Less surgery is better for women and lumpectomy is better than mastectomy

Karuna-Jaggar-2015 smallI’ve lost count of how many doctors and researchers in the last two days have expressed alarm at the fact that mastectomies are on the rise. Several studies suggest that less surgery is better for women, that lumpectomy is better than mastectomy. Whether or not women who have lumpectomy plus radiation live longer than women who have a mastectomy, it is clear that a smaller surgery is not worse for women. And lumpectomy comes with fewer complications and lower cost.

In the opening Plenary Lecture yesterday, Dr. Jay Harris noted the rise in mastectomies at the same time there has been a reduction in local recurrence rates. His talk was on radiation, and his point is that the main benefit in reducing recurrence has come from the addition of adjuvant systemic therapy, not surgery or radiation. In 1970s, the 5-year local recurrence rate was about 10%; currently, worldwide the 5-year rate is about 2%. Dr. Harris notes that it is ironic that as breast-conserving therapy gets better, more patients choosing mastectomy.

Thursday morning’s General Session ended with three papers which compared lumpectomy (typically referred to in a research setting as “breast-conserving surgery”) and mastectomy.

A paper out of the Netherlands presented by Dr. van Maaren looked at 10 year distant metastasis free survival, comparing lumpectomy plus radiation versus mastectomy, for the first time. In the 1980s, several randomized controlled studies showed equal survival for lumpectomy with radiation and mastectomy. More recent observational studies have shown better survival for breast-conserving therapy. This study used the Netherlands Cancer Registry, which includes all patients diagnosed with cancer from 1989 forward, to compare 10 year overall survival rates for 37,207 patients after either breast-conserving therapy or mastectomy. Regardless of stage at diagnosis, women with lumpectomy and radiation did better, with 20% increased overall survival compared to mastectomy.

While the question and answer session (which included questions about selection bias) revealed that the true benefit is likely not as big as this, Dr. van Maaren does believe there is a real survival benefit that comes with lumpectomy and radiation, and hypothesized that the radiation therapy contributes to the better outcomes.

The second study (S3-06) was another retrospective study, this time of nine National Cancer Institute designated comprehensive cancer centers, looked at multiple surgical options. The study looked specifically at patients treated with systemic therapy before surgery (neoadjuvant treatment), as one of the aims of neoadjuvant therapies has been to improve candidacy for breast-conserving surgeries. And yet breast-conserving surgery rates are not increasing. In this study, one third of women received lumpectomy.

As with the prior Dutch study, women who had lumpectomy and radiation did the best. By contrast, the lowest five-year disease free and overall survival was for patients with lumpectomy alone, followed by patients who had mastectomy plus radiation.

But strong selection bias exists with this study. Because women had chemotherapy prior to the surgery, treatment choice likely differed reflecting response to this treatment. (Tumors which show less response to treatment before surgery generally have worse prognosis.) Acknowledging the study limitations, the author notes that a more ideal trial which randomizes women to receive lumpectomy or mastectomy are likely not possible (as few patients would be willing to participate).

The third study (S3-07), looked at the economic burden and complications associated with different surgery options. Researchers from University of Michigan and MD Anderson looked at Medicare claims and private insurance. These researchers accepted past data showing that survival for the different surgery options are generally similar. Yet, they also noted that mastectomy rates are rising. Medical reasons driving mastectomy include genetic syndromes or multifocal disease. Other reasons that have been reported elsewhere include patient fears of recurrence/death and an underestimation of the harms of mastectomy. These researchers want to add considerations of value to the conversation by looking at cost and rates of complications.

Mastectomy plus reconstruction had two times the increased risk of any complication compared to lumpectomy plus radiation. For private insurance the cost of mastectomy plus reconstruction was nearly $90,000. (Note this was nearly double the cost for Medicare patients, who were analyzed separately.) The cost of complications associated with mastectomy and reconstruction was over $10,000. By contrast, women who had a lumpectomy had fewer complications and lower cost.

Dr. Jatoi was the Discussant commenting on these three papers dealing with breast-conserving surgery. All three were observational studies that tell us about associations, but not if the association is due to cause and effect, chance, or confounding bias. Whether or not women who have lumpectomy plus radiation live longer than women who have a mastectomy, it is clear that a smaller surgery is not worse for women.

There have been six randomized trials comparing breast conserving surgery and mastectomy, which found no survival advantage for either surgery option. In 1990, the NCI consensus panel came to the conclusion that breast-conserving surgery was the optimal treatment based on these trials. Since that time the trend in surgery choice has shifted, with breast-conserving surgery initially rising but declining since 2006 as mastectomy rates have increased. Rates of unilateral mastectomies are actually going down in the U.S., but what is driving the increase in mastectomy rates is bilateral mastectomies. Dr. Jatoi concluded that 25 years after the NCI consensus panel, randomized trials and observations studies continue to show that breast-conserving surgery is the optimal choice for most women.

In less formal settings, multiple doctors and researchers repeated some version of what Dr. Susan Love stated bluntly in the Hot Topics session on Wednesday evening: “There is no data to support bilateral mastectomy. Not better in any biological sense. I just don’t get it.”

As a surgeon herself, Love is clear that “surgery is not the answer for breast cancer”. Doing more surgery does not in fact give patients better outcomes.

In reporting the research presented at SABCS, I am clear that not all of the outcomes which patients value have not been captured or discussed. Some women I interact with have said that “symmetry” is an important outcome. And indeed Dr. Love noted that “for surgeons it’s much easier to do a mastectomy versus a cosmetic lumpectomy”. She went even further and said that it’s easier to match two breasts and do a double mastectomy—with the added benefits to surgeons of “getting paid better” with a bigger surgery.

The data shows that women who are eligible for a lumpectomy but choose mastectomy wont’ live longer and they may have higher complications and cost. Women who have a lumpectomy live as long (and possibly longer) as women who have a mastectomy, and the breast-conserving surgery was developed precisely because it’s preferable for women in many ways to removing the whole breast.

Fighting cancer from health data

molecular and clinical datadeep immune profilingWe are working to fight cancer using health data. Today at the conference on Big Data in Biomedicine , transforming lives through Precision Health at Stanford University, many  geneticists, data scientists, technologists and immune system scientists gathered to learn and collaborate in the fight against cancer. Some gaps must be addressed to reach more cancer patients and get better clinical outcomes:

  • Patient engagement is still missing when scientists are busy finding data insights from health data.
  • How do we manage cancer patients? Our health care management must be on top of patient outcomes.
  • Data monitoring cancer patient data with patient engagement must be available in the future.
  • This is still the current gap due to costs reasons.
  • Clinical trial enrollment for targeted molecular and clinical cancer therapies is still not reaching a larger set of population. Adult cancer patients are treated in communities (less likely to be enrolled in clinical trials) while pediatric cancer patients are treated in specialized hospitals.
  • Traditional cancer specialists are not trained as immunologists.
  • Technical data and health education are not reaching and digestible for health consumers. Support groups must be used to disseminate information. The increasing amount of health information and research are not reaching health consumers.

