2013年有关衰老的重要的12个问题的研究进展(下)

7. Taking a multivitamin supplement does not help prevent cognitive decline in normal healthy adults, but may prevent cognitive decline in the elderly who have depression

 Two major publication evaluating the benefits of a multivitamin supplement on cognitive health have been published in the past two years (one was actually before 2013, but I will include it here). The first study looked at the use of oral folic acid + Vit B12 supplements for the prevention of cognitive decline in older adults aged 60-74 years who had symptoms of depression (Walker, 2012). The primary purpose of supplementation was to see if the folic acid and Vit B12 could prevent cognitive decline in this “at risk” group. The study was a randomized, prospective, placebo controlled study in 900 elderly patients and for this reason, should be taken seriously. The results showed that folic acid and Vit B12 significantly reduced cognitive decline over a two-year follow-up period by 17-18% (p = 0.04 and p = 0.01). This data is consistent with previous reports of folic acid and Vit B12 for these patients.

The 2^nd major study evaluated the benefits of a multivitamin on the prevention of cognitive decline in normal, healthy male physicians. It was published online in the December 16 issue of the Annals of Internal Medicine. (Grodstein, 2013). This study was very significant since it was a prospective, placebo-controlled randomized study and was conducted for 12 years in a group of almost 6,000 doctors aged 65 and older.  The study randomized the volunteers into a placebo vitamin supplement vs a real multivitamin. All volunteers underwent validated memory testing.  At the end of 12 years, there was no effect of the multivitamin in preventing cognitive decline.  As a result, the authors, led by Dr. Francine Grodstein of Harvard’s School of Public Health, stated that “this data does not support the use of multivitamin supplements in the prevention of cognitive decline”.  It should be noted that this study only looked at cognitive memory testing and not actually the development of dementia. This was very disappointing results, but the study had very few flaws that could be used to discredit it.  As predicted, the supplement manufacturers and the Big Pharma both slammed this study as well, since it reduced the sales of supplements by both industries. (Big Pharma actually manufactures as many supplements as the “supplement industry”, even though the “supplement industry” likes to rail against the Big Pharma drug manufacturers).  Keep in mind, however, that neither the supplement industry or Big Pharma have been willing to fund studies to counter the scientific conclusions of these papers.

8. Multivitamins reduce cancer risk in males but do not reduce cancer mortality.   — Multivitamins may or may not reduce breast cancer risk in females, but eating fruits and vegetables dramatically reduces your risk of cancer in males and females

Prior studies of multivitamins and cancer risk

Prior to 2013, no large-scale, prospective, randomized placebo controlled study of multivitamins for cancer risk reduction had been conducted in the United States. Previous studies were small studies, studies done in other countries, or epidemiologic studies (which are not randomized, blinded, or placebo controlled). The largest US epidemiologic study on multivitamins and cancer risk was the  Multiethnic Cohort Study (MEC Study) in the US that involved 215,000 people. The MEC looked at the benefit of multivitamin supplements for cancer risk reduction and showed no benefit. (Park, 2011).  The largest randomized study previously reported was an old study conducted in Linxian, China in 1993. Linxian has the world’s highest rates of esophageal/gastric cardia cancer. As a result, death rates from this type of cancer are higher than any other cause of death in Linxian (32% of all deaths are due to esophageal/gastric junction cancer. 2^nd highest cause of death is cerebrovascular disease at 25%).  In the Linxian study, the researchers were able to show that a mixture of β-carotene, Vitamin E, and selenium reduced cancer rates by 13% and cancer mortality by 9%.  In the Linxian study, no reduction in cancer risk was shown with retinol, zinc, riboflavin, niacin, Vitamin C, or molybdenum supplementation  (Blot, 1993). The US population in no way resembles the Linxian population, however, since the rates of esophageal/gastric junction cancer are very low in the US.

Multivitamins for cancer risk reduction in males: new data from 2013

With this in mind, the first major report in 2013 regarding cancer prevention with multivitamins was published in May of 2013. (Gaziano, 2013).  This was a report summarizing the Physicians Health Study II (PHSII). PHSII was an 11-year, randomized controlled study comparing a multivitamin (Centrum Silver, Pfizer) to a placebo in 14,641 male physicians.  The cardiovascular risk outcome was previously reported and described above (Sesso, 2012). The PHS II study was very well designed, with a 12 week placebo run-in period that eliminated non-compliant volunteers.  It also stratified participants in the Centrum Silver group and the placebo group to make sure there was a balance in equal age, prior cancer, cardiovascular disease, etc. The study was not sponsored by Pfizer and Pfizer had no say-so in the design or administration of the clinical trial.  The primary endpoints were total cancer incidence and major cardiovascular events. All cancer diagnoses were confirmed by pathology report. The median follow-up time was 11.2 years, with 99% follow-up for cancer mortality. The results of the study showed a statistically significant reduction in total cancer incidence (Hazard ratio = 0.92) and total epithelial cell cancer incidence (HR = 0.92). However, the Centrum Silver multivitamins did not reduce cancer mortality or reduce cardiovascular mortality over the 11 year clinical trial period.

