GM1 Reduces Aggregation of α-Synuclein in an Animal Model of Parkinson's Disease

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Parkinson’s disease, like most other neurodegenerative conditions, is characterized not just by chronic inflammation and cell death, but also by protein aggregation. Solid deposits of α-synuclein form in the brain, bringing with them a halo of toxic biochemistry that harms and kills neurons. It is expected that finding ways to clear these aggregates will prove to be an effective treatment for the condition, though there remain questions about the ordering of cause and effect. Does chronic inflammation or mitochondrial dysfunction lead to protein aggregation, or vice versa? As is usually the case, the easiest way to answer these questions is to clear the aggregates in a good disease model, or in the real thing in human patients, and see what happens.


Scientists have investigated the therapeutic potential of GM1 in Parkinson’s disease for nearly 30 years. Previous research showed that Parkinson’s patients have less GM1 than healthy patients in the part of the brain most affected by Parkinson’s, the substantia nigra. Other researchers followed this work to show in cell culture models that GM1 interacts with a protein called alpha-synuclein. In Parkinson’s disease, alpha-synuclein can form clumps, which can become toxic to brain cells in the substantia nigra and lead to cell death.

In new work, researchers have shown that giving daily GM1 doses to animals that overproduce alpha-synuclein inhibits the toxic effects of the protein. “When we looked in the brains of these animals, not only did we find we could partially protect their dopamine neurons from the toxic effects of alpha synuclein accumulation, we had some evidence that these animals had smaller and fewer aggregates of alpha-synuclein than animals that received saline injection instead of GM1.” In addition to protecting brain cells from death, the treatment also reversed some early motor symptoms.

The researchers suspect that less GM1 in the brains of Parkinson’s disease patients may facilitate the aggregation of alpha-synuclein and increase its toxicity. “By increasing GM1 levels in the brains of these patients, it would make sense that we could potentially provide a slowing of that pathological process and a slowing of the disease progression, which is what we found previously in a clinical trial of GM1 in Parkinson’s disease patients.” The team is now following up on their results to find out what other effects GM1 might have on alpha-synuclein.

Link: https://www.jefferson.edu/about/news-and-events/2019/7/molecule-reduces-accumulation-of-toxic-protein-in-parkinsons.html

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Live Foreverish Podcast: Staying Focused on Long Drives

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Live Foreverish Podcast: Staying Focused on Long Drives
Do you have a long commute to work? Are you taking a road trip this summer? Between phones, kids, touch screens in the car, and everything else… distractions while driving cause thousands of people to lose their lives every year. Learn how to stay focused on the Live Foreverish podcast!

Nutrients that Support Focus

Whether you have kids in the back seat or are experiencing highway hypnosis on long drives, distracted driving is obviously dangerous. So, what is the solution? Scientists have identified nutrients such as sage and spearmint that can help improve your focus! Dr. Crystal Gossard explains the research. Available for download or Listen now on LiveForeverish.com

About Live Foreverish: Join Dr. Mike and Dr. Crystal as they sit down with some of today’s leading medical, health and wellness experts to discuss a variety of health-related topics. From whole-body health to anti-aging and disease prevention, you’ll get the latest information and helpful advice to help you live your life to the fullest. If you like what you hear, please take a moment to Give Live Foreverish a 5-star rating on iTunes!

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Fat Cell Exosomes Demonstrated to Impair the Ability of Macrophages to Remove Cholesterol from Blood Vessel Walls

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Carrying excess visceral fat tissue, the fat packed around organs in the abdomen, accelerates all of the common conditions of aging. This is most likely largely mediated by chronic inflammation, the overactivation of the immune system that fat tissue produces. Numerous mechanisms contribute to this inflammation: fat tissue generates an outsized number of lingering senescent cells that secrete inflammatory signals; dying fat cells produce DNA debris that triggers an immune response; fat cells burdened by a lot of lipids generate similar signals to those released by infected cells; and so forth.

