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Month: August 2019

Evidence for Mitochondrial Dysfunction in Smooth Muscle to be Important in Age-Related Vascular Stiffness

Evidence for Mitochondrial Dysfunction in Smooth Muscle to be Important in Age-Related Vascular Stiffness

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Mitochondria in cells throughout the body become dysfunctional with age, with the proximate cause of this issue being a decline in the quality control mechanisms responsible for clearing out damaged and worn mitochondria. Researchers here show that the increased levels of reactive oxygen species produced by mitochondria in aged smooth muscle cells is important in the stiffening of blood vessels that occurs with advancing age. This loss of the ability of blood vessels to appropriately constrict and relax in response to circumstances leads to hypertension, a chronic state of raised blood pressure that is very damaging over the long term. In this context, it is worth noting that a clinical trial of a mitochondrially targeted antioxidant showed improvement in smooth muscle function and consequent reduction in blood vessel stiffness.

Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs), and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice.

The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice.

Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature senescence and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction.


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Alternate Day Fasting and Calorie Restriction Produce Similar Outcomes in Humans

Alternate Day Fasting and Calorie Restriction Produce Similar Outcomes in Humans

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Today’s research is a comparison of alternate day fasting and calorie restriction in human subjects. Or rather, I think, one might look on it as an examination of alternate day fasting as an alternative approach to achieving calorie restriction. The type of alternate day fasting here is the better form, in which 36 hours are spent fasting, only eating in a 12 hour window every other day. In practice that means eat normally one day, then fast until the morning two days later. This tends to reduce average calorie intake down to something very similar to a straight calorie restricted diet. That calorie restricted diet might be 1500 kcal/day for an averagely sized human being, and I can assure you that it is very, very hard to eat more than 3000 kal in a 12 hour period, at least not without resorting to heavy duty junk food.

So is alternate day fasting just calorie restriction? In animal studies there are significant differences in gene expression profiles between these two approaches, which is enough to suspect that perhaps fasting and feeding versus a consistent low calorie intake are two different beasts. The effects on metabolism are sweeping in either case, which makes analysis challenging, but the important mechanisms, the upregulation of cellular stress response systems such as autophagy, appear the same. More recent research into fasting mimicking diets has attempted to find the point at which low calorie intake triggers benefits, and quantify how long the low calorie diet must be sustained. The results there suggest that additional benefits emerge after three to four days, in terms of a culling of immune cells. That work also suggests that the process of refeeding after a fast is necessary in order to obtain the full benefits.

So it is possible that neither alternate day nor straight calorie restriction are strictly optimal, and something more intermittent would be better. Still, either alternate day or calorie restriction are such a huge improvement over the dietary choices adopted by most people that it seems almost foolish to spend much time on further optimization. This is particularly true when that time and energy could be put towards advancing the development of rejuvenation therapies capable of turning back aging in ways that no amount of fasting can achieve.

Not Eating for 36 Hours Is Shown to Be a Surprisingly Sustainable Diet, Study Shows

New research outlines a novel way to intermittently restrict calorie intake, a method that achieves the same health benefits while possibly being more manageable than constantly restricting calories. An international team of researchers presented the results of a clinical trial in which “alternate day fasting” resulted in reduced calorie intake, reduced body mass index, and improved torso fat composition. Known as “ADF,” it is a diet regimen in which adherents avoid all food and caloric beverages for 36 hours, then eating whatever they want for 12 hours – donuts, cookies, dumpster pizza, whatever.

In this randomized controlled trial, 30 non-obese volunteers who had done ADF for at least six months were compared over a 4-week period to 60 healthy control subjects. While the results of this clinical trial show that ADF had similar health benefits to caloric restriction, even though the “feast days” could include a lot of unhealthy calories. The researchers also write that ADF has some distinct advantages over CR. Mainly, they say it may be easier to maintain the habit.

Previous work on intermittent fasting has shown that restricting an animal’s calories – without depriving them of adequate nutrition, of course – can increase their lifespan, though much of the work has been limited to monkeys and other non-human animals. This latest study builds on that existing research by following a mid-sized human cohort for enough time to show not just significant benefits but also no negative side effects.

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study, we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after more than 6 months.

ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.

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Blood pressure control could slow age-related brain damage

Blood pressure control could slow age-related brain damage

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According to the Centers for Disease Control and Prevention,1 1 in 3 American adults (about 75 million people) have high blood pressure, and about 46% have uncontrolled high blood pressure, which increases your risk for a number of serious health problems, including heart disease, stroke,2 kidney disease3 and dementia.4

With regard to dementia, previous research5 has found that high blood pressure disrupts regulatory mechanisms in your brain by impeding blood flow, thereby causing neuronal damage and dysfunction.

A study6 published in the August 2019 issue of JAMA concluded intensive blood pressure treatment helped limit the progression of cerebral small vessel ischemic disease — referring to common age-related changes in the small blood vessels in your brain7 — thereby lowering the risk for dementia.

Other common terms for this condition is “white matter disease” and “age-related white matter changes.”8 Previous research9 has found 95% of seniors between the ages of 60 and 90 have lesions in the white matter of their brains, and several studies10 have shown people with high blood pressure tend to have more white matter lesions and a higher risk for dementia in their later years.

Intensive blood pressure treatment may lower dementia risk

In the featured JAMA study,11,12 participants were randomly selected to receive intensive treatment to reach a systolic blood pressure goal of 120 mm Hg, or standard treatment, which required maintaining systolic blood pressure below 140 mm Hg.

The primary outcome was the change in total volume of white matter lesions from baseline. The secondary outcome was the change in total brain volume. Follow-up was scheduled to take place at four-year intervals, but the study was stopped early, after just five years, as the primary outcome benefit for those in the intensive treatment group was deemed to be higher, leaving those in the standard treatment group at a disadvantage. According to the authors:13

“In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3) in the standard treatment group (between-group difference in change, −0.54 cm3).”

Curiously, while those in the intensive treatment group suffered less brain damage (lesions) over time, they ended up losing a greater total volume of brain matter. The cause for this discrepancy is unknown, and it’s unclear what the clinical significance might be.

In the end, the researchers deemed the reduction in brain lesions to be more important, at least in terms of protecting against dementia. As noted in the study:14

“Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, −30.6 cm3) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, −26.9 cm3) in the standard treatment group (between-group difference in change, −3.7 cm3).

Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.”

Dr. Walter J. Koroshetz, director of the National Institute of Neurological Disorders and Stroke, which funded the study, commented on the findings in an NIH press release:15

“These initial results support a growing body of evidence suggesting that controlling blood pressure may not only reduce the risk of stroke and heart disease but also of age-related cognitive loss. I strongly urge people to know your blood pressure and discuss with your doctors how to optimize control. It may be a key to your future brain health.”

Do you have high blood pressure?

A blood pressure reading gives you two numbers. The upper or first number is your systolic blood pressure reading. The lower or second number is your diastolic pressure. For example, a blood pressure reading of 120 over 80 (120/80 mm Hg) means you have a systolic arterial pressure of 120 and a diastolic arterial pressure of 80.

Your systolic pressure is the highest pressure in your arteries. It occurs when your ventricles contract at the beginning of your cardiac cycle. Diastolic pressure refers to the lowest arterial pressure, and occurs during the resting phase of your cardiac cycle.