Speakers

  • Enakshi Singh SAP HANA and Cancerlinq
  • Nikesh Kotecha Parker Institute
  • Ash Alizadeh Stanford U
  • Ami Bhatt Stanford U

 

Immunoglobulin B cells from bone marrow and cytokines role during cancer expression

Antibody (or immunoglobulin) structure is made up of two heavy-chains and two light-chains. These chains are held together by disulfide bonds. The arrangement or processes that put together different parts of this antibody molecule play important role in antibody diversity and production of different subclasses or classes of antibodies. The organization and processes take place during the development and differentiation of B cells. That is, the controlled gene expression during transcription and translation coupled with the rearrangements of immunoglobulin gene segments result in the generation of antibody repertoire during development and maturation of B cells.

B-Cell Development

During the development of B cells, the immunoglobulin gene undergoes sequences of rearrangements that lead to formation of the antibody repertoire. For example, in the lymphoid cell, a partial rearrangement of the heavy-chain gene occurs which is followed by complete rearrangement of heavy-chain gene. Here at this stage, Pre-B cell, mμ heavy chain and surrogate light chain are formed. The final rearrangement of the light chain gene generates immature B cell and mIgM. The process explained here occurs only in the absence of the antigen. The mature B cell formed as RNA processing changes leaves the bone marrow and is stimulated by the antigen then differentiated into IgM -secreted plasma cells. Also at first, the mature B cell expresses membrane-bound IgD and IgM. These two classes could switch to secretory IgD and IgM during the processing of mRNAs.

Finally, further class switching follows as the cell keep dividing and differentiating. For instance, IgM switches to IgG which switches to IgA that eventually switches to IgE

The multigene organization of immunoglobulin genes

From studies and predictions such as Dreyer and Bennett’s, it shows that the light chains and heavy chains are encoded by separate multigene families on different chromosomes. They are referred to as gene segments and are separated by non-coding regions. The rearrangement and organization of these gene segments during the maturation of B cells produce functional proteins.The entire process of rearrangement and organization of these gene segments is the vital source where our body immune system gets its capabilities to recognize and respond to variety of antigens.

Light chain multigene family

The light chain gene has three gene segments. These include: the light chain variable region (V), joining region (J), and constant region (C) gene segments. The variable region of light is therefore encoded by the rearrangement of VJ segments. The light chain can be either kappa,κ or lambda,λ. This process takes place at the level of mRNAs processing. Random rearrangements and recombinations of the gene segments at DNA level to form one kappa or lambda light chain occurs in an orderly fashion. As a result, “a functional variable region gene of a light chain contains two coding segments that are separated by a non-coding DNA sequence in unrearranged germ-line DNA” (Barbara et al., 2007). Interestingly, the immunoglobulin lambda light chain locus contains protein-coding genes that can be lost with its rearrangement.[1] This is based on a physiological mechanism and is not pathogenetic for leukemias or lymphomas.[2] However,the rearrangement of several lambda variable subgenes can activate expression of an overlapping miRNA gene, which has consequences for gene expression regulation.[3]

Heavy-chain multigene family

Heavy chain contains similar gene segments such as VH, JH and CH, but also has another gene segment called D (diversity). Unlike the light chain multigene family, VDJ gene segments code for the variable region of the heavy chain. The rearrangement and reorganization of gene segments in this multigene family is more complex . The rearranging and joining of segments produced different end products because these are carried out by different RNA processes. The same reason is why the IgM and IgG are generates at the time.

Variable-Region Rearrangements

The variable region rearrangements happen in an orderly sequence in the bone marrow. Usually, the assortment of these gene segments occurs at B cell maturation.

Light chain DNA

The kappa and lambda light chains undergo rearrangements of the V and J gene segments. In this process, a functional Vlambda can combine with four functional Jλ –Cλ combinations. On the other hands, Vk gene segments can join with either one of the Jk functional gene segments. The overall rearrangements result in a gene segment order from 5 prime to 3 prime end. These are a short leader (L) exon, a noncoding sequence (intron), a joined VJ segment, a second intron, and the constant region. There is a promoter upstream from each leader gene segment. The leader exon is important in the transcription of light chain by the RNA polymerase. To remain with coding sequence only, the introns are removed during RNA- processing and repairing.[4] In summary,

Heavy chain DNA

The rearrangements of heavy-chains are different from the light chains because DNA undergoes rearrangements of V-D-J gene segments in the heavy chains. These reorganizations of gene segments produce gene sequence from 5 prime to 3 prime ends such as a short leader exon, an intron, a joined VDJ segment, a second intron and several gene segments. The final product of the rearrangement is transcribed when RNA polymerase

Mechanism of variable region rearrangements

It is understood that rearrangement occurs between specific sites on the DNA called recombination signal sequences (RSSs). The signal sequences are composed of a conserved palindromic heptamer and a conserved AT- rich nonamer. These signal sequences are separated by non-conserved spacers of 12 or 23 base pairs called one-turn and two-turn respectively. They are within the lambda chain, k-chain and The processes of rearrangement in these regions are catalyzed by two recombination-activating genes: RAG-1 and RAG-2 and other enzymes and proteins. The segments joined due to signals generated RSSs that flank each V, D, and J segments. Only genes flank by 12 -bp that join to the genes flank by 23-bp spacer during the rearrangements and combinations to maintain VL-JL and VH-DH-JH joining.

Generation of antibody diversity

Antibody diversity is produced by genetic rearrangement after shuffling and rejoining one of each of the various gene segments for the heavy and light chains. Due to mixing and random recombination of the gene segments errors can occur at the sites where gene segments join with each other. These errors are one of the sources of the antibody diversity that is commonly observed in both the light and heavy chains. Moreover, when B cells continue to proliferate, mutations accumulate at the variable regions through a process called somatic hypermutation. The high concentrations of these mutations at the variable region also produce high antibody diversity.

Class-switching

When the B cells get activated, class switching can occur. The class switching involves switch regions that made up of multiple copies of short repeatts(GAGCT and TGGGG). These switches occur at the level of rearrangements of the DNA because there is a looping event that chops off the constant regions for IgM and IgD and form the IgG mRNAs. Any continuous looping occurrence will produce IgE or IgA mRNAs.