Chronic inflammation is particularly important in the progression of atherosclerosis. Cholesterols in the bloodstream find their way into blood vessel walls, and must be removed by the innate immune cells known as macrophages, which hand off the cholesterol to high-density lipoprotein (HDL) particles for it to be carried back to the liver for excretion. With age, rising levels of inflammation and oxidative stress generate ever more oxidized cholesterols, and these damaged molecules, particularly 7-ketocholesterol, cause macrophages to become dysfunctional. Further, chronic inflammation causes macrophages to act inappropriately, becoming inflammatory themselves rather than usefully engaging in removing cholesterol from blood vessel tissue. The result is fatty lesions, formed of cholesterols and the debris of dead macrophages, overwhelmed trying to help. The more inflammatory signaling there is, the more macrophages are called in to their doom.

In the research results I’ll point out today, scientists have found another way in which fat tissue can degrade the ability of macrophages to remove cholesterol from blood vessel walls, operating independently of inflammatory mechanisms. Exosomes, a form of membrane-bound extracellular vesicle packed with signal molecules, are released by fat cells and, when taken up by macrophages, impair the ability of those macrophages to carry out the action of passing a cholesterol molecule to an HDL particle. While the study was carried out in young people, I would expect the mechanism to operate in older individuals as well. There are already countless very good reasons to avoid becoming fat: it is arguably the case that being overweight literally accelerates the aging process. Nonetheless, here is another one.

MicroRNAs from human fat cells can impair macrophage ability to eliminate cholesterol


In atherosclerosis, blood vessels that carry oxygen-rich blood throughout the body become inflamed, and macrophages settle in the vessel wall and become overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away. Extracellular vesicles (EVs) seemed likely troublemakers since they enable intercellular communication. “We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol. Fat isn’t just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world.”

Because heart disease can have its roots in adolescence, the researchers enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the “lean” group, 15 youth whose BMI was lower than 22 and the “obese” group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. The researchers collected visceral adipose tissue during abdominal surgeries. “We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight. It’s still an open question whether young people who are healthy can tolerate obesity – or whether there are specific differences in fat tissue composition that up kids’ risk for heart disease.”

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs


Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. Although primarily a disease of adults, youth with obesity show evidence of subclinical ASCVD which places them at increased risk as adults for coronary heart disease and stroke. The mechanisms by which obesity confers cardiovascular risk are not fully understood, but inflammation within visceral adipose tissue (VAT) is thought to be contributory. Further, the impact of excess adipose tissue on distal sites such as arterial wall monocytes/macrophages, direct participants in ASCVD, are also thought to contribute to disease pathogenesis.

In this study we show, for the first time, significant alterations in cholesterol efflux capacity in adolescents throughout the range of BMI, a relationship between six circulating adipocyte-derived EVs microRNAs targeting ABCA1 and cholesterol efflux capacity, and in vitro alterations of cholesterol efflux in macrophages exposed to visceral adipose tissue adipocyte-derived EVs acquired from human subjects. These results suggest that adipocyte-derived EVs, and their microRNA content, may play a critical role in the early pathological development of ASCVD.

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Damage to Lymphatic Vessels Impairs Drainage of Cerebrospinal Fluid with Age

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Impaired drainage of cerebrospinal fluid (CSF) with age is a hot topic in the field of neurodegeneration at the moment. In younger individuals, passage of CSF out of the brain via a number of routes is thought to provide a way to maintain normally low levels of metabolic waste, such as the amyloid-β associated with Alzheimer’s disease. Reduced fluid flow due to the damage and dysfunction of aging then contributes to the raised levels and aggregation of these waste products, and thus to neurodegenerative conditions. A number of companies are developing therapies based on this vision of brain aging, such as Leucadia Therapeutics. Thus we should expect to see impaired CSF drainage decisively proven or disproven as a major cause of neurodegeneration in clinical trials over the next few years. Even in advance of those trials, the evidence to date is quite compelling, however.


Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism. Scientists have now reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging.

Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question – where is the main exit for the CSF? Though mLVs in the upper part of the skull were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section.

The researchers used several techniques to characterize the basal mLVs in detail and verified that specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs.

It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function, enabling a new strategy for eliminating the buildup of aging-related toxic proteins.

Link: https://www.eurekalert.org/pub_releases/2019-07/ifbs-nim072319.php

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Reversing Somatic Mosaicism in Aged Tissue

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Somatic mosiacism is the tendency for aged tissues to display a mix of mutations, spread through cell lineages from an original mutation in a stem cell or progenitor cell. The consensus in the research community is that this degrades tissue function, contributing to the aging process, but there is a lack of evidence for whether or not this is significant across the present human life span. Clearly eventually it has to become a problem, given ways to deal with all of the other aspects of aging, but without a grasp of the size of the effect, it is hard to say whether or not this issue should be targeted now or later.