The guidelines for healthy blood pressure appear to be a bit of a moving target, having gone through a bewildering number of changes over the past several years.16 In 2014, the blood pressure goal for healthy patients over 60 was 150/90, and 140/90 for those between the ages of 18 and 59.17,18,19

As of 2017, American College of Cardiology and American Heart Association’s clinical guidelines call for a blood pressure goal of 120/80.20,21,22 Elevated blood pressure or prehypertension is defined as a systolic blood pressure between 120 and 129.

Stage 1 high blood pressure is 130 and 139 systolic, and 80 to 89 diastolic. Stage 2 high blood pressure is anything over 140 systolic and 90 diastolic. Anything over 180 systolic and/or 120 diastolic is considered a hypertensive crisis.

As noted in a 2019 review23 in the Cleveland Clinic Journal of Medicine, the 2017 guidelines increased the number of American adults diagnosed with high blood pressure from 31.9% to 45.6%. The latest guidelines also recommend monitoring your blood pressure continuously with a wearable device during daytime hours. As explained by Harvard Health:24

“This additional monitoring can help to tease out masked hypertension (when the blood pressure is normal in our office, but high the rest of the time) or white coat hypertension (when the blood pressure is high in our office, but normal the rest of the time).”

Lowered blood pressure guidelines have their risks

According to the Cleveland Clinic Journal of Medicine review,25 more intensive blood pressure control — meaning meeting the lower 120/80 threshold — “has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease.” Alas, this reduction comes “at the price of causing more adverse effects.”

According to this review, “All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.” Serious side effects experienced by people receiving intensive treatment were higher rates of:26

  • Low blood pressure (hypotension) 2.4% versus 1.4% in the standard treatment group
  • Fainting (syncope or temporary loss of consciousness) 2.3% versus 1.7%
  • Electrolyte abnormalities 3.1% versus 2.3%
  • Acute kidney injury or kidney failure 4.1% versus 2.5%
  • Other treatment-related adverse events 4.7% versus 2.5%

How to get a proper blood pressure reading

To avoid a false hypertension diagnosis, keep in mind that your blood pressure reading can vary significantly from day to day, and even from one hour to the next, so don’t overreact if you get one high reading here or there. It’s when your blood pres­sure remains consistently or chronically elevated that significant health problems can occur. The following variables can also affect the va­lidity of your blood pressure reading:

The blood pressure cuff size — If you’re overweight, taking your reading with a size “average” blood pressure cuff can lead to a falsely elevated blood pressure reading, so make sure your doctor or health care professional is using the right size cuff for your arm.

Your arm position — If your blood pressure is taken while your arm is parallel to your body, your reading will be falsely elevated. Blood pressure readings should always be taken with your arm at a right angle to your body.

Stress — “White coat hypertension” is a term used for when a high blood pressure reading is caused by the stress or fear associated with a doctor or hospital visit. This can be a transient yet serious concern. If this applies to you, stress reduction is key.

To decrease your risk of being falsely diagnosed with hypertension in this situation, take a moment to calm down (be sure to arrive for your appointment ahead of time so you can unwind), then breathe deeply and relax when you’re getting your blood pressure taken.

Common causes for high blood pressure

Several factors have been identified as contributing to high blood pressure, including but not limited to:

Insulin and leptin resistance As your insulin and leptin levels rise, it causes your blood pressure to increase.27 As noted in one study:28

“Insulin can increase blood pressure via several mechanisms: increased renal sodium reabsorption, activation of the sympathetic nervous system, alteration of transmembrane ion transport, and hypertrophy of resistance vessels. Conversely, hypertension can cause insulin resistance by altering the delivery of insulin and glucose to skeletal muscle cells, resulting in impaired glucose uptake.”

Elevated uric acid levels — Like insulin and leptin, high uric acid is also significantly associated with high blood pressure, so any program adopted to address high blood pressure needs to normalize your uric acid level as well. Tellingly, uric acid is a marker for fructose toxicity, so one effective way to do this is to minimize fructose in your diet.

Poor nutrition in childhood has been shown to raise the risk of high blood pressure in adulthood.29

Lead exposure30

Air pollution — Air pollution affects blood pressure by causing inflammation. According to one 2019 study,31 “the enhanced exposure to PM2.5 by 10 µg/m3 leads to an increase of systolic and diastolic blood pressure by 1-3 mmHg and is associated with a hazard ratio of 1.13 for the development of arterial hypertension.”

Noise pollution — Noise pollution can also affect your blood pressure, primarily by activating stress responses that affect your autonomic and endocrine (hormonal) systems. As noted in one 2017 study:32

“Chronic annoyance causes stress characterized by increased levels of stress hormones such as cortisol and catecholamines. Chronic stress may in turn cause a number of pathophysiological adaptations, such as increased blood pressure, increases in heart rate and cardiac output …”

Key lifestyle strategies for lowering your blood pressure

In my experience, elevated blood pressure — even stage 1 and 2 high blood pressure — can be successfully addressed with lifestyle interventions, to where drugs become unnecessary. The key is to be sufficiently aggressive in your diet and lifestyle modifications.

That said, if you have seriously elevated blood pressure, it would be wise to take a medication to prevent a stroke while you implement these lifestyle changes. Below, I’ll review several suggestions that can help lower your blood pressure naturally.

Address insulin resistance

As mentioned, high blood pressure is typically associated with insulin resistance,33 which results from eating a diet too high in sugar. As your insulin level elevates, so does your blood pres­sure.34

There are several reasons for this. For starters, insulin stimulates magnesium uptake.35 If your insulin receptors are blunted and your cells grow resistant to insulin, you cannot store magnesium so it passes out of your body through urination.

To ascertain whether insulin/leptin resistance is at play, be sure to check your fasting insulin level. Aim for a fasting insulin level of 2 to 3 microU per mL (mcU/mL). If it’s 5 mcU/mL or above, you definitely need to lower your insulin level to reduce your risk of high blood pressure and other cardiovascular health problems.

Keep in mind that the so-called “normal” fasting insulin level is anywhere from 5 to 25 mcU/mL, but please do not make the mistake of thinking that this “normal” insulin range equates to optimal.

Avoid fructose

Aside from raising your insulin, fructose also elevates uric acid, which drives up your blood pressure by inhibiting nitric oxide in your blood vessels. (Uric acid is actually a byproduct of fructose metabolism. In fact, fructose typically generates uric acid within minutes of ingestion.)

If you’re healthy and want to stay that way, the general rule is to keep your total fructose intake to 25 grams per day or less. If you’re insulin resistant and/or have high blood pressure, keep your total fructose to 15 grams or less per day until your condition has resolved.

Eat real food

Being high in sugar, unhealthy seed oils and synthetic chemicals, a processed food diet is a recipe for high blood pressure. Instead, make whole, ideally organic foods the focus of your diet. This will address not only insulin and leptin resistance but also elevated uric acid levels.

One 2010 study36 discovered that those who consumed 74 grams or more per day of fructose (the equivalent of about 2.5 sugary drinks) had a 77% greater risk of having blood pressure levels of 160/100 mmHg. Consuming 74 grams or more of fructose per day also increased the risk of a 135/85 blood pressure reading by 26%, and a reading of 140/90 by 30%.

According to the authors, “These results suggest that high fructose intake, in the form of added sugar, independently associates with higher [blood pressure] levels among U.S. adults without a history of hypertension.”

Also remember to swap nonfiber carbs for healthy fats such as avocados, butter made from raw grass fed organic milk, organic pastured egg yolks, coconut oil, raw nuts such as pecans and macadamia, grass fed meats and pasture raised poultry. To learn more about healthy eating, please see my optimal nutrition plan, which will guide you through the necessary changes step-by-step.