In addition, cytokines are factors that have great effects on class switching of different classes of antibodies. Their interaction with B cells provides the appropriates signals needed for B cells differentiation and eventual class switching occurrence. For example, interleukin-4 induces the rearrangements of heavy chain immunoglobulin genes. That is IL- 4 induces the switching of Cμ to Cγ to Cκ.


Cytokines

Cytokines (cyto, from Greek “κύτταρο” kyttaro “cell” + kines, from Greek “κίνηση” kinisi “movement”) are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. Their release has an effect on the behavior of cells around them. It can be said that cytokines are involved in autocrine signalling, paracrine signalling and endocrine signalling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors but generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.[1][2][3]

They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.[3]

They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in less variable concentrations and hormones tend to be made by specific kinds of cells.

They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

Lung cancer may not produce any noticeable symptoms until it is too late

Lung cancer may not produce any noticeable symptoms in the early stages. In approximately 40 percent of people diagnosed with lung cancer, the diagnosis is made after the disease has advanced. In one-third of those diagnosed, the cancer has reached stage 3.

Cough that won’t quit

Be on alert for a new cough that lingers. A cough associated with a cold or respiratory infection will go away in a week or two, but a persistent cough that lingers can be a symptom of lung cancer. Don’t be tempted to dismiss a stubborn cough, whether it is dry or produces mucus. See your doctor right away. They will listen to your lungs and may order an X-ray or other tests.

Change in a cough

Pay attention to any changes in a chronic cough, particularly if you are a smoker. If you are coughing more often, your cough is deeper or has hoarse sound, or you are coughing up blood or more mucus than usual, it’s time to make a doctor’s appointment. If a family member or friend experiences these changes, suggest that they visit their doctor.

Breathing changes

Shortness of breath or becoming easily winded can also be possible symptoms of lung cancer. Changes in breathing can occur if lung cancer blocks or narrows an airway, or if fluid from a lung tumor builds up in the chest.

Make a point of noticing when you feel winded or short of breath. If you find it’s difficult to breath after climbing stairs or performing tasks you could do before without having a hard time breathing, don’t ignore it.

Pain in the chest area

Lung cancer may produce pain in the chest, shoulders, or back. An aching feeling may not be associated with coughing. Tell your doctor if you notice any type of chest pain, whether it is sharp, dull, constant, or comes and goes. You should also note whether it is confined to a specific area or is occurring throughout your chest. When lung cancer causes chest pain, the discomfort may result from enlarged lymph nodes or metastasis to the chest wall, the lining around the lungs called pleura, or the ribs.
Stage 4: My father’s pain is on his back. It persisted for about 5 years.
Wheezing
When airways become constricted, blocked, or inflamed, the lungs produce a wheezing or whistling sound when you breathe. Wheezing can be associated with multiple causes, some of which are benign and easily treatable.

However, wheezing is also a symptom of lung cancer, which is why it merits your doctor’s attention. Don’t assume that wheezing is caused by asthma or allergies. Have your doctor confirm the cause.

Raspy, hoarse voice
If you hear a significant change in your voice, or if someone else points out that your voice sounds deeper, hoarse, or raspier, get checked out by your doctor. Hoarseness can be caused by a simple cold, but this symptom may point to something more serious when it persists for more than two weeks. Hoarseness related to lung cancer can occur when the tumor affects the nerve that controls the larynx, or voice box.

Drop in weight
An unexplained weight loss of 10 pounds or more may be associated with lung cancer or another type of cancer. When cancer is present, this drop in weight may result from cancer cells using energy. It could also result from shifts in the way the body uses energy from food.

Don’t write off a change in your weight if you haven’t been trying to shed pounds. It may be a clue to a change in your health.

Bone pain
Lung cancer that has spread to the bones may produce pain in the back or in other areas of the body. This pain may worsen at night while resting on the back. It may be difficult to differentiate between bone and muscle pain. Bone pain is often worse at night and increases with movement.

Additionally, lung cancer is sometimes associated with shoulder, arm, or neck pain, although this is less common. Be attentive to your aches and pains, and discuss them with your doctor.

Headache
Headaches may be a sign that lung cancer has spread to the brain. However, not all headaches are associated with brain metastases. Sometimes, a lung tumor may create pressure on the superior vena cava. This is the large vein that moves blood from the upper body to the heart. The pressure can also trigger headaches.


Cancer signs: Chronic cough/pain/others, lost of appetite, lost of weight.

Preventative for early stage of cancer: Vitamin C and amino acid lycine.

Detox: Sleep, green juice/smoothie, avoid sugar, alcohol, tobacco, caffeine

 

Dr Mercola’s book – Fat for Fuel

Dr Mercola’s book ‘Fat for Fuel’ book is a revolutionary diet to combat cancer, boost brain power and increase your energy.


Dr Mercola’s story…

In 1995, my understanding of chronic disease took a quantum leap. I was introduced to Dr. Ron Rosedale and his breakthrough views on clinical metabolic biochemistry.

In a nutshell, Dr. Rosedale taught me that defective metabolic processes in your mitochondria, not your genetic makeup, cause cancer and nearly all other chronic diseases, including accelerated aging.

And what causes these faulty processes?

Insulin and leptin receptor resistance from too many net carbs and activation of the mTOR metabolic signaling pathway by too much protein.

Let me put this into more easily understood terms…

When you eat too many sugars and carbs without fiber, along with too much protein, you can ignite a cascade of metabolic events that includes:

  • Widespread inflammation and cellular damage, especially your mitochondria, or your cells’ power factories
  • Faster aging and a greater risk of all cancers from the activation of your body’s most important signaling pathway from eating excess protein
  • An increase in insulin resistance that can progress to prediabetes or Type 2 diabetes because your cells have lost their ability to respond to insulin effectively
  • Overeating due to the loss of control over your appetite and knowing when you’re “full”
  • An inability to lose weight because your body is holding on to fat instead of burning it for fuel

So how can you take what I’ve learned and put it to good use? That’s the idea behind my new book, Fat for Fuel – to help you take control over obesity and chronic disease, including advanced cancer.

Why Cancer Is One Of The Most Manageable Diseases We Know Of Today

“Once you realize what cancer is, that it’s a metabolic disease, you can take charge of those kinds of things. In other words, getting cancer is not God’s will. It’s not bad luck.”

— Thomas Seyfried, Ph.D.

Human Mitochondria
An artist’s view of human mitochondria inside a cell

I believe, along with many of the experts I interviewed for Fat for Fuel, more than 90 percent of cancer cases are either preventable or treatable.
That should be very welcome news to most people – even if you’re not currently fighting cancer or have a friend or family member who is.