How does one go about repairing somatic mosiacism in any case? This is a tough question. Repairing diverse mutations in living tissue is possible in the grand scheme of things, given sufficiently advanced molecular nanotechnology, but it is possible with the tools of the next twenty years or so? That would likely mean programmable, highly efficient gene therapies, but in the open access paper here researchers demonstrate that, in the case of at least one gene, there may be other, simpler possibilities.


Normal tissues progressively accumulate cells carrying somatic mutations, some of which are linked to neoplasia and other diseases. This process is exemplified by human esophageal epithelium (EE), in which mutations generated by cell-intrinsic processes colonize the majority of normal epithelium by middle age. The most common mutations are under strong positive selection, meaning that there is an excess of protein altering over silent mutations within each gene. This indicates that these mutations confer a competitive advantage over wild-type cells and drive clonal expansions in normal tissue.

We speculated that, as in other systems of competitive selection, altering the tissue environment may change the relative fitness of particular mutations and their prevalence in the tissue. In this study, we focused on p53 mutations because these are the most enriched during malignant transformation. p53 is mutated in 5%-10% of normal EE but in almost all esophageal squamous cell carcinomas (ESCCs). This argues that ESCC emerges from the p53 mutant cell population in normal epithelium and that mutation of p53 is required for cancer development.

We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.

Link: https://doi.org/10.1016/j.stem.2019.06.011

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The Role of mTOR as a Regulator of Lifespan

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The mTOR gene is deeply involved in the regulation of cellular activities in response to nutrient sensing. It is also implicated in the many, many changes that occur to slow aging in response to a restricted calorie intake, including processes known to be important to aging such as mitochondrial function and cellular senescence. Given that most research to date on intervention in the aging process has focused on the calorie restriction response and related upregulation of stress response mechanisms, it is no surprise that mTOR has attracted a lot of attention. The first mTOR inhibitor drugs are already going through clinical trials, developed by companies such as resTORbio and Navitor Pharmaceuticals.

It is unfortunate that this strategy for modulating the pace of aging has far larger effects on life span in short-lived species than in long-lived species such as our own: calorie restriction extends life by 40% in mice, but by no more than a few years for us. This is thought to be a consequence of the seasonal nature of famine. A famine lasts a large fraction of a mouse life span, but very little of a human life span, so only the mouse has the evolutionary pressure to develop a large plasticity of life span in response to calorie restriction.

The end result of these factors is that upregulation of stress response mechanisms just doesn’t do as much in our species as it does in mice, or in any other short-lived laboratory species. Thus we shouldn’t expect therapies targeting mTOR to do much more than can already be achieved via the practice of calorie restriction. That means some degree of improved health, as illustrated in clinical trials for immune function in later life, for example, but no great extension of life span.

mTOR as a central regulator of lifespan and aging


Consistent with its role in coordinating protein synthesis, energy metabolism, and autophagy in cancer, emerging evidence suggests that mTOR may act as a central node that orchestrates many aspects of cellular and organismal biology related to aging phenotypes. Inhibition of the mTOR pathway by rapamycin or genetic means has profound effects on life span and age-associated phenotypes across a wide array of organisms. However, the underlying mechanisms are still unclear as it has been reported that during aging mTOR activity is both increased and decreased, depending on, for example, tissue or sex. It was suggested that, in spite of these variations, overall aging does not result in a generalized increase in mTOR signaling. If this is the case, it is possible that mTOR activity aligns with the antagonistic pleiotropy theory of aging, whereby its levels are beneficial during development but limit the health span in adult life.

Owing to its central role in age-related processes, mTOR represents an appealing target to ameliorate age-related pathologies. Despite its capacity to expand life span, the function of rapamycin (and of rapalogs) as an immunosuppressant might be of concern, as a decline in immune function (immunosenescence) already occurs in the elderly, leading to infection-related morbidity and mortality. Intriguingly, several studies in both mice and humans suggest that mTOR inhibitors could reduce immunosenescence. In mice, rapamycin can restore the self-renewal and hematopoiesis of hematopoietic stem cells and enable effective vaccination against the influenza virus. A randomized trial testing the effects of rapalog RAD001 in a cohort of healthy elderly patients also showed an enhanced response to the influenza vaccination.

