Metformin And mTOR Signaling

Metformin seems to block mTOR signaling; abstract:

Recent findings have shed new light on the mechanisms of action through which biguanides exert their anti-aging and cytostatic effects in Caenorhabditis elegans and human cell lines. The drop in energy charge resulting from the metformin mediated inhibition of mitochondrial activity affects the function of the nuclear pore complex, blocks mTOR signaling and enhances the expression of ACAD10. Whether the inhibition of this pathway is truly responsible for the anti-diabetic and cancer effects of the drug in mammals remains to be established.

The importance of mTOR is explained here.  This pathway has been linked to a number of disorders, and so these are important findings.  But lifestyle changes also play an important role in preventing, or treating, diseases like diabetes and cancer that drugs are used for.  Always ask your physician when the drug is prescribed: is there anything else I should be doing?  Should I also change my diet? Exercise?  

Primary Cilia And Energy Metabolism

One can only imagine the new excuse: “I’m fat because of my primary cilia.”  Abstract:

Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity. Recent studies have demonstrated involvement of cilia-related cellular signaling pathways in transducing metabolic information in hypothalamic neurons and in determining cellular fate during adipose tissue development. In this review, we summarize the current knowledge about cilia and cilia-associated signaling pathways in the regulation of body metabolism.

Coffee And Glycogen Recovery In Athletes

Coffee and athletic glycogen recovery; abstract:

Coffee is one of the most consumed beverages in the world and it can improve insulin sensitivity, stimulating glucose uptake in skeletal muscle when adequate carbohydrate intake is observed. The aim of this review is to analyze the effects of coffee and coffee components on muscle glycogen metabolism. A literature search was conducted according to PRISMA and seven studies were included. They explored the effects of coffee components on various substances and signaling proteins. In one of the studies with humans, caffeine was shown to increase glucose levels, Ca2+/calmodulin-dependent protein kinase (CaMK) phosphorylation, glycogen resynthesis rates and glycogen accumulation after exercise. After intravenous injection of caffeine in rats, caffeine increased adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, and glucose transport. In in vitro studies caffeine raised AMPK and ACC phosphorylation, increasing glucose transport activity and reducing energy status in rat muscle cells. Cafestol and caffeic acid increased insulin secretion in rat beta-cells, and glucose uptake into human muscle cells. Caffeic acid also increased AMPK and ACC phosphorylation, reducing the energy status and increasing glucose uptake in rat muscle cells. Chlorogenic acid did not show any positive or negative effect. The findings from the current review must be taken with caution due to the limited number of studies on the subject. In conclusion, various coffee components had a neutral or positive role in the metabolism of glucose and muscle glycogen, whilst no detrimental effect was described. Coffee beverages should be tested as an option for athlete's glycogen recovery.

Diabetes Drugs Against Alzheimer’s Disease

Some findings of interest, relevant sections:

Studies in a mouse model of Alzheimer’s disease (AD) have shown how a drug that was originally developed to treat diabetes demonstrates what researchers in the U.K. and China call “clear promise” as a treatment for AD and other neurodegenerative disorders in humans. The studies, led by Christian Hölscher, Ph.D., at the U.K.’s Lancaster University, confirmed that AD mice treated using a triple-receptor agonist (TA) showed “significantly reversed memory loss,” as well as reduced neuroinflammation and oxidative stress, lower amyloid plaque load in the brain, and increased levels of brain-derived neurotropic factor (BDNF), a key growth factor that protects synaptic function… 

…Type 2 diabetes mellitus (T2DM) is a known risk factor for AD, and this association has motivated scientists to investigate whether antidiabetic drugs might also be effective against AD. Studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which have antidiabetic properties, can play a neuroprotective role in the brain and have demonstrated promising effects in animal models of AD. 

  Prof. Holscher’s team turned to a triple-receptor agonist that activates GIP-1, GIP, and glucagon receptors…The results showed that a daily injection of TA reversed memory loss in AD mice, which was assessed in a spatial water maze test. The drug also reduced levels of the mitochondrial proapoptotic signaling molecule BAX, increased the antiapoptotic signaling molecule Bcl-2, and boosted levels of BDNF. Levels of synaptophysin were also elevated, which the researchers say demonstrates protection against the synaptic loss that is seen in AD…

 

 …“Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus,” the authors write. “The results demonstrate for the first time that the novel GLP-1/GIP/Gcg receptor agonist has clear neuroprotective effects in the APP/PS1 mouse model of AD.” 

Given the “impressive” preclinical data demonstrating the neuroprotective properties of GLP-1, GIP, and glucagon receptor agonists, clinical trials are now under way to investigate the neuroprotective effects of the GLP-1 receptor agonists extendin-4 (Byetta®, Bydureon®) and liraglutide (Victoza®) in patients with AD or with Parkinson's disease, the authors note. “A pilot study testing the GLP-1 analogue liraglutide in AD patients showed promising results.”

That sounds like a very promising advance in the field of Alzheimer’s therapy, and also underscores the relationship between that disease and metabolic disorders.

"Divide and conquer" - does it work in cancer care

Fotogeniss -

Philip-ii-of-macedon

"Divide and conquer" may have worked for Philip II of Macedon; however, is it an effective strategy in understanding cancer development and providing cancer care?    

Have you seen the talk by Dr. Gary Fettke, "Nutrition and Cancer - Time to Rethink"? The talk leads to the conclusion that cancer is a disease of our metabolism. The chromosomal changes, including any gene mutations, seem to be bystanders in the unfolding madness of cancer development.