In summary, this is the only large prospective study that shows much benefit for the use of multivitamins. Even here, the benefit is very small and only a fraction of the benefit that could be obtained from eating lots of fruits and vegetables (multivitamin = 8% risk reduction in cancer incidence; high fruit & vegetable intake = 20-30% risk reduction in cancer incidence).

Folate, B-vitamins, and Methionine for breast cancer risk reduction in females: new data in 2013

Two small epidemiologic studies were reported in 2013 that looked at folic acid, B vitamins, and methionine and the risk of cancer. The first report in 2013 was a study in 2,325 Hispanic females, where they looked at their dietary intake of folic acid, B Vitamins (B₂, B₆, B₁₂), and methionine. Although there was no overall association with breast cancer, those that took the most folic acid, B vitamins, and methionine had a lower risk of breast cancer (Yang, 2013).

The 2^nd report in 2013 was done by a different group of researchers and looked at the risk of breast cancer in African American females and females of European descent (Gong, 2013).

For African American females, there was a significant correlation between dietary folic acid intake and a risk reduction in premenopausal breast cancer as well as in post menopausal ER+ breast cancer. For American females of European descent, there was no correlation between breast cancer and dietary folate. (Instead, there was a very small increased risk of breast cancer in those that took synthetic folate supplements).

Old data on dietary folate consumption vs folate supplements and breast cancer risk

 Previous studies (before 2013) have shown inconsistent results. Some thought that dietary folate consumption reduces breast cancer risk (Shrubsole, 2001)(Maruti, 2009). Other studies have shown no reduction in breast cancer risk with dietary folate consumption (Rohan, 2000). One of the largest studies looking at this association was the Prostate, Lung, Colorectal, and Ovarian cancer screening trial, which looked at 25,400 women and their folate consumption over 10 years. This study showed an 19% increased risk of breast cancer with folic acid supplements but no increased risk with dietary folic acid intake (Stolzenberg-Solomon, 2006). In summary, the data keeps saying the same thing – dietary folic acid is good for you, but taking folic acid supplements may not have any benefit or may even be dangerous.

Older studies (prior to 2013) of multivitamin supplements and breast cancer risk

There have been several older studies published prior to 2013 that looked at multivitamin supplementation and cancer risk. Some show an increased risk of breast cancer with multivitamin supplement use by as much as 19-33% (Ewertz 1990), (Stolzenberg-Solomon, 2006). Other studies have shown no increase in breast cancer risk or a decrease in breast cancer risk (Nagel, 2010)(Kushi, 1996). However, it should be pointed out that the risk factors of obesity, high fat diet, lack of exercise, high alcohol intake, smoking, and the practice of of estrogen and progesterone hormone replacement therapy in post menopausal breast cancer are so much larger risk factors for breast cancer that at this point, multivitamins are minor issues compared to the “big six” preventable risk factors for breast cancer, which would lower breast cancer risk by 13-23% (Wienecke, 2013)(Friedenreich, 2010).

9.   “Enough is Enough” – The case is closed on Multivitamin supplements

The three major papers mentioned above led to an Editorial that was published in the Annals of Internal Medicine on December 16, 2013 (Guallar, 2013).  Dr. Edgar Miller, co-author of the editorial and professor of medicine and epidemiology at Johns Hopkins School of Medicine stated that “We believe the case is closed – supplementing the diet of well-nurished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful”.  He went on to say that “vitamins should not be used for chronic disease prevention. Enough is enough”.  They went on to urge consumers to “stop wasting your money on multivitamins”. Instead, they recommended was that consumers spend their money on fruits, vegetables, nuts, beans, low fat dairy, and exercise; which have all been shown over and over and over again in scientific studies to be beneficial in preventing heart disease, cognitive decline, cancer, and recurrent heart attacks.  (Unfortunately, this is not what the American public want to hear).  As expected, this editorial was visciously attacked by the supplement industry.  Steve Mister, president and CEO of the supplement industry lobbying group called the Council for Responsible Nutrition said “It’s a shame for consumers that the authors refuse to recognized the real-life need for vitamin and mineral supplementation, living in a fairy-tale world that makes the inaccurate assumption that we’re all eating healthy diets and getting everything we need from food alone”.  Obviously Steve Mister did not read the recommendations of Dr. Edgar Miller – you CAN  get all that you need from food….you just have to start eating fruits, vegetables, nuts, and beans instead of pizza, French fries, and burgers!  In other words, what I am saying is that no vitamin or mineral will counter-act an unhealthy diet and no exercise.  In my opinion, the authors of these studies are right and Mr. Steve Mister is merely trying to defend his industry’s profits.