In addition to what you eat, when you eat can also have a significant impact on your insulin sensitivity (and hence blood pressure). Intermittent fasting is one of the most effective ways I’ve found to normalize your insulin/leptin sensitivity. It’s not a diet in conventional terms, but rather a way of timing your eating in such a way as to promote efficient energy use.

Increase your nitric oxide levels

Nitric oxide helps your vessels maintain their elasticity, so nitric oxide suppression increases blood pressure. A specific food that has been found to have a beneficial effect on blood pressure is beetroot juice,37 thanks to its ability to convert the nitrate in the beetroot juice into bioactive nitric oxide.

In one small placebo-controlled trial,38 one glass (250 milliliters or 8.5 ounces) of beetroot juice per day for one month reduced blood pressure in those diagnosed with high blood pressure by a mean of 7.7/2.4 mm Hg when measured in a clinic setting, and 8.1/3.8 mm Hg when measured at home. The treatment group also saw a 20% improvement in endothelial function. Arterial stiffness was also reduced.

Optimize your magnesium and sodium-to-potassium level

Magnesium inhibits high blood pressure39 by combating inflammation, relaxing your arteries and helping prevent thickening of your arteries, allowing for smoother blood flow. Magnesium stored in your cells relaxes muscles, including your blood vessels. If your magnesium level is too low, your blood vessels will constrict, thereby raising your blood pressure.

According to one scientific review,40,41 which included studies dating as far back as 1937, low magnesium appears to be the greatest predictor of heart disease, and other recent research42 shows even subclinical magnesium deficiency can compromise your cardiovascular health.

Your sodium-to-potassium level is also a crucial factor.43 According to Lawrence Appel, lead researcher on the DASH diet and director of the Welch Center for Prevention, Epidemiology and Clinical Research at Johns Hopkins, your diet as a whole is the key to controlling hypertension — not salt reduction alone.

He believes a major part of the equation is this balance of minerals — i.e., most people need less sodium and more potassium, calcium and magnesium. In a 2014 interview, he told USA Today,44 “Higher levels of potassium blunt the effects of sodium. If you can’t reduce or won’t reduce sodium, adding potassium may help. But doing both is better.”

Indeed, maintaining a proper potassium to sodium ratio in your diet is very important, and hypertension is but one of many side effects of an imbalance. A processed food diet virtually guarantees you’ll have a lopsided ratio of too much sodium and too little potassium. Making the switch from processed foods to whole foods will automatically improve your ratios.

Optimize your omega-3 index

Research also highlights the importance of animal-based omega-3 fats for healthy blood pressure — especially in young adults.

In one 2018 study,45 those with the highest serum levels of omega-3 also had the lowest blood pressure readings. On average, their systolic pressure was 4 mm Hg lower and their diastolic pressure was 2 mm Hg lower compared to those with the lowest omega-3 blood levels.

The best way to boost your omega-3 is to eat plenty of oily fish that are low in mercury and other pollutants. Good options include wild caught Alaskan salmon, sardines and anchovies. Alternatively, take a high-quality krill oil supplement.

For information about how to measure your omega-3 level, what the ideal level is and how your omega-3 index affects your risk for heart disease, see the hyperlink above.

Optimize your vitamin D level

Vitamin D deficiency, associated with both arterial stiffness and hypertension,46 is another important consideration. According to researchers from the Emory/Georgia Tech Predictive Health Institute,47 even if you’re considered generally “healthy,” if you’re deficient in vitamin D then your arteries are likely stiffer than they should be.

As a result, your blood pressure may run high due to your blood vessels being unable to relax. In their study, having a serum level of vitamin D lower than 20 nanograms per milliliter (ng/ml) was considered a deficiency state that raises your hypertension risk. Less than 30 ng/ml was deemed insufficient.

Previous research48 has also shown that the farther you live from the equator, the higher your risk of de­veloping high blood pressure. Blood pressure also tends to be higher in winter months than during the summer. Exposing your bare skin to sunlight affects your blood pressure through a variety of different mechanisms, including the following:

  • Sun exposure causes your body to produce vitamin D. Lack of sunlight re­duces your vitamin D stores and increases parathyroid hormone produc­tion, which increases blood pressure.
  • Vitamin D deficiency has also been linked to insulin resistance and metabolic syndrome, a group of health problems that can include insulin resistance, elevated cholesterol and triglyceride levels, obesity and high blood pressure.
  • Research49 shows that sun exposure increases the level of nitric oxide in your skin. This dilates your blood vessels, thereby reducing your blood pressure. (For comparison, and to show how various factors tie together, uric acid, produced when you eat sugar/fructose, raises your blood pressure by inhibiting nitric oxide in your blood vessels — the opposite effect of sun exposure.)
  • Vitamin D is also a negative inhibitor of your body’s renin-angiotensin sys­tem (RAS), which regulates blood pressure.50 If you’re vitamin D deficient, it can cause inappropriate activation of your RAS, which may lead to high blood pressure.

Exposure to ultraviolet rays is also thought to cause the release of endor­phins, chemicals in your brain that produce feelings of euphoria and relief from pain. Endorphins naturally relieve stress, and stress management is an important factor in resolving high blood pressure. To learn more about vitamin D testing, please see “How Vitamin D Performance Testing Can Help You Optimize Your Health.”

Exercise regularly

A comprehensive fitness program can go a long way toward regaining your insulin sensitivity and normalizing your blood pressure. To reap the greatest rewards, I recommend including high-intensity interval exercises in your routine.

While the nitric oxide dump I previously promoted is OK to do, I have learned a far superior strategy that not only increases nitric oxide but also increases muscle strength. It is called blood flow restriction training and I should have detailed instructions and videos on this in the next month.

Strength training is particularly important if you’re insulin resistant. When you work individual muscle groups, you increase blood flow to those muscles, and good blood flow will increase your insulin sensitivity.

I also recommend training yourself to breathe through your nose when exercising, as mouth breathing during exercise can raise your heart rate and blood pressure, sometimes resulting in fatigue and dizziness. To learn more about this, please refer to my previous article on the Buteyko breathing method.

Address pollution and stress

Smoking is known to contribute to high blood pressure, as are other forms of air pollution, and even noise pollution. To address these, avoid smoking, consider using ear plugs during sleep if you live in a noisy neighborhood (provided you cannot move), and take steps to improve your indoor air quality.

The connection between stress and high blood pressure is also well documented, yet still does not receive the emphasis it deserves. Suppressed negative emotions such as fear, anger and sadness can severely limit your ability to cope with the unavoidable every day stresses of life.

It’s not the stressful events themselves that are harmful, but your lack of ability to cope. The good news is, strategies exist to quickly and effectively transform your suppressed, negative emotions, and relieve stress.

My preferred method is the Emotional Freedom Techniques (EFT), an easy to learn, easy to use technique for releasing negative emotions. EFT combines visualization with calm, relaxed breathing, while employing gentle tapping to “reprogram” deeply seated emotional patterns.

