the current state of knowledge, seems to primarily occur through a loss of muscle cell size rather than number. The cells seem to adjust in size through loss of organelles, cytoplasm, and proteins in such a way as to preserve the size of the nuclear domain, the cell domain surrounding the muscle nuclei. Thus, loss of muscle size occurs through loss of nuclei within the cell. And, we know that nuclei are lost when motorneurons fail to signal the nuclei. Disuse, oxidative damage to the neurons or neural plate junction at the muscle, inflammatory damage, or atrogene expression are factors in the loss of nuclei of muscle cells.

So, the bottom line is: preserve muscle, keep your myonuclei, the nuclei of your muscle cells. Two major points follow:

1. This is primarily linked to the alpha signaling of motorneurons. Evidence comes from experiments that down regulate the opposing beta signals to the motorneurons, which is shown to result in hypertrophy and a conversion from slow to fast fibers. That says, in short, that increasing alpha signaling produces hypertrophy and slow to fast muscle fiber conversion. We know how to do this and my “system” does it very well (more below)
2. The interesting link in muscle signaling is that it depends on mechanical load at the sarcomere, the basic unit of muscle contractive machinery, which is transmitted from there to the nucleus to affect muscle gene expression.

Now, we are really getting somewhere. The giant, elastic protein titin spans half the sarcomere from the Z disk to the M band and interacts with a large number of muscle proteins. Down in the M-band there is a region that alters gene expression that is affected by stretching or contraction of titin. In the absence of stretching or contraction of the titin protein, SRF (serum response factor) a muscle gene expression factor is exported from the muscle cell nucleus.  Without SRF, it seems muscle does not grow. Experimental depletion of SRF genes causes severe muscle hypoplasia.

There is another mechanical sensor in muscle that could play a role in muscle size. Dystrophin glycoprotein complex (DGC) anchors the muscle skeleton to the cell membrane. DGC couples the working part of the cell to its membrane and is essential for translating muscle contraction into force. Dystrophin is lost when muscle atrophies and may even be part of the atrophic signaling. Dystrophin measures the disuse of a muscle and may be an active force in disuse atrophy.

So, we have at least two important mechanical sensors measuring stress on the muscle cell or disuse --- titin (contraction or stretch) and dystrophin (disuse). I don't think one can understand why stretching a muscle causes it to become larger unless you recognize that the TITIN long protein is stretched and dystrophin is stressed. Nor can one understand disuse atrophy without recognizing that dytrophin is a sensor of disuse and functions as a trigger for the atrogenes.

This post has gotten to be too long, so the exercise that I developed with these insights will have to wait for the next post. Hint: the stress sensors and how they alter gene expression play a large part of it.

This is brief and somewhat speculative. I question that endurance exercise is really beneficial.

The problem is a bit definitional. What is endurance exercise? It seems that in almost all discussions, it is either running or biking for a sufficiently long period of time. How long? It depends, but usually the minimum is about 30 minutes at least 3 times per week. Less than that amount is seldom considered to be endurance exercise. And less than 30 minutes is usually not thought to bring adaptations that would be sufficient to place one in the endurance exercise category. You would not ordinarily become proficient enough at it to be considered an endurance exerciser.

Does endurance exercise give one endurance? Only if you do enough of it. Is it the only way to build endurance? No, one can achieve high levels of endurance by sprinting in brief intervals. Endurance exercise is not necessary for building endurance and it may not be sufficient for many reasons but primarily if the volume is not sufficient.

Then again, what sort of endurance do you want? Is endurance the ability to "get through the challenges of life"? An endurance exerciser may not have any more of that ability than someone who does a different form of exercise. For example, endurance for an NBA basketball player is a matter of being able to recover quickly from power moves of high intensity. Endurance in baseball may be the ability of an MLB baseball player to retain power and last through a long season. On a more mundane but more important level, endurance is the ability to get up every morning and do a hard day of work. An endurance exerciser may so exhaust his or her adaptive capacity as to reduce this more important measure of endurance. An MLB player who ran 30 miles a week through a season of baseball would likely end up spent by August and sitting on the bench.

A softball player I played with was an endurance exerciser, a good runner at that, who could not sprint to first base or hit a ball out of the infield. His endurance exercise depleted his power and speed, but he could run around the bases all day long. Not so useful in that aspect of his life and likely not so useful in his daily life. Will he have the capacity to recover from the hip or knee replacements he almost surely has ahead of him?