10.  James D Watson weighs in again with insights about cancer

The year 2013 opened with a controversial publication, written by a  “Hall of Famer “ in science, James D. Watson (who has also been controversial before).  Watson, Crick, and Wilkins won the Nobel Prize in 1962 for deciphering the molecular structure of DNA. For the past 50 years, Watson has been studying the genetics of cancer and is unquestionably a leading expert in this field.  In January, he published a paper entitled “Oxidants, antioxidants, and the current incurability of metastatic cancers”.    Among the many important messages is that Exogenous antioxidants may help cancer survive just as much as they may help you.

In this article, he discussed why science has not won the “War on Cancer”, which was officially started by President Nixon in December, 1971. Step-by-step, he explains the molecular reasons for this failure, and then outlines a plan of how we could “win the war”. In the article, he describes how only several hundred genes out of the 21,000 human genes account for cancer development by “driving” cell growth and division via growth-factor-induced signal transduction pathway up-regulation. This is accompanied by the evasion of programmed cell death (apoptosis resistance), which is the primary reason for why cancer cells are initially resistant to chemotherapy and radiation therapy.  Cross talk between these growth factor induced signal transduction pathways develop as more and more DNA mutations occur. This cross talk activates new signal transduction pathways when existing pathways are blocked by a single drug. (An example is the resistance that develops with melanoma against the drug Zelboraf, which blocks BRAF, yet cancers become resistant to it).  Another reason for drug resistance is due to changes in the epithelial-to-mesenchymal transition (EMT) that occurs with cancer due to the hypoxic surrounding environment, which induces the “VGEF/HIF-1α driver pathway” for EMT activation. It is this EMT activation that “drives” the development of “cancer mesenchymal cells” which have also been referred to as “cancer stem cells”. Activating the EMT allows cells to loose their attachments to surrounding cells and become free floating. As a result, they can invade and metastasize to a new location. Only when they move to these locations does cancer kill people.  This is central to the fundamental molecular biology of cancer.

Note that an evil role for hypoxia and HIF-1α comes up both here and in the inhibition of expression of mitochondrial proteins mentioned in the #1 item above in my 2013 list.  That is why I no longer believe in inducing hypoxia as a useful health-inducing hormetic intervention.  Vince and I are therefore now closing down the Hypoxia Bar described in our blog entry THE HORMESIS BARS.  It appears to be a public health menace.

The link between cancer and aging (and why Aspirin and other anti-inflammatories prevent cancer)

Watson then goes on to explain that while cancer biologist have mainly focused on the Wnt signaling pathway as the primary “early driver” of cancer. there is something else going on too..  Wnt drives β-catenin into the nucleus where it activates the transcription factor TCF to “turn on” the EMT.  Watson believes an “even more important villain than Wnt signaling has been virtually staring us in the face for two decades”. That “villain” is interleukin 6 (IL-6). IL-6 is the master cytokine mediator of inflammation and immunity. Recently, IL-6 has also been found to be the principle biomarker for cellular senescence.  Specifically, senescent cells secrete the senescence associated secretory phenotype (SASP), which is a group of over 70 cytokines secreted by senescent cells. This explains why the two phenomena, aging and cancer, are chronologically linked. IL-6 can generate paracrine and autocrine feedback loops, thereby activating nearby cells to become cancerous and self-activating the production of more IL-6.  This in turn induces apoptosis-resistance by blocking genes required for programmed cell death.  It is this IL-6 driven autocrine feedback loop that is blocked by anti-inflammatory drugs like aspirin, COX-2 inhibitors, as well as anti-immune drugs like rapamycin.  Thus, a simple way to win the war on cancer would be for everyone to block IL-6 driven signal transduction pathways, which occur early in cancer. These drugs block cell proliferation, not cell division (and are therefore not toxic like chemotherapy drugs that block cell division). This strategy is one Dr. Watson wholeheartedly supports. Thus, he points out preventing IL6-driven autocrine feedback loops is a major goal for cancer prevention