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Clinical Trial of a Cross-Link Breaker to Treat Presbyopia in the Aging Eye

Clinical Trial of a Cross-Link Breaker to Treat Presbyopia in the Aging Eye

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Presbyopia in the aging eye manifests as a difficulty in focusing on close objects. It is caused by hardening of the lens, which is in part the result of cross-linking in the extracellular matrix of that tissue, though other mechanisms are involved as well. Cross-links are hardy metabolic byproducts resulting from the normal operation of metabolism, capable of degrading the structural properties of tissue, particularly elasticity, by linking proteins together and restricting their motion. Cross-linking is likely of great importance in skin aging and cardiovascular aging. The primary age-related cross-links of the lens are not the same as those of other soft tissues in the body, however: disulphide bonds rather than glucosepane. So this research is interesting for all of us heading towards older age and dysfunctional vision, but only in the context of dysfunctional vision. As a first attempt, there is clearly some room for improvement in the degree to which the approach taken breaks cross-links, but, given this proof of principle, that further improvement should follow in the years ahead.

A new topical agent is coming closer than ever to improving the accommodative range for presbyopes. The agent, lipoic acid choline ester (UNR844, Novartis, formerly EV06), is a reducing agent that is purported to reduce the disulfide bonds that form between lens proteins, thus increasing the deformability of the crystalline lens. “This chemical was designed to improve the internal rheology of the cytosol within the lens fibers inside the lens capsule. It is safe, well-tolerated, and showed statistically significant near visual acuity improvement in clinical trials compared to placebo. The widespread use of this drug stands to radically alter the visual performance of humans within our lifetimes.”

Presbyopia is not just a matter of lens compliance. It is caused by a few different events, each of which constitutes a potential treatment target: the crystalline lens enlarges over time (ectoderm), the ciliary body undergoes atrophic changes, the vitreous becomes less viscous, and the lens loses its flexibility. The hypothesis that drove the development of UNR844 addressed lens flexibility or the lack thereof in presbyopia. When lens proteins become oxidized over time, disulfide bonds form, rendering them less able to move relative to one another during the act of accommodation.

“The theory was that if we had a way to chemically reduce these disulfide bonds, the proteins would regain increased degrees of freedom and allow a greater range of deformation of the lens, translating into a greater dynamic range of accommodation.” Lipoic acid is a naturally occurring antioxidant and reducing agent. To allow the reducing agent to achieve sufficient concentration within the eye, researchers developed a prodrug to improve the compound’s penetration, allowing it to metabolize and convert to its active form (dihydrolipoic acid [DHLA]) once within the lens. DHLA reduces disulfide bonds between lens proteins and restores lens microfluidics. Proof of concept was confirmed in vitro with human cadaver lenses and in vivo in rabbit eyes, where in both trials the drug produced lens softening and an increase in lens deformability.

The Phase 1/2 clinical study evaluated safety and efficacy of EV06 ophthalmic solution 1.5% in improving distance corrected near visual acuity (DCNVA) in subjects with presbyopia. The prospective, randomized, double-masked, placebo-controlled study included 75 patients (45-55 years) with hyperopia, myopia, or emmetropia, and a diagnosis of presbyopia. At baseline, the study patients had DCNVA below 20/40 in each eye. The study drug was given for 91 days and patients were monitored during a 7-month follow-up period. Visual acuity improvements were most pronounced when subjects employed bilateral vision, with 84% achieving 20/40 bilateral vision or better versus 52% in the placebo group.


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The CellAge Database of Genes Associated with Cellular Senescence

The CellAge Database of Genes Associated with Cellular Senescence

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The accumulation of lingering senescent cells is a cause of aging, via the inflammatory and other signals secreted by these cells. This is now widely accepted in the research community, and the first senolytic drugs that can selectively clear some of the burden of senescent cells already exist. Unfortunately it is not yet widely appreciated that these first low cost rejuvenation therapies do in fact exist, and are easily obtained and used. Hundreds of millions of people suffer from inflammatory conditions of aging that can likely be effectively treated via even just a single dose of senolytic drugs. Producing more human data for these existing treatments and bringing them to the vast patient population who would benefit should be much more of a priority than it is today.

Given that any new understanding of the biochemistry of senescent cells might lead to a novel basis for therapies that can greatly improve health in old age, there is a great deal of funding these days for efforts to map the biochemistry of the senescent state. These efforts are giving rise to new startup biotech companies, a few every year, and new candidate small molecule senolytics at an accelerated rate. Here, researchers announce a new database of genes associated with cellular senesence, one of a number of scientific initiatives likely to accelerate progress towards a full understanding of the biochemistry of senescent cells.

Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of ageing and has been linked to ageing-related diseases like cancer. Senescent cells have been shown to accumulate in tissues of aged organisms which in turn can lead to chronic inflammation. Many genes have been associated with cell senescence, yet a comprehensive understanding of cell senescence pathways is still lacking. To this end, we created CellAge, a manually curated database of 279 human genes associated with cellular senescence, and performed various integrative and functional analyses.

We observed that genes promoting cell senescence tend to be overexpressed with age in human tissues and are also significantly overrepresented in anti-longevity and tumour-suppressor gene databases. By contrast, genes inhibiting cell senescence overlapped with pro-longevity genes and oncogenes. Furthermore, an evolutionary analysis revealed a strong conservation of senescence-associated genes in mammals, but not in invertebrates.

Using the CellAge genes as seed nodes, we also built protein-protein interaction and co-expression networks. Clusters in the networks were enriched for cell cycle and immunological processes. Network topological parameters also revealed novel potential senescence-associated regulators. We then used siRNAs and observed that of 26 candidates tested, 19 induced markers of senescence. Overall, our work provides a new resource for researchers to study cell senescence and our systems biology analyses provide new insights and novel genes regarding cell senescence.


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Recent Work on APOE in Alzheimer's Disease

Recent Work on APOE in Alzheimer's Disease

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Apolipoprotein E (APOE) is a well studied gene, given that variants are associated with a greater risk of developing Alzheimer’s disease. That said, high blood pressure and high blood cholesterol levels are just as important as risk factors for Alzheimer’s disease when compared against all but the worst APOE variant, APOE4. Looking beyond Alzheimer’s, in most cases lifestyle choices and their consequences on the operation of metabolism, particularly becoming overweight, have larger effects on risk of age-related disease than genetic variants. The common wisdom of a 75%/25% split between environment and genetics respectively in the matter of age-related disease and mortality may be overestimating the contribution of genetics, per more recent data.

The point of investigating the activities of specific protein variants in which risk or scope of age-related is shifted is this: that the work may lead towards points of effective intervention. Not the gene or protein itself, usually, but something in the mechanisms with which it interacts. The late stages of all age-related conditions are enormously complex, and having the example of differences that affect the progression of the condition can help to pin down which of the many, many possible metabolic processes are most important. That is somewhat in evidence in the research materials here, but of course says nothing about how to effectively target those important mechanisms.

Rare Luck: Two Copies of ApoE2 Shield Against Alzheimer’s

Mention ApoE and Alzheimer’s, and the conversation turns to the E4 allele, the strongest susceptibility gene for the disease. But ApoE has another side, in ApoE2. Though this isoform protects against AD, scientists have barely studied it. Now ApoE2 is attracting scrutiny as scientists are asking exactly how some people maintain their mental acuity into old age. A study of ApoE genotypes in 5,000 autopsy-confirmed cases of AD revealed that people with two copies of E2 see their risk of dementia plummet by a stunning 90 percent compared with those with the common E3/E3 genotype. Other work suggested that this could be because ApoE2 reduces amyloid and tau pathology, and boosts gray-matter volume in critical brain regions. E2’s benefits seem specific to Alzheimer’s, not generic to neurodegeneration.