All this is just to add some complexity to the issue that I think is treated too simply by many. I am not questioning the value of exercise, which is considerable, but I am questioning the form and the amount. Not so new perhaps, but here is the different part of the picture I want to bring out.

Running or biking long distances has a very short and shallow curve of benefits before it turns and becomes damaging. Beyond 30 miles of running per week, the running damages health. Running more than 30 miles a week will increase running endurance, but it will increase the risk of organ and cardiovascular damage. See the link on my Facebook page or in the WSJ here. Now consider the shape of the benefits curve. No one knows where it peaks and no one knows the benefits curves of either running (or biking or a pure endurance exercise of some other form) or short intervals of more intense running, lifting weights, or of some form of anaerobic exercise, which is not considered to be endurance exercise.

Anaerobic exercise confers strength, lean muscle mass, and endurance. Endurance exercise confers only the latter and usually alters to body composition so as to shed muscle and cause the loss of strength.

But there is more to consider as my friend Nassim Taleb likes to recall. Of the hours he used to pedal to work he concluded that the hardest climb during the trip gave him most or all of the benefits of the considerable time he spent cycling. He and I prefer convex exercise where the upward curvature of the benefits curve created a situation in which the average benefit lies above the benefits of the average effort. Non-endurance exercise is naturally limited by the capacity of the system to supply energy and oxygen. Up to the point of exhaustion, the curve remains convex.

Endurance exercise does not have that sort of convex benefits curve. The benefits are concave and have a shallow peak.

Mathematically, you are better off going intensely and letting the body's protective mechanisms keep you from overdoing it. Not that I ever exhaust myself, which is mostly a matter of supplying enough oxygen to maintain high energy output and preventing the accumulation of lactate to the point of limiting power. This keeps you in the convex part of the curve and, provided you do not overdo it, has a better chance of creating the highest benefits of exercise. I never overdo it because I not seeking endurance or anything else. I have no goals other than to realize the benefits of exercise --- more endurance, strength, adequate muscle and high capacity.

So far, not so surprising and not speculative at all, I think.

Now for a more controversial and speculative conjecture. I think we now know that anaerobic exercise is not inferior to aerobic exercise and may be superior. I think it is. But, I do not promote a particular point of view on that as I think exercise is important and fun. But, endurance exercise is more likely to be harmful than helpful relative to the anaerobic alternatives. Again, I am not comparing NO exercise to either form. NOT exercising is harmful. But, so is endurance exercise.

I am putting forth the proposition that endurance exercise is inherently harmful. For beginners, it is inherently harmful because it is easy to overcome the oxygen delivery to tissues and ischemia will occur in some tissues. There are many warnings on running sites advising beginners to "go slow or easy" pointing out the dangers of inadequate blood and oxygen supplies to some tissues. There are also warnings against progressing too rapidly. But, how is one to know? You do not have ischemia warning signals that I know of that will protect you. And, how is one to know that you are not overdoing the volume? This is easier since you will show elevated cortisol and an elevated heart rate if you are overdoing it. It is the volume that kills because it leads to lessened immune function and accumulation of cortisol (a contributor to damage in many tissues and a factor in aortic function and damage that can progress into aneurysm and aortic dissection, extreme events that it may take years to progress into). Body builders and older persons training on weight doing 3 sets of 10 reps at the 80% of their one repetition maximum may also show elevated cortisol (some cross fitters also show elevated cortisol as I learned from Robb Wolf).

I think it is the volume that kills. This can hold for any type of exercise. So, aside from a few overzealous body builders and over-trained seniors following a similar level of volume, it is the endurance exercisers who are more likely to see damage from their exercise. And, the least benefits but for stylized measures of endurance that do not relate so well to the natural world.

I will have to think more about that to fashion an evolutionary explanation and even that may to too stylized. But, I think it is safe to point out that, without sophisticated testing, it is far too easy to enter into the region of harm because endurance itself becomes a goal and there are few, if any, warning signals to all but the very experienced and informed endurance exerciser. Evolution would not program such a warning system because there was no  need for it. Natural exhaustion would occur first and it would call a cease to the danger in all but life-threatening circumstances where the warning could not be heeded any way.

Anyway, don't hate me for this. I am just posing questions. And, the evidence does hint at this conclusion.

Statins block an enzyme that occurs early in the long chain of events leading to the production of cholesterol. Many other fats and enzymes originate on that chain as well, so statins may have far-reaching effects on many elements of the body and of metabolism.