Why metabolic inhibitors can help us prevent or treat cancer

Dr. Watson then goes on to explain that cancer cells are running at high metabolic rates and are mostly dependent on aerobic glycolysis for generating ATP (i.e. the Warburg effect).  This two factors make cancer cells more vulnerable to metabolic inhibitors than normal cells. For this reason, he suggest that we simultaneously use hexokinase inhibitors (which block glycolysis) and mitochondrial inhibitors (which block oxidative phosphorylation).  Examples of this would be 3-Bromopyruvate, which block both hexokinase and OXPHOS, or combining 2-deoxyglucose (2DG) and Mito-Q. (2DG blocks hexokinase and Mito-Q blocks OXPHOS).  Metabolic inhibitors probably then block cancer via AMPK activation and mTOR inhibition.  This is one of the ways that metformin and rapamycin can be used for cancer. Dr. Watson wholeheartedly recommends metabolic inhibition as a way of winning the war on cancer.

There appears to be a contradiction between this recommendation and the suggestion in Story 1 above..  On the one hand, Sinclair et al suggests we want to maintain normal mitochondrial-based metabolism – and that evil and cancer occurs when pseudohypoxia results in such metabolism being blocked leading to glycolysis and the Warburg effect taking over.  On the other Hand, James D Watson here is suggesting that to treat cancers we block BOTH glycolysis and normal mitochondrial phosphorylation.  It appears that Sinclair wants to keep cells alive and Watson wants to suffocate them.  One way to reconcile this is to adopt the first strategy for healthy cells free of cancer and the second strategy once a cancer exists and where the Warburg effect is already operating,

How p53 over expression kills cancer cells by generating ROS

Dr. Watson then goes on to explain that most all effective strategies to kill cancer require increasing p53, which results in a ROS-mediated cell death. Almost all genotoxic chemotherapy drugs increase p53 in cancer cells. In cancers with a functional p53 signaling, this increases the expression of genes that control mitochondrial ROS production. As a result, chemotherapy increases ROS in cancer cells via a p53-mediated, mitochondrial mechanism, thereby causing ROS-induced cell death.  In cancers with a non-functional p53 pathway (due to p53 epigenetic silencing or mutations of the p53 gene), effective cancer therapies must directly induce ROS independently of p53. This is why Dr. Watson is “bullish” about the “first in class” ROS generating drug, Elesclomol, which induces ROS independently of p53.

Regardless of whether p53 is functional or non-functional in a cancer, the efficacy of chemotherapy and radiation can be abolished with anti-oxidants like N-acetylcysteine.  This has lead many scientists, including Dr. Watson, to enquire if resistant cancers produce their own endogenous antioxidants and if the use of exogenous anti-oxidant supplements were counterproductive. Today the evidence is quite strong – cancer cells do up regulate endogenous antioxidants via the Nrf2 pathway, which is the major reason why these anti-oxidant generating cells are resistant to chemotherapy. Even Elesclomol will not work in these cells.  Specifically, cancer cells up regulate the Nrf2 pathway when they are exposed to chemotherapy and radiation therapy.  Over-expression of both the RAS and MYC oncogenes in cancer results in up-regulation of Nrf2 because most cancer cells have multiple copies of RAS and MYC that are constitutively “turned on”.  This explains much of the confusion over the role of antioxidants in cancer prevention and why they don’t work (see “Top stories” item #8 above).  This understanding has solved a major mystery in cancer prevention that has not been previously explained well until Dr. Watson’s article.

Taking exogenous anti-oxidants just help cancer cells survive

All of the above molecular biology is NOT controversial and is well established scientific fact. What is controversial and new about this paper is that James Watson then suggests that “free radical destroying anti-oxidative nutritional supplements may have caused more cancers than they prevented.”  By making this statement, Dr. James Watson has again directly attacked the multi-billion dollar supplement industry that uses the term “antioxidant” as a marketing strategy to sell thousands of different kinds of supplements.  This attack has brought a lot of opposition from both the $30 billion dollar supplement industry and the $1.2 trillion dollar pharmaceutical industry that also sells multivitamins.  (In fact, Big Pharma probably produces more multivitamins than the supplement industry. They make all of the Centrum brand multivitamin supplements).  In publishing this paper, Dr. Watson has not suggested that we stop eating fruits and vegetables.  Instead, he has challenged the old rationale for eating fruits and vegetables – i.e. they are good for you because they are rich in “antioxidants”.  Watson’s paper has generated major backlash from even the nutritional sciences establishment.  Despite all this vitriol, the “nutrition establishment,” the supplement industry, and Big Pharma has not provided any good evidence to counter Watson’s views. For this reason, I listed this paper as #10 in my “top 10 list” for 2013.  This may end up being #1, ten years from now, however.