But here’s something that I think should be even more reassuring…

Many people don’t realize that their chances of developing cancer are slim if their mitochondria are healthy and functional.

Researcher Dr. Peter Pederson from Johns Hopkins, recently made a fascinating discovery:

One characteristic that cancer cells share with one another is that they have a radically reduced number of fully functional mitochondria.

Maybe you remember learning about mitochondria in science class…

These tiny organelles, originally thought to have evolved from bacteria, exist in nearly all your cells. Most cells have several thousands of them, and can comprise up to 50 percent of your cells’ volume!

Your mitochondria are truly your body’s lifeline. They supply over 90 percent of your body’s energy needs by converting the food you eat and the air you breathe into usable energy.

Powerful Strategies For Repairing And Nurturing Your Mitochondria

As you age, your body produces fewer mitochondria, so that makes taking care of the ones you have all the more important.

When a significant percentage of your mitochondria stops functioning properly, your health can falter and leave you more vulnerable to cancer and other chronic diseases.

However, we now know there are powerful strategies that can repair and improve the health of your mitochondria.

What I believe to be the most valuable strategy for repairing your mitochondria is the main subject of my newest book:
Fat for Fuel: A Revolutionary Diet to Combat Cancer, Boost Brain Power, and Increase Your Energy.

You see, everything you eat affects your mitochondria – positively or negatively.

When you make food choices that boost your mitochondrial health, you reduce the risk of damage to your cells’ genetic material or DNA that can lead to disease or cancer.

In Fat for Fuel, here’s just a sampling of what you will learn:

  • How to trigger powerful changes in your health in just a few days
  • How to avoid feeding cancer cells’ mitochondria while repairing your healthy mitochondria
  • How to starve out cancer cells (and not harm your healthy cells!)
  • How to permanently shed unwanted pounds and inches faster than you ever thought possible
  • How to feel sharper mentally and improve your memory just by changing how and when you eat
  • How to boost your physical stamina and endurance
  • How to eliminate excessive hunger pangs and food cravings
  • How to explain to your friends, family, and doctor exactly what you’re doing and get their unwavering support
  • How to monitor your progress and find the least expensive supplies

Beyond Ketogenic Diets: The Eating Program That Can Heal Your Mitochondria

“A truly revolutionary program. . . Fat for Fuel will change the way you think about nutrition and your health.”

— Leo Galland, M.D.

Author of The Allergy Solution

Let me be very clear… you don’t need to be sick, overweight, or have cancer, heart disease or Alzheimer’s to benefit from the information in Fat for Fuel.

This book is designed for anyone wishing to improve his or her health. There’s tremendous value in repairing and nurturing damaged mitochondria just to feel more energetic and to help live a long life free from disease.

However, the sicker you are or the older you are (because you now have fewer mitochondria), the more you stand to benefit from the strategies I present in Fat for Fuel.

My program, Mitochondrial Metabolic Therapy, or MMT, is a system of eating that aims to heal the root cause of chronic disease and aging – and your mitochondria themselves.

MMT Benefits
Greater energy and stamina are just two benefits of MMT

It does this by shifting your metabolism from burning glucose as your primary fuel to burning fat instead.

When you replace carbs with fat for fuel, potentially:

  • You optimize your mitochondrial function
  • You turn on your body’s ability to burn body fat
  • Your metabolism runs more efficiently
  • You enjoy long-lasting energy and stamina
  • Your brain functions more efficiently and you feel sharper mentally

Glucose is a “dirty” fuel, while fat burns much cleaner. So by replacing carbs with healthy fats, your cells’ mitochondria are less likely to suffer damage from free radicals that are caused by reactive oxygen species or ROS.

Since 90 percent or more of the total ROS in your body are produced within your mitochondria, these fragile components of your cells are continually under siege when there are excessive ROS. Some are needed for crucial cellular functions, but too many cause devastating damage.

Previously, it was thought excessive ROS could be addressed by taking antioxidants, but we now know that this was a flawed strategy and it is far better to prevent their production by eating an optimal fuel mixture.

MMT can help your cells’ mitochondria reach the “Goldilocks” zone for producing ROS — not too much and not too little, but just the “right” amounts for healthy cellular and mitochondrial function.

Why You Need Mitochondrial Metabolic Therapy (MMT)

What many people may not realize is that switching over to fat-burning is not an instantaneous “aha” moment. Nor is it a one-size-fits-all plan.

That may be why, if you’ve ever tried a ketogenic diet, you weren’t able to reach or remain in ketosis long enough to produce significant health effects.

My MMT program is a highly customizable, multi-step process that can take a few days or as long as a few months to become fully fat-adapted. Everyone is different.

Fat for Fuel walks you through the complete step-by-step process. You learn which foods and practices work best for you.

My goal is to help you get there smoothly and as easily as possible, identifying and removing potential challenges ahead of time that can derail you off course.
 

Ketogenic Diet Plan
You’ll receive my step-by-step plan for reaching nutritional ketosis

Here are some of the valuable insights you’ll gain from Fat for Fuel to help you succeed:

  • The 7 most common symptoms to expect while shifting to fat burning and simple ways to ward them off
  • How to use timing and spacing of meals to propel your results
  • The weight loss bonus that will hook you in your first few days on MMT
  • How to overcome emotional roadblocks that may arise before and during MMT
  • One simple way to tell if you’re exercising too much (or too little) while adjusting to fat burning
  • The 7 most common challenges people face when adopting a fat-burning eating plan and how to face them head on
  • How to customize MMT for you so you’ll want to continue it for life (although you’ll most likely be convinced that long-term is for you once you experience how much better you feel when eating this way!)
  • Why your brain loves ketones (Hint: it has to do with how easily they are whisked across your blood-brain barrier into your brain tissue)
  • Why it’s easier to lose weight on a ketogenic diet (and especially my MMT plan) and keep it off
  • The greatest tool I’ve found to help keep on track, pinpoint nutritional deficiencies in my diet – and to stay motivated
  • The effective and inexpensive long-term alternative to blood tests for monitoring ketones
  • My guidelines for long-term optimum fat-burning, including the ideal amount of protein to eat at any meal to avoid activating mTOR
  • The other side of eating that most people ignore, yet it’s equally important for your body to function at its best (it happens to be the oldest dietary intervention in the world!)
  • Why taking too many antioxidants can be dangerous and actually aid the survival of cancer cells
  • The popular cooking oils that can harm your cell membranes and threaten your mitochondrial health
  • Why it may be a big mistake to follow your conventional doctor’s advice about fat in your diet

Why MMT Is One Of The Most Powerful Strategies For Lasting Weight Loss And Much More…

“Beautifully lays out the history—and the myths—behind the high-carbohydrate, low-fat diet that has been at the root of so much illness and death in the last half-century.”