Another limitation of rapamycin is that its chronic exposure in mice leads to mTORC2 inhibition in, for example, hepatocytes. Active-site mTOR inhibitors also inhibit mTORC2. Strikingly, selective suppression of mTORC2 reduces life span and is associated with changes in endocrinology and metabolism (for example, insulin resistance), which have a negative impact on health span. Thus, developing specific inhibitors which effectively suppress all mTORC1 outputs, but do not exert a major effect on mTORC2, appears to be warranted as a strategy to target age-related pathologies and improve health span. Interestingly, in a recent trial of healthy elderly patients, the combination of low-dose RAD001 (rapalog) and BEZ235 (dual mTOR/PI3K catalytic inhibitor) was proposed to selectively inhibit mTORC1 and not mTORC2 and led to enhanced immune function and a reduction in infections. However, it is important to note that complete inhibition of mTORC1 can be deleterious.

Biguanides (for example, metformin) are pharmaceuticals which are thought to have a beneficiary effect (in aging) that indirectly impinges on mTOR. Metformin is a first-line anti-diabetic drug which has been used for more than 60 years in the clinic and has very few side effects. It was shown to modulate life span in model organisms, to affect several processes dysregulated in aging (for example, cellular senescence, inflammation, autophagy, and protein synthesis), and to improve cognitive function and neurodegeneration in humans. By inhibiting mitochondrial complex I, metformin causes energetic stress which results in mTORC1 inhibition through AMPK-dependent and independent mechanisms.

Although many studies have uncovered possible targets of metformin action in the cell in the context of aging, the full extent of metformin’s mechanism of action at the cellular and organismal levels is still incompletely understood. Nonetheless, clinical trials in which metformin is used to improve health span or aging-related conditions are being proposed. For instance, in the TAME (targeting aging with metformin) clinical trial, a placebo-controlled multi-center study of about 3000 elderly patients who are 65 to 79 years old, the effects of metformin on the development of age-associated outcomes like cardiovascular events, cancer, dementia, and mortality will be monitored.

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Cholesterol does not cause heart disease

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For the past six decades, the U.S. dietary advice has warned against eating cholesterol-rich foods, claiming dietary cholesterol promotes arterial plaque formation that leads to heart disease. We now have overwhelming evidence to the contrary, yet dogmatic thinking can be persistent, to say the least.

After decades’ worth of research failed to demonstrate a correlation between dietary cholesterol and heart disease, the 2015-2020 Dietary Guidelines for Americans1,2 finally addressed this scientific shortcoming, announcing “cholesterol is not considered a nutrient of concern for overconsumption.”

To this day, the evidence keeps mounting, showing there’s no link between the two. Similarly, the evidence supporting the use of cholesterol-lowering statin drugs to lower your risk of heart disease is slim to none, and is likely little more than the manufactured work of statin makers — at least that’s the implied conclusion of a scientific review3 published in the Expert Review of Clinical Pharmacology in 2018.

Cholesterol myth kept alive by statin advocates?

The 2018 review4 identified significant flaws in three recent studies “published by statin advocates” attempting “to validate the current dogma.” The paper presents substantial evidence that total cholesterol and low-density lipoprotein (LDL) cholesterol levels are not an indication of heart disease risk, and that statin treatment is of “doubtful benefit” as a form of primary prevention for this reason. According to the authors:5

“According to the British-Austrian philosopher Karl Popper, a theory in the empirical sciences can never be proven, but it can be shown to be false. If it cannot be falsified, it is not a scientific hypothesis. In the following, we have followed Popper’s principle to see whether it is possible to falsify the cholesterol hypothesis.

We have also assessed whether the conclusions from three recent reviews by its supporters are based on an accurate and comprehensive review of the research on lipids and cardiovascular disease (CVD) …

Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on misleading statistics, exclusion of unsuccessful trials and by ignoring numerous contradictory observations.”

As reported by Reason.com:6

“A comprehensive new study on cholesterol, based on results from more than a million patients, could help upend decades of government advice about diet, nutrition, health, prevention, and medication …

The study … centers on statins, a class of drugs used to lower levels of LDL-C, the so-called ‘bad’ cholesterol, in the human body. According to the study, statins are pointless for most people …

The study also reports that ‘heart attack patients were shown to have lower than normal cholesterol levels of LDL-C’ and that older people with higher levels of bad cholesterol tend to live longer than those with lower levels.