A striking aspect of statin use is pointed to by Stephanie Seneff in her essay Why Statins Don't Work. "Statins, then, slowly erode the muscle cells over time. After several years have passed, the muscles reach a point where they can no longer keep up with essentially running a marathon day in and day out. The muscles start literally falling apart, and the debris ends up in the kidney, where it can lead to the rare disorder, rhabdomyolysis, which is often fatal. In fact, 31 of our statin reviews contained references to "rhabdomyolysis" as opposed to none in the comparison set. Kidney failure, a frequent consequence of rhabdomyolysis, showed up 26 times among the statin reviews, as opposed to only four times in the control set. "

Statin-induced damage to muscle can be detected in tests for creatine kinase in the blood. Here is her elegant summary of the four complications of statin therapy for muscles: "
The skeletal muscle cells are severely affected by statin therapy. Four complications they now face are:

(1) their mitochondria are inefficient due to insufficient coenzyme Q10,

(2) their cell walls are more vulnerable to oxidation and glycation damage due to increased fructose concentrations in the blood, reduced cholesterol in their membranes, and reduced antioxidant supply,

(3) there's a reduced supply of fats as fuel because of the reduction in LDL particles, and

(4) crucial ions like sodium and potassium are leaking across their membranes, reducing their charge gradient. Furthermore, glucose entry, mediated by insulin, is constrained to take place at those lipid rafts that are concentrated in cholesterol. Because of the depleted cholesterol supply, there are fewer lipid rafts, and this interferes with glucose uptake. Glucose and fats are the main sources of energy for muscles, and both are compromised."

As a result, muscle metabolism becomes dependent on anaerobic metabolism and the production of lactate. The mitochondria can no longer keep up energy supply and the FTb fibers atrophy and the release of contents from the damaged muscle damages the nerves. No wonder so many older individuals, most of whom are likely on statin therapy lose their ability to generate force rapidly or to maintain activity for long periods.
 
There is a nice summary of rhabdo, its causes and its consequences (often death). http://www.medicinenet.com/rhabdomyolysis/article.htm

This might be interesting because I am departing from a few old practices in light of my age and a knee and hip replacement. I am not lifting heavy weights, or not what I consider to be heavy weights. The plastic parts of my new joints will not take a lot of load or will wear too quickly. Besides, what I am doing gives me all the strength I need. Between the operations and the recovery period, I did lose some muscle mass. Now the problem was to build up mass without lifting heavy weights. It was EASY. Let me tell you how I did it.

As always, I focussed on the X-look, which is upper back and shoulder mass and filling out the calves and thighs (front and back). I wanted to stay lean and have found that my impedance scale reading, maybe not the most accurate test, is between 5.6% and 8% body fat. My deltoids, upper traps and upper lats are very cut and full. My arms are really thicker than I want them to be. I tend to get large in the triceps and biceps and don't like that thick feeling. So, I do only one set of curls and few over head presses. I don't even do pec work, they just get used when I do some incline presses.

I do just one or two sets of about 8 reps in each exercise and follow the last one with some negative version of the same exercise. That might mean using two arms or legs to lift the weight and one to lower it. I am doing a LOT of deltoid work. Bent over DB lateral raises, two sets of 8, "Arnold DB presses" 3 sets to close to failure each time. Machine lateral raises of 10, 8, 4 reps and a few negatives after (just raise the lever with both arms and lower with one.) Then just a few shrugs or dead lifts with an Olympic bar. I treat this as a shaping and stretching movement and focus on a long line from the neck to the shoulder cap in the trapezius. I do 8 reps of one-legged leg presses one or two sets, followed by a couple of negatives (push up with both legs, lower with one.) Always some calve raises on a maching that does not load the lower back or one-legged raises on a block.

So far, not so exotic. Just a fair amount of volume for those delts. Here is the surprise: I do this almost every day in such a brief work out that I can do it right after tennis or before I shoot some baskets. This is the surprise, if there is one. I always felt that muscle quality was best working out at least 4 times a week. I am probably hitting 5 and 6 work outs a week, always doing roughly the same work out. So, the volume of the training is fairly great over a week's time but small in each work out. This really works for me. I can feel the muscle quality, see the definition, and the mass is more than enough. I swear half the gym stops to watch when I do my bent over lateral raises if I am wearing a "muscle" shirt, which I seldom do. It may be the combination of mass and shape in the deltoids and the shedded look they have.