— Ron Rosedale, M.D.

Weight Loss
Your waistline measurement is your greatest gauge of health

As a healthy child, you had healthy metabolic flexibility. When you ate a limited amount of sugar and net carbs (carbs minus the fiber) and greater amounts of healthy fat, you were easily able to burn clean burning fats as your primary fuel.

After eating a high net-carb diet, your body loses its ability to switch effortlessly from glucose-burning to fat-burning. And, if you’re like the majority of adults, your health — especially your metabolic health — has suffered as a result.
One visual gauge of your current metabolic health is the amount of body fat you’re carrying, especially around your waistline. This is largely unhealthy visceral fat.

You need a certain amount of body fat to protect your organs, but too much puts you at higher risk for chronic diseases like cancer, diabetes and heart disease.

By making MMT part of your everyday life, you can regain that long-lost metabolic advantage. And that puts you squarely into control of your health – and weight – like no other step you could possibly take!

Similar to a ketogenic diet, MMT is a high-fat, low-carb, and moderate-protein eating plan. But unlike a ketogenic diet, it emphasizes on high-quality, unprocessed whole foods.

Since your body was designed to run more efficiently on fats than on carbs, when you successfully shift over to what’s called nutritional ketosis, you optimize your mitochondrial function and your body’s ability to burn body fat.

While fitting into your favorite skinny jeans is certainly a valuable side effect of MMT, my plan’s primary aim goes much deeper – to heal your metabolism at the cellular level and ward off the development of most common chronic diseases and premature aging, including:

  • Cancer
  • Type 2 diabetes
  • Alzheimer’s disease
  • Parkinson’s disease
  • Atherosclerosis and heart disease
  • Cataracts

And of course, that includes the core causes of obesity!

Please Don’t Confuse Paleo With My Advanced Version Of Ketogenic…

Meat Protein
Paleo promotes far too much protein

Paleo diets are one of the hottest eating trends today. Many people claim eating that way helps them feel more energetic. Others swear by them for weight loss.

But it’s not the same thing as MMT…

While there are many advantages to the Paleo diet – it’s certainly a big step above the typical American diet – it doesn’t initially control net carbs.

Paleo restricts grains, dairy, starches, and processed foods, but the diet allows some starchy vegetables, fruits, and sugars like honey and coconut sugar.

And it encourages protein from meat, seafood, and nuts and seeds – lots of it! Many people who follow the Paleo diet consume far too much protein.

Too much sugar and too much protein can make it impossible to maintain a state of ketosis, especially if you are new to nutritional ketosis.

Eating too much protein can also activate your body’s most important signaling pathway – mTOR, or the mammalian target of rapamycin – and boost your risk of cancer. Your mTOR pathway organizes all the nutrient sensors in your body to regulate metabolism, growth, cell differentiation, and cellular survival.

Researchers have discovered that low-protein diets extend lifespan in flies because they improve mitochondrial function and inhibit mTOR.

MMT or my version of the ketogenic diet provides very precise protein recommendations to help avoid activating mTOR and, at the same time, restore health to your mitochondria.

With the guidance I provide in Fat for Fuel, you’ll know how to determine the exact amount of protein that’s right for you!

Just As Important As What You Eat Is What You Don’t Eat

“Fat for Fuel . . . reveals truths the food industry won’t tell you about the food you eat and starts you on a path to radically transforming your health.”

— Mark Hyman, M.D.

#1 New York Times best-selling author of Eat Fat, Get Thin and
director of the Cleveland Clinic’s Center for Functional Medicine

Water Fasting
If water fasts aren’t for you, I introduce you to 5 other types of fasts in Fat for Fuel

Sometimes we get so wrapped up in what we should eat that it’s easy to forget the other side that’s equally important for your mitochondrial health. And that’s not eating.

Consider your early ancestors… They didn’t have ready access to food 24 hours a day, 7 days a week. Instead, they evolved to withstand extended periods without food. You and I are here today, so they obviously thrived.

Could your body perhaps be equipped to function optimally by not eating?

Fasting can rapidly accelerate your transition to fat-burning and immediately begin to improve metabolic pathways involved with many health challenges.

Think of it as a jump start to success… Starting MMT when you’re already adapted to burning fat through fasting makes your eating plan much easier to implement and stick with.

Fasting also provides numerous benefits in itself. When you fast, your:

  • Blood sugar stabilizes
  • Insulin levels fall and insulin resistance improves
  • Digestive tract gets to rest and repair its mucosal lining
  • Immune system participates in the regeneration of your body’s organs
  • Stem cells produce new white blood cells to boost immunity
  • Body produces ketones to fuel your brain and nervous system while preserving muscle mass
  • Metabolic rate increases to provide energy in the absence of food
  • Damaged cells are cleared out through a natural cleansing routine
  • Excess body fat is shed without the loss of lean body mass
  • Levels of pro-inflammatory cytokines and cancer-promoting hormones drop
  • Rate of aging slows as does the accumulation of cellular free radicals
  • Brain function is protected by higher levels of brain-derived neurotropic factor (BDNF) and other chemicals

Your Biggest Decision Likely Won’t Be If You’ll Fast, It’ll Be Which Fast Will You Choose?

Working Out
Want to kick-start your results? Choose one of my fasts

I think you’ll agree that fasting provides an exceptional way to jump-start your mitochondria and become fat-adapted in as short a time as possible, and start reaping the many benefits of fat burning.

You can do a traditional 2- to 3-day water fast where you drink nothing but water plus minerals, or you can take your pick of at least 5 other types of fasts to make the transition to fat-burning even easier.

You’ll find detailed information about each type of fast in Fat for Fuel, including:

  • How to find the “right” fast for you
  • The fast that burns through your glycogen stores the quickest and pushes your body to start using fat for energy (You’ll want this one if you’ve just received a very serious diagnosis)
  • How to get the benefits of water fasting without the typical loss of energy
  • How to quickly shed your cravings for sweets and carbs while fasting
  • How to optimize your body’s repair and rejuvenation processes
  • How to use timing to reap many of the same benefits as long-term calorie restriction without the pain, suffering, and compliance challenges
  • How to know if fasting is safe for you (Especially if you have low blood pressure, thyroid disease, diabetes, cardiovascular disease, or are taking diuretics or blood pressure medications)
  • The fast where you’re still eating food (This may be a tougher approach!)
  • What you need to know about exercising while fasting
  • How to fast without upsetting your body’s circadian rhythm
  • A quick trick to help extend your fast while warding off your hunger without raising your blood sugar (Many will enjoy this taste treat!)
  • The 3-hour window when you never want to eat (To help optimize your mitochondrial function and prevent cellular damage and faster aging)
  • My favorite form of fasting – and the one I personally use (It’s the easiest to maintain once you’ve shifted over to fat-burning)

Is There Life After MMT?