No evidence cholesterol influences heart disease risk

Indeed, the authors of the Expert Review of Clinical Pharmacology analysis point out that were high total cholesterol in fact a major cause of atherosclerosis, “there should be exposure-response in cholesterol-lowering drug trials.”7 In other words, patients whose total cholesterol is lowered the most should also see the greatest benefit. Alas, that’s not the case.

A review of 16 relevant cholesterol-lowering trials (studies in which exposure-response was actually calculated), showed this kind of exposure-response was not detected in 15 of them. What’s more, the researchers point out that the only study8 showing a positive exposure-response to lowered cholesterol used exercise-only as the treatment.

Patients with high total cholesterol should also be at increased risk of death from CVD, but the researchers found no evidence of this either, not-so-subtly pointing out that this is “an idea supported by fraudulent reviews of the literature.” They provide the following example of how research has been misrepresented:9

“The hypothesis that high TC [total cholesterol] causes CVD was introduced in the 1960s by the authors of the Framingham Heart Study. However, in their 30-year follow-up study published in 1987, the authors reported that ‘For each 1 mg/dl drop in TC per year, there was an eleven percent increase in coronary and total mortality’.

Three years later, the American Heart Association and the U.S. National Heart, Lung and Blood Institute published a joint summary concluding, ‘a one percent reduction in an individual’s TC results in an approximate two percent reduction in CHD risk’. The authors fraudulently referred to the Framingham publication to support this widely quoted false conclusion.”

Contradictory findings routinely ignored or misrepresented

To determine whether the three reviews under analysis had misrepresented previous findings, they scoured the three papers for quotations from 12 studies reporting results “discordant with the cholesterol hypothesis.” Only one of the three reviews had quoted articles correctly, and even then, only two of the dozen studies were quoted correctly.10

“About half of the contradictory articles were ignored. In the rest, statistically nonsignificant findings in favor of the cholesterol hypothesis were inflated, and unsupportive results were quoted as if they were supportive. Only one of the six randomized cholesterol-lowering trials with a negative outcome was cited and only in one of the reviews.”

The researchers also highlight a large meta-analysis that simply ignored “at least a dozen studies” in which no or inverse association was shown. Overall, the Expert Review of Clinical Pharmacology analysis found that “the association between total cholesterol and CVD is weak, absent or inverse in many studies.”

No link between LDL and heart disease either

The Expert Review of Clinical Pharmacology paper11 also tears apart claims that high LDL causes atherosclerosis and/or CVD. Just as with total cholesterol, if high LDL was in fact responsible for atherosclerosis, then patients with high LDL would be diagnosed with atherosclerosis more frequently, yet they’re not, and those with the highest levels would have the greatest severity of atherosclerosis, yet they don’t.

The researchers cite studies showing “no association” between LDL and coronary calcification or degree of atherosclerosis. Ditto for LDL and CVD. In fact, a study looking at nearly 140,000 patients with acute myocardial infarction found them to have lower than normal LDL at the time of admission.

Even more telling, another study, which had originally reported similar findings, still went ahead and lowered the patients’ LDL even more. At follow-up three years later, they discovered that patients with an LDL level below 105 mg/dl (2 mmol/L) had double the mortality rate of those with higher LDL.12

Interestingly, the authors suggest this inverse relationship may be due to low LDL increasing your risk for infectious diseases and cancer, both of which are common killers.

They also review evidence showing older people with high LDL do not die prematurely — they actually live the longest, outliving both those with untreated low LDL and those on statin treatment. One such study13,14 — a meta-analysis of 19 studies — found 92% of individuals with high cholesterol lived longer.

Benefits of statin treatment are overblown

Lastly, the Expert Review of Clinical Pharmacology paper analyzes statin claims, showing how studies exaggerate benefits through a variety of different tactics. Again, in some cases, by simply excluding unsuccessful trials.