ApoE is the major cholesterol-carrying protein in the brain. It has been studied since its discovery as an AD risk gene in the early 1990s, but is newly emerging as a hub for glial responses to amyloid and tau aggregate deposition. The gene exists as three polymorphic alleles – E2, E3, and E4 – with a worldwide frequency of 8 percent, 78 percent, and 14 percent, respectively. Several mutated forms are also known. ApoE4 receives by far the most attention from AD researchers, because it boosts the risk of AD up to 15-fold depending on the study population, and occurs in 40 percent of people with AD. E2, the protective allele, has received scant attention, because it is the least common of the three and largely absent from AD samples.

ApoE4 Glia Bungle Lipid Processing, Mess with the Matrisome

It is suggested that ApoE4 predisposes people to Alzheimer’s disease by modulating astrocytes and microglia. Researchers describe transcriptional differences between iPSC-derived human astrocytes and microglia that express ApoE4/4 or ApoE3/3. The ApoE4/4 glia generated more cholesterol than their E3/3 counterparts. They exported and degraded it poorly, causing lipid to build up inside them. The E4/4 glia also pumped out greater amounts of proinflammatory cytokines and extracellular matrix proteins than E3/3s.

Does this have anything to do with Alzheimer’s? Lo and behold, in Alzheimer’s disease brains, astrocytes and microglia behaved quite similarly to these ApoE4/4 glia. They accumulated lipid and ratcheted up inflammation. Importantly, they did so regardless of their ApoE genotype. The data imply that ApoE4 may nudge microglia and astrocytes toward an Alzheimer’s-like state. Perhaps faulty lipid metabolism is one of the earliest changes on the path to Alzheimer’s. If so, restoring glial lipid regulation could be a therapeutic approach.

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How to increase your health span

How to increase your health span

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Ivor Cummins is a biochemical engineer with a background in medical device engineering and leading teams in complex problem-solving. On his website,,1 he offers guidance on how to decode science to transform your health.

In the featured lecture, “Avoiding and Resolving Modern Chronic Disease” presented at the Low Carb Denver 2019 conference,2,3 Cummins discusses the root causes of heart disease and other chronic health problems that rob us of our health span.

His father, who died of heart disease, also suffered with vascular dementia for about 15 years. In total, Cummins believes his father lost about 20 years of his health span — years he could have had, had he had access to better information.

According to the statistics Cummins cites, about 30% of people lived past the age of 70 in 1925. Since then, our life span has improved. Nowadays, a greater percentage of people live well into their 80s and 90s, compared to 1925.

However, Cummins believes that with appropriate nutrition and lifestyle modifications, we could live well past 100, and more importantly, remain healthier far longer than we are now.

As noted by Cummins, there’s little point in living longer if you’re chronically ill and cannot enjoy your life. He proposes that the primary hindrance to extended health span is the process of atherosclerosis, the hardening of your arteries, which is the No. 1 cause of heart disease.

By implementing the appropriate lifestyle strategies, you can prevent or at the very least stabilize the disease progression, thereby avoiding a life-threatening heart attack.

Understanding your CAC score

In his lecture, Cummins discusses the importance of your coronary artery calcium or CAC score, which he refers to as “the master measure for cardiac disease.”

As noted by the American College of Cardiology,4 a CAC scan “is one way to estimate someone’s risk of developing heart disease or having a heart attack or stroke.” The reason for this is because calcium deposits in your arteries signal buildup of plaque, which over time hardens and narrows your arteries.

The thicker your arteries, the higher your score. Cummins cites research5 showing that having a CAC score of zero in middle age means you have a very low risk (1.4%) of heart attack in the following decade.

A low score between 1 and 100 raises your risk to 4.1%, an intermediate score between 101 and 400 raises your risk to 15%, and a high score between 400 and 1,000 puts your risk at 26%. Above 1,000, your risk of a heart attack within the next 10 years is 37%.

He also cites data from the Framingham study showing the cardiovascular disease (CVD) risk for seniors with a zero CAC score is nearly identical to that of a 50-year-old with a zero score. Ditto for those with intermediate scores.

In other words, while age is typically seen as the primary risk factor for CVD, the CAC score takes precedence when it comes to identifying your real risk, and transcends other risk factors. Needless to say, if you stop the progression of calcification, you decrease your future risk of CVD, and the earlier you catch it, the better.

The CAC scan takes about 30 minutes and costs between $100 and $400.6 While some health insurance plans may pay for this test, most do not, so check your plan details. Ideally, discuss your need with your doctor, who can refer you to a facility that performs the scan. There are also walk-in CAC scan clinics around the U.S.,7 but you’ll still need to share the results with your doctor to have him or her interpret them for you.

What drives CVD progression?

To prevent atherosclerotic progression, you need to know what the driving factors are. Cummins compares data of calcification rates in Western white men and those of indigenous cultures.

The differences are provocative, with indigenous Tsimane men having virtually no calcification even into their later years, and even though they have very similar low density protein (LDL) particle counts (a well-recognized risk factor for CVD and the focus of Cummins’ lecture) as white men.

What lifestyle differences may account for these discrepancies? According to Cummins, these indigenous tribesmen have:

  • An all-natural, unprocessed diet and healthy omega-3-to-omega-6 ratios
  • Low blood glucose and insulin levels
  • No diabetes, metabolic syndrome or hyperinsulinemia syndrome
  • No hypertension
  • No central obesity

Heart healthy strategies

If you want to protect your heart and live a healthy life well into your retirement, Cummins believes the following factors are the most important. As you will see below (and in his lecture), these factors are all underlying drivers of atherosclerosis. Thus, to avoid CVD you’ll want to:

Avoid glucose spikes and insulin resistance

Avoid inflammatory drivers

Maintain healthy blood pressure

Limit oxidative stress

Address mineral and vitamin deficiencies

Avoid iron overload

Avoid heavy metal exposure and/or addressing heavy metal toxicity

Address autoimmune issues

Avoid and address infections

Quit smoking

Factors that influence the effects of LDL

Cummins presents a model based on the airline industry’s airplane crash trajectory. There are many defense systems in place, and a failure must appear in each system layer for a crash to occur. The same model can be applied to CVD. In order for a heart attack to occur, more often than not, multiple factors must line up.

You’re probably familiar with the theory that high LDL particle count can be a significant risk factor for CVD. Cummins warns that should a dietary change cause your LDL particle count to skyrocket, you’d be wise to investigate further. To assess whether high LDL particle count is actually a problem, the following factors need to be taken into account, as they all play a role:

Oxidized LDL in your bloodstream — According to Cummins, recent research shows it’s damage to the LDL in your blood that leads to oxidized LDL. Oxidized LDL is allowed into your arterial wall through the LOX-1 receptor, thereby contributing to the atherosclerotic process.

Meanwhile, undamaged LDLs “do not appear to partake in the process in a meaningful way,” Cummins says. So, if you have high LDL particle count, you’ll want to know whether or not they’re oxidized. The list above (of strategies that will protect your heart), are things that will affect the oxidation of your LDL.

Damaged glycocalyx — The glycocalyx are tiny hair-like protrusions on the inside of your artery that act as a sieve for LDL. It regulates many of the components that determine which particles will be allowed to enter the artery wall.

The paper8 “Hypothesis: Arterial Glycocalyx Dysfunction Is the First Step in the Atherothrombotic Process” details the role of the glycocalyx. According to Cummins, scientists have identified the following factors as being damaging to the glycocalyx, which also match his list of CVD prevention strategies above:

Diets high in sugar and processed foods

High blood pressure

Oxidative stress

Oxidized LDL (but not native LDL)


Arterial morphology

Damaged endothelium — The endothelium is a single-celled layer inside your artery that manages the damaged LDLs entering the arterial wall. (In his lecture, Cummins explains the two ways in which LDL’s can enter your arterial wall.)