Healthy Diet
Once you regain the ability to burn fat as your primary fuel you’re ready for more variety in your diet

As I show in Fat for Fuel, switching to burning fat as your primary fuel is a very powerful strategy for improving the health of your mitochondria, and in turn, your overall health.

But maybe you’re wondering, “Do I have to eat this way for the rest of my life?”

The short answer is, no you do not. In fact, I don’t want you to.

In Fat for Fuel, I help you determine how long is enough for you based on your genetic and mitochondrial differences, as well as any hormonal challenges you may have.

MMT is not intended to be a long-term deprivation diet. Once you regain the ability to burn fat as your primary fuel you’re ready to listen to your body and increase the flexibility in your diet.

By mimicking the eating pattern of many of our ancient ancestors, you can use what I call “feast-famine cycling,” a strategy that many in the body-building community have embraced to optimize their performance.

There are multiple ways to use this clever strategy and I review them all in Fat for Fuel. When done correctly, you’ll enjoy a greater variety of delicious, wholesome foods without harming your body’s newly regained ability to burn fat.

And I think you’ll agree… With greater variety and flexibility, it’s much easier to stick to a lifetime of healthy eating!

The Stealth Threat Facing Every Man And Postmenopausal Woman, Exposing You To Obesity, Cancer, Cognitive Decline, And Heart Disease

Weight Management
If you struggle with weight issues, excess iron may be a factor

My MMT Program helps control the production of damaging ROS and secondary free radicals in three important ways. The first two are the foods you eat and when you eat them.

The third is such a serious threat to overall health that it absolutely astounds me that more doctors aren’t giving it the attention it deserves, including many holistic practitioners.

This threat targets every single man and postmenopausal woman, and it isn’t related to a reckless lifestyle or poor eating habits.

You could even be following my MMT eating plan and be at high risk for this health-wrecking threat!

I’m talking about iron.

Excess iron can lead to one of the most dangerous reactions in your body — the Fenton reaction — that decimates your mitochondrial DNA, proteins, and membranes and contributes to system-wide inflammation.

And all you may initially notice is some joint pain, fatigue, gut pain, memory fog, or an irregular heartbeat!

Even moderately elevated levels of iron can contribute to:

  • Obesity — Obese individuals are more likely to have high levels of iron in their bodies.
  • Cancer — Elevated levels of iron are found in patients with many types of cancer, including breast cancer, melanoma, pancreatic cancer, renal cell carcinoma, and Hodgkin’s lymphoma.
  • Alzheimer’s, Parkinson’s and ALS — High levels of iron in your brain tissue (which can easily happen as you age) can lead to cognitive impairment and inflammation.
  • Cardiovascular disease — Women’s risk of heart disease rises significantly after they either go through menopause or have a hysterectomy (and stop losing blood each month through menses).
  • Diabetes — Men with high iron stores were found to be 2.4 times as likely to develop Type 2 diabetes as men with lower levels.
  • The growth of pathogens — High iron levels facilitate the growth of disease-causing bacteria, fungi, and protozoa.
  • Osteoporosis — Too much iron in your body can damage your bones, but unfortunately, symptoms don’t typically appear until your levels are dangerously high.

What You Learn About Iron In Fat For Fuel Could Literally Save Your Life

Iron Test
Serum iron tests won’t tell you if there’s a problem

Many doctors, including some Naturopathic physicians, aren’t doing the right test to give you the information you need about your iron levels.

Yet, they’ll insist they know best, and may even try to talk you out of the test you really need.

It’s much easier to manage your situation if you discover your high levels early, which is just one of the reasons why I’ve become so passionate about this topic.

Fat for Fuel is your guide to repairing and nourishing your mitochondria. But, you simply can’t optimize your mitochondrial health – or that of your entire body – if you have excess iron.

I’ve dedicated an entire chapter to the topic of excess iron, where you’ll learn:

  • The real test that you need to find out how high your levels truly are
  • The ideal range you want to maintain (it’s not what labs and most doctors consider “normal”)
  • The 7 things that increase your absorption of iron (it’s not only cast iron pans)
  • What to avoid eating or drinking with a steak to minimize your absorption of iron from red meat
  • The fastest way to lower excess iron levels (and what I do each month to help maintain safe low levels)
  • The 6 alternative strategies that can lower your absorption of iron as much as 95 percent
  • The 3 popular beverages that help protect you from the iron in foods
  • When never to take vitamin C or calcium supplements as they can increase your absorption of unwanted iron
  • The controversial strategy that provides the same iron level reduction as donating blood (it even provides up to a 75 percent lower rate of certain cancers), but it may not be for everyone

Your iron levels are so crucial, I’ve made getting them tested the right way a prerequisite before proceeding with my MMT plan!

10 Bonus Strategies To Boost Your Mitochondrial Health

Healthy Mitochondria
Diet isn’t the only way to improve the health of your mitochondria

Without question, my MMT diet is the most effective way to improve the health of your mitochondria. But it’s not the only way…

In Fat for Fuel, I outline 10 other powerful strategies for boosting mitochondrial health. At least half of them you can do at home without any special tools or equipment!

In this bonus chapter, I show you:

  • How to use photobiology to create energy to improve your mitochondrial function (first, make sure your cells have enough of this beneficial fatty acid)
  • The two-part strategy to gain a powerful synergy that could help reverse any health challenge
  • How to use light to deeply penetrate your tissues to deliver energy to your mitochondria for increased ATP production (it must be this certain hard-to-find wavelength!)
  • How to renew damaged proteins inside your cells, inside of allowing them to accumulate and form plaque deposits in your brain and vascular systems
  • The inexpensive tool to help protect your circadian rhythms and natural melatonin production to help you sleep better at night and help lower your cancer risk
  • The simple change you can make in your home to nearly duplicate the sun’s healthy, natural lighting for your eye health
  • What to do if you wake up before sunrise, especially during the darker months of winter (and continue to do it until the sun rises)
  • How to stimulate the production of new mitochondria and boost the destruction of diseased ones
  • The 20-second trick to double your body’s production of norepinephrine for improved focus and attention and to boost mood and alleviate pain
  • The four supplements to avoid if you have (or suspect) cancer as they can make cancer cells stronger and more resistant to anti-cancer treatment (this is a mistake many natural medicine practitioners make!)
  • The ancient healing method that’s been shown to be useful in treating pain conditions, depression, age-related mental decline, and Alzheimer’s (I use it every night to help quell free radicals and protect against EMFs)
  • Two ways to help your body increase levels of healthier “structured” water inside your cells and two simple ways to create it yourself from regular drinking water

Why My Book May Not Be For Everyone

Is Fat for Fuel for You
Is Fat for Fuel for you?