“Furthermore, the most important outcome — an increase of life expectancy — has never been mentioned in any cholesterol-lowering trial, but as calculated recently by Kristensen et al.,15 statin treatment does not prolong lifespan by more than an average of a few days,” the authors state.16

Indeed, the study they’re referring to, published in BMJ Open in 2015, which looked at 11 studies with a follow-up between two and 6.1 years, found “Death was postponed between -5 and 19 days in primary prevention trials and between -10 and 27 days in secondary prevention trials.” The median postponement of death in primary prevention trials was 3.2 days, and in secondary prevention trials 4.1 days!

Considering the well-documented health risks associated with statins, this is a mind-bending finding that really should upend the dogma. And yet, the dogma remains, and may even strengthen in coming days.

JAMA editorial calls for end to ‘fake news’ about statins

The cholesterol myth has been a boon to the pharmaceutical industry, as cholesterol-lowering statins — often prescribed as a primary prevention against heart attack and stroke — have become one of the most frequently used drugs on the market. In 2012-2013, 27.8% of American adults over the age of 40 reported using a statin, up from 17.9% a decade earlier.17,18 But that was six years ago, I suspect over a third of adults over the age of 40 are now using statins.

In addition to the BMJ Open study cited above, an evidence report19 by the U.S. Preventive Services Task Force, published November 2016 in JAMA, found 250 people need to take a statin for one to six years to prevent a single death from any cause; 233 had to take a statin for two to six years to prevent a single cardiovascular death specifically. To prevent a single cardiovascular event in people younger than 70, 94 individuals would have to take a statin.

As noted in a 2015 report,20 “statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease.” The paper points out that by using a statistical tool known as relative risk reduction, the trivial benefits of statins appear greatly amplified.

Scientific findings such as these are the core reason why statins are given negative press. However, we may soon see a reversal in the news cycle, with negative statin articles being tagged as “fake news.”

According to a June 2019 editorial21 in JAMA Cardiology, written by cardiologist Ann Marie Navar,22 statins are the victim of “fear-based medical information,” just like vaccines, and this is what’s driving patient nonadherence. Cardiovascular Business reported:23

“We know that what people read influences their actions, Navar said, and indeed, one 2016 study in the European Heart Journal found that on a population level, statin discontinuation increased after negative news stories about statins surfaced in those communities.

In another study, more than one in three heart patients said they declined a statin prescription solely for fears of adverse effects. ‘Measles outbreaks are highly visible: a rash appears, public health agencies respond, headlines are made and the medical community responds vocally,’ Navar wrote.

‘In contrast, when a patient who has refused a statin because of concerns stoked by false information has an MI, the result is less visible. Nevertheless, cardiologists and primary care physicians observe the smoldering outbreak of statin refusal daily.’”

Cardiovascular Business summarizes Navar’s suggestions for how doctors can fight back against false information about statins and build adherence, such as handing out yearlong prescriptions with automatic refills.24

When I first wrote about the censorship of anti-vaccine material occurring on every single online platform, I warned that this censorship would not stop at vaccines. And here we’re already seeing the call for censoring anti-statin information by glibly labeling it all “fake news.”

Chances are, the censoring of anti-statin information is already underway. A quick Google search for “statin side effects” garnered pages worth of links talking about minor risks, the benefits of statins, comparison articles, looking at two different brands — in other words, mostly positive news.

The scientific fact is, aside from being a “waste of time” and not doing anything to reduce mortality, statins also come with a long list of potential side effects and clinical challenges, including:

An increased risk for diabetes

Decreased heart function25

Nutrient depletions — Including CoQ10 and vitamin K2, both of which are important for cardiovascular and heart health

Impaired fertility — Importantly, statins are a Category X medication,26 meaning they cause serious birth defects,27 so they should never be used by a pregnant woman or women planning a pregnancy

Increased risk of cancer — Long-term statin use (10 years or longer) more than doubles women’s risk of two major types of breast cancer: invasive ductal carcinoma and invasive lobular carcinoma28

Nerve damage — Research has shown statin treatment lasting longer than two years causes “definite damage to peripheral nerves”29

How to assess your heart disease risk

cholesterol levels

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As a general rule, cholesterol-lowering drugs are not required or prudent for the majority of people — especially if both high cholesterol and longevity run in your family. Remember, the evidence overwhelmingly suggests your overall cholesterol level has little to nothing to do with your risk for heart disease.