11. The only scientifically proven way to lengthen your telomeres is free!

 As most of you that read Vince Giuliano’s blogs know, there has been a great deal of interest in telomere lengthening as a way of living longer.  In 2013, a landmark study was published that unfortunately went largely unnoticed (Ornish, 2013).  In a paper published in August, 2013, Dean Ornish and Elizabeth Blackburn showed that you can lengthen telomeres by 10% over 5 years without pills by merely altering your diet, exercising, and managing your stress.  (Even the expensive astragalus supplement made by TA Sciences has been unable to lengthen telomeres.  It only reduces the rate of telomere shortening). Elizabeth Blackburn won the 2009 Nobel Prize with Carol Greider and Jack Szostack for discovering telomerease in tetrahymena.

(reference). I think she is a much more credible source of information than the astragalus supplement industry. In this small study, Dean Ornish put a group of elderly males with low grade prostate cancer on a diet that was low in fat (10% of calories), was plant-based (vegan), was high in whole grains, fruits, vegetables, legumes, and was low in refined carbohydrates. (They also had to take one serving of tofu per day and a soy protein powder drink, a selenium supplement, Vitamin C, fish oil, and Vitamin E). They also walked for 30 minutes a day, 6 days per week. The stress management, program including 60 minutes of yoga-based stretching, breathing, meditation, imagery, and progressive relaxation 6 days a week.  They also participated in a one hour support group once a week. The study was a 5-year prospective clinical trial with a control group who did not do the above. At the end of the clinical trial, telomere lengths were measured in blood leukocytes and noted to be 10% longer than at the beginning of the trial.  On the other hand, the control group had telomeres that were 3% shorter than at the beginning of the trial.  This is a remarkable study, considering that no prior study and no supplements have been shown to lengthen telomeres (only reduce the rate of shortening).  None of the above interventions are expensive and are not supplement based, except for the selenium, Vitamin C, fish oil, and Vitamin E. (Although it has been shown that exercise and fish oil can affect telomere length, the results of this trial cannot be explained by the fish oil supplements or exercise alone). The conclusion of this study is consistent with the scientific data that supports the idea that telomere length is NOT a biological clock that keeps accurate “biological age” but instead, telomere length is another measure of oxidative stress and that oxidative stress can be managed with lifestyle.

12. Consuming vegetables can impact breast cancer risk

This final story reporting new data from 2013 relates to breast cancer risk as associated with consumption of fruits and vegetables.  An analysis study called the Pooling Project of Prospective Studies of Diet and Cancer (Pooling Project) pools the data from multiple published prospective cohort studies. This analysis included the data from 20 studies that met all of the following criteria: At least one publication on any diet and cancer associations, a comprehensive assessment of dietary intake, validation of dietary intake, and stratification of the data by estrogen receptor positivity. This Pooling Project study specifically looked at the effects of fruits and vegetable intake and the risk of ER+ and ER- breast cancer in a pooled population of 993,466 females (Jung, 2013). The results showed no overall reduction in risk of breast cancer, but a statistically significant reduction in ER- breast cancer risk in those who ate vegetables, but no reduction in ER+ breast cancer risk and vegetable intake.  Fruit intake did not alter breast cancer risk for either ER+ and ER- subtypes. For the highest quartile of vegetable intake, there was an 18% reduction in the risk of ER- breast cancer (OR = 0.82) but not ER+ breast cancer (OR = 1.04).  In summary, this new 2013 paper suggests that vegetables reduce your risk of ER- breast cancers, but not ER+ breast cancer.  This is the first study that looked a breast cancer risk reduction separately for ER+ vs ER- cancers, which is a good idea, since the overwhelming “driver” of ER+ breast cancer is estrogen.  Thus, it would be difficult to show that fruits and vegetables made a huge difference in ER+ breast cancer. More importantly, this new data is consistent with what we know about other types of cancer and the benefits of eating fruits and vegetables.  Specifically, eating fruits and vegetables would reduce the risk of stomach cancer by 19%, the risk of esophageal cancer by 20%, the risk of lung cancer by 12%, and the risk of colorectal cancer by 2% (Lock, 2005). It has been estimated that 2,635,000 deaths per year are due to the inadequate consumption of fruits and vegetables (Lock, 2005).