Chances are if you’re still reading this, Fat for Fuel is exactly what you need to make significant strides in your health.

But I’ll be very blunt… Fat for Fuel isn’t for everyone.

If all you want are some smart but quick fixes, this is not the right book for you.

If you just want to upgrade your nutrition and improve your eating habits and overall health with small, simple tweaks to what you’re doing now, you may be better served by my last book Effortless Healing.

Effortless Healing walks you through nine powerful principles or steps that you can apply right away to your daily life to create healthy new habits and radically improved health.

Or you can go to Mercola.com and review the Nutritional Plan on the right side of the home page. Here you’ll find plenty of useful information, and if you sign up for my free newsletter, you’ll receive regular cutting edge health updates.

Fat for Fuel digs deeper – much deeper – into the very source of cancer, obesity, diabetes, mental decline and other chronic diseases that are affecting Westerners especially in epidemic numbers.

And it provides a real solution that works.

However, you’ll have to do more than just read the book… Getting the amazing benefits and results that my MMT plan offers takes a focused commitment and action.

Is Fat For Fuel For You?

“This book should be read by anyone interested in maintaining their health without toxic pharmaceuticals.”

— Thomas Seyfried, Ph.D.

Author of Cancer as a Metabolic Disease and professor of biology at Boston College

To help you decide if Fat for Fuel: A Revolutionary Diet to Combat Cancer, Boost Brain Power, and Increase Your Energy is right for you, take a moment and see if any of these statements resonate with you:

  • You have a serious health issue and need effective help now
  • You’re frustrated with your current health treatments and feel like there’s something missing in your care
  • You’d like to see a chronic condition ease up or disappear entirely (be sure to work with your health care provider as you may need to reduce or eliminate medications as your health improves!)
  • You want to lose weight (and keep it off) without sacrificing lean muscle mass
  • You’d like to get rid of your “brain fog” and enjoy greater mental clarity
  • You want to stay healthy and live independently for as long as possible
  • You’d like more sustained energy for everyday tasks and for the things you enjoy doing
  • You need to lower your fasting blood glucose levels, regain insulin receptor sensitivity and reduce inflammation throughout your body
  • You’ve dabbled with a low carb or ketogenic diet and would like to learn how to customize it for real results
  • You’re following a ketogenic, low carb or whole foods diet now and want to take it to the next level
  • You’d like to go through your day without feeling excessively hungry and craving sweets and carbs
  • You want to experience improved digestion, less bloating and reflux, and more regular bowel movements (a 2016 autism study confirms that you may notice significantly improved gut and microbiome health)

If you agree with just one of these statements, then I can assure you there is solid value waiting for you within the covers of Fat for Fuel.

Dr. Perlmutter Praises Fat For Fuel

Dr. David Perlmutter, board-certified neurologist and author of the #1 New York Times bestseller Grain Brain and The Grain Brain Whole Life Plan has provided his endorsement to Fat for Fuel. He states:

“…Fat for Fuel eloquently presents the leading edge of science, exploring how best to power your body. This is a life-changing text that not only provides a deep dive into why choosing fat as our primary fuel source powerfully correlates with health and disease resistance, but also delivers in terms of how the reader can easily bring about this fundamentally important change.”

Get Rewarded When You Take Action Now

Maybe you feel like you have time to wait before making profound changes to your health. Or maybe you don’t.

Either way, I believe in rewarding action.

The strategies I present in Fat for Fuel: A Revolutionary Diet to Combat Cancer, Boost Brain Power, and Increase Your Energy are just too important for your health and well-being to set aside and “wait until the timing feels right.”

You’re growing older each day. Your body is producing fewer mitochondria, so that puts you at a disadvantage right from the gate. Time really may not be on your side.

http://www.fatforfuel.org/?utm_source=Newsletter&utm_campaign=71168fc8de-EMAIL_CAMPAIGN_2017_05_04&utm_medium=email&utm_term=0_07a277e311-71168fc8de-103250557&mc_cid=71168fc8de&mc_eid=e7144aecc8

Muscle Enzyme Explains Weight Gain in Middle Age, Cancer and Aging

By Dr. Francis Collins

The struggle to maintain a healthy weight is a lifelong challenge for many of us. In fact, the average American packs on an extra 30 pounds from early adulthood to age 50. What’s responsible for this tendency toward middle-age spread? For most of us, too many calories and too little exercise definitely play a role. But now comes word that another reason may lie in a strong—and previously unknown—biochemical mechanism related to the normal aging process.

An NIH-led team recently discovered that the normal process of aging causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies show it also slows down metabolism, making it more difficult to burn fat. To see if reducing DNA-PK levels might rev up the metabolism, the researchers turned to middle-aged mice. They found that a drug-like compound that blocked DNA-PK activity cut weight gain in the mice by a whopping 40 percent!

met.JPG

Jay H. Chung, an intramural researcher with NIH’s National Heart, Lung, and Blood Institute, had always wondered why many middle-aged people and animals gain weight even when they eat less. To explain this paradox, his team looked to biochemical changes in the skeletal muscles of middle-aged mice and rhesus macaques, whose stage in life would be roughly equivalent to a 45-year-old person.

Their studies, published recently in Cell Metabolism, uncovered evidence in both species that DNA-PK increases in skeletal muscle with age [1]. The discovery proved intriguing because the enzyme’s role in aging was completely unknown. DNA-PK was actually pretty famous for a totally different role in DNA repair, specifically its promotion of splicing the DNA of developing white blood cells called lymphocytes. In fact, lymphocytes fail to mature in mice without a working copy of the enzyme, causing a devastating immune disorder known as severe combined immunodeficiency (SCID).

Further study by Chung’s team showed that DNA-PK in the muscle acted as a brake that gradually slows down metabolism. The researchers found in these muscle cells that DNA-PK decreases the capacity of the mitochondria, the powerhouses that burn fat for energy. The enzyme also causes a decline in the number of mitochondria in these cells.

The researchers suspected that an increase in DNA-PK in middle age might lead directly to weight gain. If correct, then blocking the enzyme should have the opposite effect and help stop these mice from piling on the pounds.