Factors that damage your endothelium, allowing LDLs to be driven across it, include the following. Again, most of the items on Cummins’ list of things to avoid to protect your heart will trigger these endothelia damaging factors:9

C-reactive protein

Oxidized LDL

Oxidant induction

Reactive oxygen species

Lipopolysaccharide ingress from infections and leaky gut syndrome that causes an immune reaction

Tumor necrosis factor

Angiotensin II

Interleukin-I 7

Proteoglycan reactivity — Proteoglycans are hair-like structures inside your arterial wall that can trap LDL particles and cause them to oxidize. What makes LDL particles get stuck here?

According to Cummins, the research shows it’s not LDL particle size per se that matters most. Heart attack patients, Type 2 diabetics and those with insulin resistance all have higher proteoglycan reactivity, and Cummins believes his list (above) covers most of the issues that these people have. 

Damaged high density lipoprotein (HDL) efflux — High HDL is typically viewed as being protective, but that’s not the whole story. As explained by Cummins, HDL helps remove cholesterol from your arterial wall.

As long as the HDL can keep up with the incoming cholesterol, buildup is prevented. Problems can occur, however, if your HDL become inefficient at their task. The importance and impact of HDL functionality is detailed in the paper10 “HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events.”

The researchers measured not just the HDL level but the actual functionality of the participants’ HDL. Those with highly functional HDL had a significantly lower risk of CVD than those with poorly functioning HDL. “This is the real story on HDL,” Cummins says. So, how do you lower the functionality of your HDL? Fail to address the items on Cummins heart-health list.

Ketogenic diet is part of the answer

In short, the risk factors Cummins lists (high glucose and insulin levels, inflammation, high blood pressure, oxidative stress and so on), all damage your arteries in ways that allow LDL to cause CVD. Yet for the past half-century, the medical community has been near-exclusively focused on cholesterol while largely ignoring the root causes.

Unfortunately, as noted by Cummins, the media has been complicit in creating bad press and misleading information about lifestyle strategies that can effectively address these root causes, such as nutritional ketosis. The “keto crotch” disinformation, for example, was a PR ploy designed to scare people away from the ketogenic diet. 

“All of this media has a chilling effect in applying low-carb or keto, and because a majority of our adult population are now essentially diabetic, we need low-carb and keto to fix the real root causes,” Cummins says.

To extend your health span (and not just your life span), Cummins points out you need to do your due diligence as early as possible, which means addressing the root causes as early in life as possible.

A cyclical ketogenic diet can go a long way toward addressing those issues, lowering inflammation, normalizing your blood glucose, insulin and blood pressure and so on. Aside from eating a low-carb diet, Cummins also recommends:

  • Eliminating industrial seed oils and processed foods from your diet
  • Eat more low-mercury fish and optimize your omega-3 index
  • Eat nutrient-dense whole foods, including eggs, butter and other healthy fats
  • Get healthy sun exposure on a regular basis (making sure not to burn)

Diagnostic recommendations

In summary, Cummins recommends getting regular lab work done to track your status. If your CVD risk based on your lab work is really low, you probably don’t need a CAC scan.

If your lab work indicates high risk, you don’t need a CAC scan, as you need to take action to lower your CVD risk anyway. CAC is best for those in the middle, who want to fine-tune their risk assessment.

If your CAC score is low, maintain a healthy lifestyle and retest in five to seven years to make sure you’re still on track. Midrange scores are indicative that changes are needed, if you want to lower your CVD risk. If you haven’t already implemented the prevention strategies listed earlier, now’s the time.

If your score is high, Cummins recommends following up with expert assessment of more comprehensive blood panels — such as A1C, GGT, ferritin, homocysteine and others — to pinpoint where the problem lies.

In the case of a high score, you may want to do another scan in about two years to get an idea of what your trajectory is — are the changes you’re making producing the desired results? If not, what may you be doing wrong, or what have you failed to address?

A high score also means you have little room for cheating — you’d be wise to implement as many healthy lifestyle strategies as possible, and be strict about maintaining them.

Just remember, your body has a remarkable way of self-healing, given half the chance, and as Cummins notes, we now know a whole lot more about what’s required for good health than we did in decades past. The key is to implement this knowledge.

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A flavonoid a day keeps the doctor away

A flavonoid a day keeps the doctor away

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Flavonoids may not have the name recognition vitamins and minerals do, but as antioxidants with the power to fight disease and premature aging,1 plus decrease inflammation, they can make a dramatic difference in your health if you know where to find them.

Believe it or not, there are more than 6,000 distinct flavonoids, and every one of them communicates a unique benefit for your body. Found in fruits, vegetables, nuts and herbs, these phytonutrients have the capacity to prevent many of the most common illnesses in the world. Several of them are becoming more familiar to savvy consumers.2

Findings from a recent study collaboration between several researchers in Denmark and Australia, as well as one each from Northern Ireland and France, show you can lower your risk of developing heart disease, cancer and all-cause mortality when you regularly eat foods containing flavonoids.

The featured study, published in Nature Communications and known as the Danish Diet, Cancer and Health cohort, is the work of researchers who spent 23 years scrutinizing the diets of 53,048 Danish people. They found lower risks of death from cancer and heart disease in those who consumed more flavonoids. According to the scientists:

“A moderate habitual intake of flavonoids is inversely associated with all-cause, cardiovascular- and cancer-related mortality … The inverse associations between total flavonoid intake and mortality outcomes are stronger and more linear in smokers than in non-smokers, as well as in heavy vs. low-moderate alcohol consumers …

Fruit and vegetable intakes are associated with a lower risk of cardiovascular disease (CVD), cancer, and all-cause mortality, with an estimated 7.8 million premature deaths worldwide in 2013 attributable to a fruit and vegetable intake below 800 (grams per) day.”3

Can your risk of death be lowered?

According to the CDC,4 in 2016, heart disease topped the list of the leading causes of death in the U.S., with cancer in the second position. Stroke and diabetes — two of the five risk factors for metabolic syndrome that also raise your risk for heart disease — take the fifth and seventh slots.

But researchers at Edith Cowan University’s School of Medical and Health Sciences in Australia looked at the data from the Danish Diet, Cancer and Health cohort and backed up the Danish cohort with a report5 that eating apples and drinking tea lower both cancer and heart disease risks. Both of those are high in flavonoids.

They also found a link between regular flavonoid consumption, drinking alcohol and smoking. People who were at a high risk of developing chronic diseases due to smoking and drinking more than two alcoholic drinks a day seemed to benefit the most from eating flavonoid-rich foods. Specifically, “Participants consuming about 500 [milligrams] of total flavonoids each day had the lowest risk of a cancer or heart disease-related death.”6

However, even the Danish study listed negative effects from smoking and drinking; besides being carcinogenic, it’s also damaging to endothelial and platelet function and culpable in such problems as thrombosis, inflammation and elevated blood pressure.7 An article in Health also didn’t give a pass to people who excessively drink and smoke:

“That doesn’t mean that eating flavonoid-rich foods will wipe out the harmful effects of excessive drinking and smoking, the researchers warn. But, the study found, it may help lower the risk of developing chronic diseases from these habits.”8

Nicola Bondonno, lead researcher for the Edith Cowan University study, agreed that eating lots of flavonoid-rich foods won’t outweigh the damage done by heavy tobacco and alcohol use, but that reducing them would at least help. She stressed that both habits damage blood vessels and increase inflammation, but flavonoid intake targets both of those specifically. She added:

“We know these (kinds) of lifestyle changes can be very challenging, so encouraging flavonoid consumption might be a novel way to alleviate the increased risk, while also encouraging people to quit smoking and reduce their alcohol intake.”9

Flavonoid intake: How much is enough?