For more information about cholesterol and what the different levels mean, take a look at the infographic above. You can also learn more about the benefits of cholesterol, and why you don’t want your level to be too low, in “Cholesterol Plays Key Role in Cell Signaling.” As for evaluating your heart disease risk, the following tests will provide you with a more accurate picture of your risk:

HDL/Cholesterol ratio — HDL percentage is a very potent heart disease risk factor. Just divide your HDL level by your total cholesterol. That percentage should ideally be above 24%.

Triglyceride/HDL ratio — You can also do the same thing with your triglycerides and HDL ratio. That percentage should be below 2.

NMR LipoProfile Large LDL particles do not appear to be harmful. Only small dense LDL particles can potentially be a problem, as they can squeeze through the lining of your arteries. If they oxidize, they can cause damage and inflammation.

Some groups, such as the National Lipid Association, are now starting to shift the focus toward LDL particle number instead of total and LDL cholesterol to better assess your heart disease risk. Once you know your particle size numbers, you and your doctor can develop a more customized program to help manage your risk.

Your fasting insulin level — Heart disease is primarily rooted in insulin resistance,30 which is the result of a high-sugar diet. Sugar, not cholesterol or saturated fat, is the primary driver. Clinical trials have shown high fructose corn syrup can trigger risk factors for cardiovascular disease within as little as two weeks.31

Any meal or snack high in carbohydrates like fructose and refined grains generates a rapid rise in blood glucose and then insulin to compensate for the rise in blood sugar.

The insulin released from eating too many carbs promotes fat accumulation and makes it more difficult for your body to shed excess weight. Excess fat, particularly around your belly, is one of the major contributors to heart disease.

Your fasting blood sugar level — Research has shown people with a fasting blood sugar level of 100 to 125 mg/dl have a nearly 300% increased higher risk of coronary heart disease than people with a level below 79 mg/dl.32,33

Your iron level — Iron can be a very potent oxidative stress, so if you have excess iron levels you can damage your blood vessels and increase your risk of heart disease. Ideally, you should monitor your ferritin levels and make sure they are not much above 80 ng/ml.

The simplest way to lower them if they are elevated is to donate your blood. If that is not possible you can have a therapeutic phlebotomy and that will effectively eliminate the excess iron from your body.

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Investigating the Mechanisms of FOXO3 Effects on Longevity

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The relationship between normal genetic variations and consequence differences in life expectancy is enormously complex. Countless genetic variations have tiny, contingent, interacting effects on health and late life resilience to the damage of aging. Correlations found in epidemiological studies are rarely replicated between study populations. FOXO3 is one of the very small number of genes for which effects on longevity are found in multiple species and human populations. These effects are not large: a modestly increased chance of living longer. It is also worth noting recent research that downgraded the expected size of effect for FOXO3 based on more rigorous assessment of data. Here, researchers discuss some of the low-level mechanisms that might explain this association.


Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs.

FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes.

Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.

Link: https://doi.org/10.1016/j.csbj.2019.06.011

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A Consistent Transcriptomic Signature of Cellular Senescence

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As numerous senolytic therapies to clear senescent cells continue their progress towards the clinic, the research and development communities find themselves in ever greater need of better biomarkers for cellular senescence. Those that presently exist, such as staining tissue samples for senescence-associated β-galactosidase, are good enough for much of the present scope of research use, but not a suitable basis for either clinical assays or more sophisticated investigation of the mechanisms of senescence. As (a) there are numerous paths by which cells become senescent, prompted by different circumstances, and (b) senescence may vary in other ways between tissue types, and (c) different senolytics have different degrees of effectiveness across these varied classes and cells, it is the case that better and more consistent biomarkers would help to speed progress in this field.


Senescence is a state of indefinite growth arrest. It can be induced by various sublethal stresses, including telomere shortening, genomic injury, epigenomic damage and signaling from oncoproteins. Senescence is also characterized by a senescence-associated secretory phenotype (SASP) whereby cells produce and secrete pro-inflammatory cytokines. Senescence is beneficial for tissue remodeling, embryonic development, wound healing, and tumor suppression in young individuals. However, in old individuals it promotes aging-associated declines and diseases.