Indeed, it did. When the researchers treated obese mice with a drug called a DNA-PK inhibitor, they gained considerably less weight while fed a high-fat diet. The treatment also protected the animals from developing early signs of diabetes, which is associated with obesity. Fortunately, there was no sign of trouble in the immune systems of middle-aged mice treated with the DNA-PK inhibitor, presumably because those essential DNA splicing events in lymphocytes had already occurred. Neither was there a sign of serious side effects, such as cancer.

As people age and their weight increases, they also tend to become less physically fit. The new evidence implicates DNA-PK in that process, too. Obese and middle-aged mice treated with the DNA-PK inhibitor showed increased running endurance. With treatment, they ran about twice as long on a tiny mouse treadmill than they would normally.

While the findings are in mice, they suggest that an increase in DNA-PK could explain why it becomes so frustratingly difficult for many of us to stay lean and fit as we age.

It also paves the way for the development of a new kind of weight-loss medication designed to target this specific biochemical change that comes with middle age.

Chung says they are now looking for DNA-PK inhibitors that might work even better than the one in this study. But given the fact that DNA-PK has other roles, testing its safety and effectiveness will take time.

While we await the results, the best course to help fight that middle-age spread hasn’t changed. Eat right and follow an exercise plan that you know you can stick to—it will make you feel better. Take it from me, a guy who decided eight years ago that it was time to shape up, stopped eating honey buns, got into a regular exercise program with a trainer to keep me accountable, and lost those 30 pounds. You can do it, even without a DNA-PK inhibitor!

Reference:

[1] DNA-PK promotes the mitochondrial, metabolic, and physical decline that occurs during aging. Park SJ, Gavrilova O, Brown AL, Soto JE, Bremner S, Kim J, Xu X, Yang S, Um JH, Koch LG, Britton SL, Lieber RL, Philp A, Baar K, Kohama SG, Abel ED, Kim MK, Chung JH. Cell Metab. 2017 May 2;25(5):1135-1146.

Links:

Overweight and Obesity (National Heart, Lung, and Blood Institute/NIH)

Health Tips for Older Adults (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Jay H. Chung (National Heart, Lung, and Blood Institute/NIH)

NIH Support: National Heart, Lung, and Blood Institute; Office of the Director


From wiki

DNA damage appears to be the primary underlying cause of cancer,[8][9] and deficiencies in DNA repair genes likely underlie many forms of cancer.[10][11] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[12][13] Such mutations and epigenetic alterations may give rise to cancer.

PRKDC (DNA-PKcs) mutations were found in 3 out of 10 of endometriosis-associated ovarian cancers, as well as in the field defects from which they arose.[14] They were also found in 10% of breast and pancreatic cancers.[15]

Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily even more frequent than mutational defects in DNA repair genes in cancers.[16]

DNA-PKcs expression was reduced by 23% to 57% in six cancers as indicated in the table.

Frequency of reduced expression of DNA-PKcs in sporadic cancers

Cancer Frequency of reduction in cancer Ref.
Breast cancer 57% [17]
Prostate cancer 51% [18]
Cervical carcinoma 32% [19]
Nasopharyngeal carcinoma 30% [20]
Epithelial ovarian cancer 29% [21]
Gastric cancer 23% [22]

It is not clear what causes reduced expression of DNA-PKcs in cancers. MicroRNA-101 targets DNA-PKcs via binding to the 3′- UTR of DNA-PKcs mRNA and efficiently reduces protein levels of DNA-PKcs.[23] But miR-101 is more often decreased in cancers, rather than increased.[24][25]

HMGA2 protein could also have an effect on DNA-PKcs. HMGA2 delays the release of DNA-PKcs from sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing chromosomal aberrations.[26] The let-7a microRNA normally represses the HMGA2 gene.[27][28]

In normal adult tissues, almost no HMGA2 protein is present. In many cancers, let-7 microRNA is repressed.

As an example, in breast cancers the promoter region controlling let-7a-3/let-7b microRNA is frequently repressed by hypermethylation.[29] Epigenetic reduction or absence of let-7a microRNA allows high expression of the HMGA2 protein and this would lead to defective expression of DNA-PKcs.

DNA-PKcs can be up-regulated by stressful conditions such as in Helicobacter pylori-associated gastritis.[30] After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma tissues.[31]

The ATM protein is important in homologous recombinational repair (HRR) of DNA double strand breaks. When cancer cells are deficient in ATM the cells are “addicted” to DNA-PKcs, important in the alternative DNA repair pathway for double-strand breaks, non-homologous end joining (NHEJ).[32] That is, in ATM-mutant cells, an inhibitor of DNA-PKcs causes high levels of apoptotic cell death. In ATM mutant cells, additional loss of DNA-PKcs leaves the cells without either major pathway (HRR and NHEJ) for repair of DNA double-strand breaks.

Elevated DNA-PKcs expression is found in a large fraction (40% to 90%) of some cancers (the remaining fraction of cancers often has reduced or absent expression of DNA-PKcs). The elevation of DNA-PKcs is thought to reflect the induction of a compensatory DNA repair capability, due to the genome instability in these cancers.[33](As indicated in the article Genome instability, such genome instability may be due to deficiencies in other DNA repair genes present in the cancers.)

Elevated DNA-PKcs is thought to be “beneficial to the tumor cells”,[33] though it would be at the expense of the patient.

As indicated in a table listing 12 types of cancer reported in 20 publications,[33] the fraction of cancers with over-expression of DNA-PKcs is often associated with an advanced stage of the cancer and shorter survival time for the patient. However, the table also indicates that for some cancers, the fraction of cancers with reduced or absent DNA-PKcs is also associated with advanced stage and poor patient survival.

Aging

Non-homologous end joining (NHEJ) is the principal DNA repair process used by mammalian somatic cells to cope with double-strand breaks that continually occur in the genome.

DNA-PKcs is one of the key components of the NHEJ machinery. DNA-PKcs deficient mice have a shorter lifespan and show an earlier onset of numerous aging related pathologies than corresponding wild-type littermates.[34][35]

These findings suggest that failure to efficiently repair DNA double-strand breaks results in premature aging, consistent with the DNA damage theory of aging. (See also Bernstein et al.[36])

————

Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.

MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E).
  • Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4.
  • Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex.
  • Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1.

To maintain energy homeostasis,  mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A.

  • mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at ‘Ser-758’, disrupting the interaction with AMPK and preventing activation of ULK1.
  • Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP.
  • mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor.
Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at ‘Ser-473’ of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at ‘Ser-422’. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity).

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

  • Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1.
  • Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1.
  • Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906).
On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity.
  • mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.8 Publications

GO – Molecular functioni

GO – Biological processi