According to Bondonno, about 500 milligrams (mg) of flavonoids were consumed by the study participants on a daily basis to lower their disease risks. She offered advice to replicate that outcome:

“It’s important to consume a variety of different flavonoid compounds found in different plant based food and drink. This is easily achievable through the diet: one cup of tea, one apple, one orange, 100 [grams] of blueberries, and 100 [grams] of broccoli would provide a wide range of flavonoid compounds and over 500 mg of total flavonoids.”10

The Danish study specified that 500 mg of flavonoid intake positively influenced outcomes for cardiovascular diseases, but with regard to cancer-related death, 1,000 mg per day was found to lower the “hazard ratios.” Another point was significant regarding flavonoid intake for optimal health:

“That the thresholds for each of the flavonoid subclasses approximately sum to the threshold for total flavonoid intake is consistent with the idea that all are important and afford added benefit. Interestingly, these threshold levels exist well within daily dietary achievable limits … In this population it is likely that tea, chocolate, wine, apples, and pears were the main food sources of flavonoids.”11

Flavonoids are abundant in most plant-based foods

Dark-hued fruits and vegetables as well as dark chocolate, red wine and tea typically provide ample flavonoids. There are six flavonoid categories, with similar names because of their chemical structure. It’s important to note that the chemical structure of these compounds is also responsible for generating changes in bioactivity and metabolism, and that’s where the health advantages are introduced. The Journal of Nutritional Science states:

“Flavonoids are associated with a broad spectrum of health-promoting effects and are an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is because of their antioxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme functions.”12

Both the journal and the USDA database on flavonoids13 note several flavonoid classes and subclasses. They’re listed below with examples of their sources and health benefits (with other studies cited):

Flavones — Luteolin is antitumor and anti-inflammatory; it blocks oxidative stress and is heart protective14 (found in Mexican oregano and rosemary); apigenin is beneficial for addressing diabetes, amnesia, Alzheimer’s disease, depression, insomnia and cancer15 (found in celery, broccoli, green peppers, thyme, parsley, mint and oregano)

Flavonols — Quercetin and kaempferol contain antioxidants and lower your vascular disease risk (found in squash and spinach); myricetin and isorhamnetin inhibit tumors in breast cancer16 (found in bananas, apples, blueberries, peaches, pears, green tea, grape seeds and red peppers)

Flavan-3-ols — Catechin and epicatechin are known for their antimicrobial properties; epicatechin 3-gallate, epigallocatechin and epigallocatechin-3-gallate are most abundant in green tea, and are shown to both treat and prevent infections17; theaflavin, theaflavin 3-gallate and theaflavin 3′-gallate (found in chocolate and milk); epicatechin works as an insulin receptor activator and may exert “insulin-potentiating activity on the utilization of glucose”18

Flavanones — Hesperetin, or naringenin, a strong antioxidant, promotes gene expression, reduced adiposity (obesity) in animal models and is found useful in treating metabolic syndrome19) and eriodictyol; these are linked to free radical scavenging (found in all citrus fruits, such as oranges and lemons as well as grapes)

Anthocyanins — Cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin compounds have high levels of antioxidants; they are shown to be chemoprotective; they are also heart protective and neuroprotective and fight diabetes, inflammation and obesity; they also help vision20 (found in cranberries, black currants, dark-hued grapes, sweet potatoes and berries)

Isoflavones — Genistin, genistein, daidzein, glycetein and daidzin, also called phytoestrogens, protect cells against oxidative DNA damage; they may reduce your risk of osteoporosis21; studies show they may contribute to fewer instances of prostate cancer22 and breast tumors23 (found in soybeans (which should be non-GMO, organic and fermented for optimal health) and legumes, although consumption should be limited); which exert oestrogenic activity24

Studies on prominent flavonoids

A Harvard Health article says one reason avid tea drinkers are less prone to developing heart disease may be because of potency of the flavonoids in tea leaves. Part of the benefits of drinking tea, particularly for strengthening the blood vessels in your heart, stems from catechin and epicatechin compounds. Specifically:

“Research suggests that flavonoids help quell inflammation, and that in turn may reduce plaque buildup inside arteries. Green tea has slightly higher amounts of these chemicals than black tea …

Short-term studies have shown that drinking tea may improve vascular reactivity — a measure of how well your blood vessels respond to physical or emotional stress. There’s also evidence that drinking either black or green tea may lower harmful LDL cholesterol levels … Several large, population-based studies show that people who regularly drink black or green tea may be less likely to have heart attacks and strokes.”25

A 2019 study found that the flavonoids in citrus fruits specifically are an example of how hard working and far reaching they are, notably zapping free radicals, improving both insulin sensitivity and glucose tolerance. They can break down fat for energy (lipid metabolism), decrease inflammation, fight obesity and improve endothelial function. All of these things lead to a healthier heart and improved blood sugar levels.26

In a study published in the Journal of Translational Medicine,27 it was observed that the more flavonoid-rich foods people eat, the less apt they are to develop heart disease, experience a nonfatal heart problem or die from heart disease. And from 12 studies used in a meta-analysis, it was reported in PLoS One28 that the incidence of breast cancer “significantly decreased” in women who reported a high intake of flavonols and flavones from their food.

For just one example of how powerful flavonoids are for your health, the one known as hesperetin in citrus fruits has alone exhibited dramatic health benefits, being “anticarcinogenic, antihypertensive, antiviral, antioxidant, antidiabetic, hepatoprotective [preventing liver damage], and anti-inflammatory.”29

When you realize the real pharmacological mechanisms these compounds can jump-start, it becomes clear how important they are in treating and preventing diseases and infections in multiple areas of your body.

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NASA takes astaxanthin into space

NASA takes astaxanthin into space

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The space program was in the news in mid-2019, not for the extended time astronauts are spending in space, moon landings or space stations, but as a result of a medical error that took the life of Neil Armstrong. Armstrong was one of the Apollo 11 crew that took a four-day journey through space to land on the surface of the moon.

He was the first to step onto lunar soil when he uttered the now famous quote: “That’s one small step for a man, and one giant leap for mankind.”1 At the age of 82, Armstrong underwent heart surgery at Mercy Health Hospital in Cincinnati Ohio.

Two weeks later he died, which his sons insisted was caused by medical error. Two years later, the family received a medical malpractice settlement, which was revealed after a reporter at The New York Times2 received a secret document in the days following the 50th anniversary of the moon landing.

The space program is again receiving attention as NASA announced it is testing the potential benefits of taking microalgae into space. Their hope is the microalgae can be used during long missions as a source of oxygen, nutrition and potentially biofuel.3

NASA considers astaxanthin essential for astronaut health

“Algae have long been known to offer a number of benefits to support long duration human space exploration. Algae contain proteins, essential amino acids, vitamins, and lipids needed for human consumption, and can be produced using waste streams, while consuming carbon dioxide, and producing oxygen.