The weather has been awful (but nothing like you are having back East) so I go to the gym for activity and relaxation. But, being there often has been the secret to the reshaping of my body. It is the repeated stimulus to growth that is causing my rapid gains. Each individual work out is a brief and not so challenging stimulus. So, I need little time for recovery and can do it again the next day. 5 or 6 brief stimuli in a week seems to be better than an exhausting stimulus once a week. I am inclined to think that is true, given my experience and knowing that the most massive hypertrophy (big muscles) occurs when a weight is tied to, say, a pigeon's wing and left there for a week or two. This is true for animals as well. The growth stimulus is almost constant since the weight is not removed. Yet, the stress is not so massive that the wing breaks down or that the pigeon becomes exhausted. 

So, 5 or 6 brief work outs a week, plenty of deltoid work, 4 grams of Guardian branched chain amino acids and 2 meals a day have brought me back. Maybe it will work for you.

I love this and no one knows about it. No need to  talk of the theory, though I love to do that. It is a micro work out in the totality of a workout, which is always a mixture of the hard and easy.

You might want delts that stop people in their tracks. I  may have them because I see people all around me looking. They may wonder, but I will only say it here. Ignore this if you think this is overblown because it might be. No 76 year old, who takes it easy in his life, ought to get the kind of attention I seem to get in the gym.

Here is my secret sauce delt work out.

1. Bent over lateral delt raises. Bend over, standing or sitting, and raise a relatively heavy weight up and out. Raise it with some help from a slight heave and lower the DB slowly. The slow lowering stresses the FT fibers, the most important muscle as you age.
2. Right after, with the same DB, to Arnold Presses.
   
3. Right after that, do alternating DB curls.

That is one set, done with the same DB. No stopping, no rest. 8 reps. No more. Then again, twice. Move on.

There is a bit more to the delt work out I described in my last post.

When I have finished the mini-work out I head for the lateral raise machine (a Cybex in this gym) and do 8 reps at a starting weight then increase the weight about 20% and do 4 reps, then finish with one-armed negatives with that same weight. How do you do a one-armed negative? You lift the lever with the arm but help it with your free hand. Once it is up, lower it with just one arm. I try to do 4 of those.

Then I move to the Smith Rack and load about 135 to 185 onto the bar and do some shrugs. I am careful to control the shrug to get the "line" from the trap a the neck to the shape I want to the shoulder. No thick, bunchie traps needed. Just a graceful, full line from the neck to shoulder.

With that done, I move on to a few more exercises.

I have begun investigating the activities of those so-important stem cells. They are cell precursors that can differentiate to become almost any sort of cell. They are crucial to making and repairing muscle and, it is increasingly evident, play an important role in bone health. Osteoporosis and osteoarthritis are pathologies that are linked to stem cell failures.

If you think about stem cells as baby cells waiting to become whatever sort of cell the body needs for growth or repair, then you realize how important they are for health and the delay aging. Expose these stem cells to reactive oxygen species (ROS) and they are damaged. They may not proliferate or differentiate into the  type of cell the body needs and there may be fewer of them if they succumb to the damage. Fortunately, they have ROS defenses but they can be depleted if their glutathione levels are depressed.

Here are two important articles about the role of ROS, reactive oxidation species, and the activity of stem cells. We know of the advanced glycation end products, the AGEs, as an end product of the action of oxygen and glucose on proteins (it is sometimes called a browning of the protein since it resembles the same reaction in toasting bread, which browns the protein in as it reacts with starches in bread under heat and oxidative load.

Advanced oxidation end products alter stem cell activity: their rate of proliferation is reduced, fewer of them differentiate to become osteogenic cells, and their activity is reduced.