However, recent research indicates that all cancer cell changes (mutations and metabolic changes), the immediate environment of the cancer cells (influenced by external environmental and internal factors), and the metabolism at the organism level are interconnected, and contribute to the neoplastic growth.

It is not any single element, it is rather the congregation of factors that allows for the abnormality of cancer to emerge, persist, and eventually kill.

We should be mindful of the perils of reductionism in science and cancer prevention/treatment, and try to adopt a holistic view on cancer. Here are the precise definitions of the two approaches:

Reductionism,
the practice of analyzing and describing a complex phenomenon in terms of simpler, more fundamental phenomena...

versus...

Holism,
the theory that parts of a whole are in intimate interconnection, such that they cannot exist independently of the whole, or cannot be understood without reference to the whole...

For more examples on misleading reductionism see here.



ACTIONABLES:
Yes, we should be aware of not only what we eat but how we eat it.

Yes, we should stop drinking to death, and I am not even referring to drinking alcohol.

Yes, we should learn how to cook for ourselves, since the food industry is force-feeding us with loads of sugar.

Yes, you should educate yourself, and not rely on your doctors and mainstream media to do so.

Yes, all of us should be aware that it is easier to deal with a just-born, immature troublemaker than a fully established, mature enemy; in other words, cancer prevention is more effective than cancer treatment.

Yes, we should try to integrate mainstream and alternative approaches to cancer care.

And yes, for all of you cancer researchers and enthusiasts: analyzing a phenomenon by breaking it down to its elements/building blocks and addressing only a single element is not going to bring a success. Cancer prevention and treatment need to address all aspects of the cancer development.

More Excuses for Obesity?

There is an ongoing debate about the causes of the obesity epidemic. A recent academic study, described here, reported the following:

A given person, in 2006, eating the same amount of calories, taking in the same quantities of macronutrients like protein and fat, and exercising the same amount as a person of the same age did in 1988 would have a BMI about 2.3 points higher. In other words, people today are about 10 percent heavier than people were in the 1980s, even if they follow the exact same diet and exercise plans.

What may be cause of this observation (assuming it is valid)? We read:

In an interview, Kuk proffered three different factors that might be making harder for adults today to stay thin. 

First, people are exposed to more chemicals, some of which might be weight-gain inducing. Pesticides, flame retardants, and the substances in food packaging might all be altering our hormonal processes and tweaking the way our bodies put on and maintain weight.

Second, the use of prescription drugs has risen dramatically since the ‘70s and ‘80s. Prozac, the first blockbuster SSRI, came out in 1988. Antidepressants are now one of the most commonly prescribed drugs in the U.S., and many of them have been linked to weight gain. 

Finally, Kuk and the other study authors think that the microbiomes of Americans might have somehow changed between the 1980s and now. It’s well known that some types of gut bacteria make a person more prone to weight gain and obesity. Americans are eating more meat than they were a few decades ago, and many animal products are treated with hormones and antibiotics in order to promote growth. All that meat might be changing gut bacteria in ways that are subtle, at first, but add up over time. Dr. Kuk believes the proliferation of artificial sweeteners could also play a role.

Let’s consider these hypotheses (which may or may not eventually be supported by future data).

Diet affects the microbiome; in the article, meat is mentioned.  Other studies, including those in “humanized” mice, have shown that only one day on a “junk food diet” can alter the microbiome, the bacterial colonizing our gut.  Studies in human volunteers have shown the same.  These changes seem to be reversible. Diet is something that we have control over; we can eat less meat, and a healthier and higher-fiber diet enriched in while grains, fruits, and vegetables. Artificial sweeteners can be avoided. Other dietary factors linked to obesity, such as high fructose corn syrup or sugary sodas should be eliminated.

The researchers notes that the use of certain prescription drugs that have weight-gain as a side-effect has “risen dramatically.”  Although some people no doubt require such medications, the sharp increase in antidepressant use suggests the possibility that perhaps they are being over-prescribed and are not always necessary. This is another modifiable risk factor at both the individual and societal level.

Chemical exposure is a factor, one that can be avoided to the extent possible, although their ubiquity makes that difficult.  However, that same ubiquity suggests to us to look closely at the fact that while most Americans are sharing these same exposures, not all are obese/overweight.

What about other hypotheses and/or variables that can be controlled for? Was muscle-fat composition controlled for? If people today have, for original lifestyle reasons, more fat and less muscle than those in past generations, then this would account for less “burning” of calories, since muscle is more metabolically active than fat. So, it is possible people become overweight, with a higher body fat percentage, due to modifiable lifestyle changes, and then find that this change in body composition makes losing weight more difficult. There is the “cause vs. effect” issue here; one bottom line is prevention – it is better not to become overweight to start with, since losing weight will become much more difficult.

There’s an underlying problem with how this study is being presented, which mirrors how “fat gene” studies are also presented: the idea that things are beyond our control, no one is at fault, and we must be accepting of the obesity epidemic.  But, as stated, even if the abovementioned hypotheses are correct, many are modifiable, and it is imperative that these modifications be attempted.

After all, the problem can be looked at academically from another perspective: compare individuals from the same age group, contrasting those of normal weight to those overweight and obese. Let us compare their diet and activity level.  One hypothesis: those of normal weight will have healthier diets, and more activity, than those overweight and obese.

The problem exists and must be dealt with. Eat properly (including less [red] meat and artificial sweeteners. Do not take mind-altering medication unless it is truly necessary. Be more active. Avoid to the extent possible environmental stressors that promote obesity. We need to work together to eliminate as many of those stressors as possible. Do not accept an epidemic destroying the health of individuals and a society.