Progress to identify senescent cells in order to exploit them therapeutically has been hampered by a lack of robust and universal measurable traits. Thus far, senescence has been studied in a range of cell types induced by diverse triggers such as replicative exhaustion, DNA damage, oxidation and other stress conditions like signaling through oncoproteins. Due to this heterogeneity, finding broad biomarkers of senescence has been challenging and senescent cells are currently found through the combined detection of multiple biochemical markers such as p16, p53, p21 and SA-βGal, despite the fact that they are not exclusively nor consistently induced in senescence.

In this study, we sought to identify universally expressed transcripts across various senescent cell models. We performed RNA sequencing (RNA-seq) analysis after triggering senescence in human WI-38 and IMR-90 fibroblasts, human umbilical vein endothelial cells (HUVECs) and human alveolar endothelial cells (HAECs) through replicative exhaustion (WI-38, IMR-90), exposure to ionizing radiation (WI-38, IMR-90, HUVEC, HAEC) or doxorubicin (WI-38) or expression of an oncogene (oncogene-induced senescence, OIS) (WI-38). Comparisons of all the patterns of expressed transcripts revealed 68 RNAs that were increased (50 RNAs) or decreased (18 RNAs) across all senescence models, although a mimimum of 5 RNAs were sufficient to identify senescent cells bioinformatically. Most RNAs altered during senescence were protein-coding transcripts, but the long non-coding RNA PURPL (p53-upregulated regulator of p53 levels) was one of the most strikingly elevated transcripts.

Link: https://doi.org/10.1093/nar/gkz555

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More Evidence for Defects in the Formation of Autophagosomes to be Important in the Age-Related Decline of Autophagy

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Autophagy is a collection of cellular maintenance processes that act to recycle damaged structures in the cell, thereby maintaining cell health and function. On the one hand, the efficiency of autophagy declines with age, and this loss of function is associated with numerous age-related diseases, particularly of the central nervous system and its population of very long-lived neurons. On the other hand, increased autophagy is an important component of many of the interventions shown to slow aging in short-lived species, such as via calorie restriction. A fair number of research groups are working on ways to upregulate autophagy in our species, but this has been going on for a while with little concrete movement towards the clinic.

Autophagy is a complicated process of multiple steps, and at every step there are plausible proximate causes for a faltering of the system with age. The formation of autophagosomes to encapsulate materials to be recycled can break down, as is the case in today’s open access paper. The mechanisms by which autophagosomes are transported to a lysosome for deconstruction of their contents are degraded. The lysosome itself becomes filled with metabolic waste that it struggles to break down, making it bloated and inefficient.

In the case of defects relating to autophagosomes it is unclear as to why the breakage happens, how it relates to the underlying molecular damage that causes aging. Given this, approaches to therapy tend to focus on overriding proximate changes. Researchers find regulatory systems that can be adjusted in order to force the relevant mechanism to work despite its normal reaction to systemic damage in and around cells. In principle this should always be worse as a strategy than identifying and repairing the damage, but it can produce benefits in some cases. In the example here, researchers find a way to override the failure to form autophagosomes that is observed in old neurons.

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons


Unlike most of the cells in our body, our neurons are as old as we are: while other cell types are replaced as they wear out, our neurons must last our entire lifetime. The symptoms of disorders such as Alzheimer’s disease and ALS result from neurons in the brain or spinal cord degenerating or dying. But why do neurons sometimes die?

One reason may be that elderly neurons struggle to remove waste products. Cells get rid of worn out or damaged components through a process called autophagy. A membranous structure known as the autophagosome engulfs waste materials, before it fuses with another structure, the lysosome, which contains enzymes that break down and recycle the waste. If any part of this process fails, waste products instead build up inside cells. This prevents the cells from working properly and eventually kills them.

Aging is the major shared risk factor for many diseases in which brain cells slowly die. Could this be because autophagy becomes less effective with age? Researcher isolated neurons from young adult, aging and aged mice, and used live cell microscopy to follow autophagy in real time. The results determined that autophagy does indeed work less efficiently in elderly neurons. The reason is that the formation of the autophagosome stalls halfway through. However, increasing the amount of one specific protein, WIPI2B, rescues this defect and enables the cells to produce normal autophagosomes again.

As long-lived cells, neurons depend on autophagy to stay healthy. Without this trash disposal system, neurons accumulate clumps of damaged proteins and eventually start to break down. The results identify one way of overcoming this aging-related problem. As well as providing insights into neuronal biology, the results suggest a new therapeutic approach to be developed and tested in the future.

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