Effect of advanced oxidation protein products on the proliferation and osteogenic differentiation of rat mesenchymal stem cells
By:Sun, N (Sun, Nan)[ 1 ] ; Yang, L (Yang, Li)[ 1 ] ; Li, YB (Li, Yingbin)[ 2 ] ; Zhang, H (Zhang, Hua)[ 1 ] ; Chen, H (Chen, Hong)[ 1 ] ; Liu, D (Liu, Duan)[ 1 ] ; Li, QN (Li, Qingnan)[ 2 ] ; Cai, DH (Cai, Dehong)[ 1 ]
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
Volume: 32  Issue: 2  Pages: 485-491
DOI: 10.3892/ijmm.2013.1402
Published: AUG 2013
View Journal Information
Abstract
Advanced oxidation protein products (AOPPs) as a novel marker of oxidative stress, are involved in a variety of diseases, including osteoporosis. Although a number of studies have shown the possible functions of AOPPs in biological processes, little is known about the role of AOPPs in the pathogenesis of osteoporosis. In this study, we aimed to investigate the effect of AOPPs on the proliferation and osteogenic differentiation of rat mesenchymal stem cells (MSCs). MSCs, isolated from bone marrow, were cultured in the absence or presence of AOPPs (50, 100, 200 and 400 mg/ml). MTT assay was used to determine the proliferative ability of the cells. Alkaline phosphatase (ALP) activity, the mRNA expression of ALP and collagen I and bone nodule formation were detected to assess osteogenic differentiation. Reactive oxygen species (ROS) generation was analyzed with the probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The expression of receptor of advanced glycation end-products (RAGE) at the mRNA and protein level was detected by real-time PCR and western blot analysis, respectively. Compared with the control group, AOPPs inhibited MSC proliferation in a dose- and time-dependent manner. Moreover, AOPPs induced a significant reduction in ALP activity, as well as a decrease in ALP and collagen I mRNA levels in the MSCs; bone nodule formation was also inhibited. Furthermore, AOPPs increased ROS generation in the MSCs, and upregulated the expression of RAGE at the mRNA and protein level. These results suggest that AOPPs inhibit the proliferation and osteogenic differentiation of MSCs, possibly through the AOPPs-RAGE-ROS pathway; this may be an important mechanism in the development of osteoporosis.

This article shows a pathway for the development of osteoporosis through the AOPPs-RAGE-ROS pathway. But, what can one do about it? Can the pathway be turned off or reduced in activity? Yes, of course. Reduce the simple sources of glucose that contribute to the glycation of stem cells. Reduce the sources of ROS in your diet --- glucose, alcohol, smoking, simple carbohydrates, certain oils and rancid fats. Dampen ROS damage with a diet higher in natural antioxidants and use a good source for glutathione, which is the key molecule in controlling ROS. You can use the Guardian patented source by going up the that link or use precursors to glutathione; they may be effective if you retain your ability to synthesize glutathione from precursors in adequate amounts. Me, I take Guardian.

The next article says that stem cells can cope with oxidation, but not when they fail to have adequate cellular glutathione content.

Human mesenchymal stem cells efficiently manage oxidative stress.

Araceli Valle-Prieto and Paulette A PA Conget
Stem Cells and Development 19(12):1885 (2010) PMID 20380515

The transplantation of mesenchymal stem cells (MSCs) proves to be useful to treat pathologies in which tissue damage is linked to oxidative stress (OS). The aim of our work was to evaluate whether primary human MSCs (hMSCs) can manage OS. For this, in vitro we assessed the following parameters: (1) cell viability of hMSCs exposed to increasing concentrations of reactive oxygen species (ROS; source: hydrogen peroxide), reactive nitrogen species (RNS; source: S-nitroso-N-acetylpenicillamine), or both (ROS and RNS; source: 3-morpholinosydnonimine hydrochloride); (2) intracellular level of reactive species in hMSCs exposed to ROS and RNS; (3) basal gene expression and activity of superoxide dismutases, catalase, and glutathione peroxidase of hMSCs; (4) basal level of total glutathione (GSx) of hMSCs; and (5) cell viability of GSx-depleted hMSCs exposed to ROS and/or RNS. Results showed that hMSCs have a high resistance to OS-induced death, which correlates with low levels of intracellular reactive species, constitutive expression of enzymes required to manage OS, and high levels of GSx. When hMSCs were depleted of GSx they lose their capacity to manage OS. Thus, in vitro hMSCs were able to scavenge ROS and RNS and efficiently manage OS. If this potential is maintained in vivo, hMSCs could also contribute to tissue regeneration, limiting OS-induced tissue damage.

I wonder often how Paleo Diets evolved towards a high-fat diet. This is not the Paleo diet as our ancestors knew it and there are many problems with a high-fat diet. It MAY be slightly superior to a modern diet, which is high in processed carbohydrates and altered proteins, such as those in processed milk, that promote AGEs and ALEs --- advanced glycation end products and advanced lipoxizided end products. Both feature altered protein and fat molecules that promote dysfunction, inflammation, and disrupted metabolism. The real problem is not so much the source of energy, but excess of energy intake, and the altered molecules that we consume. Maybe the latter are the primary problem and that is mediated in the context of excess energy relative to activity. This is the line of research I am pursuing and I will have more later.

I spoke in Paris a month ago to a group of doctors about diabetes, inflammation and the eyes. I am told they liked the talk and gave positive reviews. It sure was fun, but challenging.