In comparison with higher plants, algae have higher growth rates, fewer environmental requirements, produce far less “waste” tissue, and are resistant to digestion and/or biodegradation. As an additional benefit, algae produce many components (fatty acids, H2, etc.) which are useful as biofuels.”4

NASA wrote this in 2015 in a conference paper presented at the 66th International Astronautical Conference.5 Of the different species of microalgae being considered, chlorella vulgaris and Haematococcus pluvialis are the two that have risen to the top. Currently, chlorella is used in biofuels,6 human nutrition,7 biofertilizer8 and wastewater treatment.9

Haematococcus pluvialis is a microalga that produces astaxanthin when it becomes stressed. This is the pigment that gives salmon a bright pink color. NASA writes10 that a supply of astaxanthin from natural sources could potentially prevent the negative effects of radiation exposure, damage to the eyes,11 damage to the cardiovascular system12 and bone loss known to occur in space.13

Astaxanthin is a strong antioxidant with the potential to prevent damage from ionizing radiation.14 Studies have demonstrated it crosses the blood retinal barrier and protects the eyes against fatigue. It also protects eye tissue.15

Animal research demonstrates astaxanthin has an anti-inflammatory property and is a therapeutic agent against oxidative stress in the heart.16 Additionally, data from another study demonstrate that astaxanthin can inhibit the activity of osteoclasts, cells in the bone that dissolve bone tissue.17

Since NASA believes astaxanthin may provide astronauts with protection against some of the same oxidative stresses you experience on Earth, it may be worth considering increasing your natural intake, or using a natural supplement. The antioxidant can mitigate the effects of exposure to radiation during flight, blue light from digital monitors, cardiovascular stress and bone loss during your senior years.

What is astaxanthin?

Astaxanthin is a red pigment molecule belonging to the carotenoid family. It is produced in marine algae18 when the algae become stressed.19 When eaten by crustaceans and other sea life, it tends to lend a reddish hue to the shells, or the flesh of salmon. Marine birds like flamingos also get their color from eating microalgae full of astaxanthin.20

In the body it works as an antioxidant, helping to protect against reactive oxygen species and oxidation, which plays a role in aging, heart disease, Alzheimer’s disease and Parkinson’s disease.21 Studies have also shown astaxanthin works from the inside out to protect your skin from free radical damage.

From an antiaging standpoint, researchers22 have found 6 mg of astaxanthin taken over six to eight weeks may reduce the appearance of crow’s feet and age spots while enhancing elasticity and skin texture.

NASA is interested in investigating whether the effects of microgravity in space on haematococcus pluvialis will produce the antioxidant astaxanthin.23 They hypothesize that since it orients to gravity, the lower gravity experienced in space could be enough stress to support the production of astaxanthin.

Biological activity and health benefits

While astaxanthin is a carotenoid and a fat-soluble pigment, it does not have pro vitamin A activity Inhumans. Testing has found that it is superior to fish oil when it comes to improving the immune response and lowering the risk of infectious diseases. Since it is a fat-soluble compound, absorption is increased when it’s consumed with fats.24

In animal studies, astaxanthin offered the best protection against free radicals. Researchers have also found that the antioxidant activity is 10 times greater than zeaxanthin, lutein and beta-carotene.25 In part, this additional protection may be related to the molecular structure that enables it to reside inside and outside the cell membrane.26

Researchers have reported astaxanthin may reduce oxidative damage and thus improve the immune response. Others have reported a lower number of inflammatory cells in the lungs when astaxanthin is present.27

In an animal study28 Haematococcus had a protective effect on gastric ulcers in rats. In another, astaxanthin demonstrated a protective effect on the epithelial cells of the kidney from high glucose oxidative stress.

When compared against other carotenoids, it demonstrated significant antitumor activity and was able to inhibit the growth of fibrosarcoma, breast and prostate cancer cells in a test tube.29 Astaxanthin has also been shown to have a potential therapeutic effect against atherosclerotic cardiovascular disease and the reduction of heart damage following a heart attack.30

Astaxanthin is an activity and longevity promoter

Astaxanthin may also help improve your strength and stamina and decrease your post exertional recovery time. This is one of the reasons salmon have the strength and endurance to swim up-river for days. Hiroaki Yoshida, trail runner and judo therapist talks about his experience with astaxanthin:31

“While devoting myself to the conditioning and treatment of athletes and runners on a daily basis, I also participate in road races – mainly trail races – throughout the entire year. However, just after turning 33, I started to notice a drop in performance because I wasn’t recovering from fatigue after rigorous training and races.

That’s when I encountered astaxanthin. I noticed something about ten days after I started taking it. Even though it was the middle of the summer, which is an intense training period, I was able to wake up easily in the morning and my physical movements felt smoother and lighter.”

Research supports the case studies from athletes, finding heavy exercise and competition may increase damage due to reactive oxygen and nitrogen species. Antioxidants may help prevent and delay the damage.32 Further research33 in building strength and endurance in the elderly found astaxanthin improved muscle strength and increased the ability to endure walking longer distances.

Benefits to your heart and cardiovascular system, neuroprotective effects and anticancer effects all contribute to reducing your risk of disease and early death. But, astaxanthin may participate even further in lengthening your life. Forkhead box 03 (FOX03) is a gene belonging to the forkhead family of transcription factors. The gene is believed to function as a trigger for apoptosis.34

This gene is one of only two for which changes have exhibited an association with longevity.35 Researchers from the University of Hawaii found one in every three people has a version of the gene.

By activating the FOXO3 gene, scientists found they can make it behave like the “longevity” gene and that astaxanthin is the component activating it.36 In an animal study, researchers “measured a nearly 90% increase in the activation of the gene” in heart tissue, placing astaxanthin at the head of the line as an anti-aging therapy.37

Make sure your astaxanthin is natural and not synthetic

There are some natural sources of astaxanthin: the microalgae that produce it when the water supply dries up, the algae that use it as protection from ultraviolet radiation and the sea creatures that eat it. Synthetic astaxanthin is now commonly used to supplement fish feed in order to get the pink to orange red color you’ve come to associate with high-quality salmon.

However, synthetic astaxanthin is made from petrochemicals and does not confer the health benefits of natural astaxanthin. Cultivating enough algae to produce natural astaxanthin is challenging and a technical process. Synthetic versions are sometimes referred to as “nature identical” or “nature equivalent.”38

One of the biggest differences between them is that natural astaxanthin is more than 95% esterified, meaning fatty acids are attached to one or both ends. However, “synthetic astaxanthin is all free form, or unesterified.”39 In the past, it was easy to tell the difference between farmed salmon and wild-caught salmon as the vibrant pink color was a dead giveaway of wild caught fish.

Currently, aquaculture farmers are using beta carotene infused fish feed to mimic the color of wild caught salmon.40 However, while they may look similar, there are nutritional differences found in the lab. Using a fatty acid methyl ester analysis, researchers can determine whether salmon is wild-caught or raised on a farm and fed synthetic infused fish feed.41

Astaxanthin is found naturally in algae, salmon, trout, krill and crayfish.42 A common type of feed additive used is Carophyll Pink or Carophyll Stay Pink, manufactured by DSM.43

In one research comparison, data reveal that juvenile trout fed varying degrees of astaxanthin increased pigmentation but not antioxidant capacity.44 However, the diet of the fish was made up of Carophyll Pink containing a mere 10% astaxanthin.45

Choose your salmon wisely

Marketing and advertising executives understand the link between visual appeal and increasing sales. As a result, they found a niche market in fish feed. Makers of Carophyll Pink, DSM are very open in their description the effect their food additive has on farmed fish:46

“Much of the pleasure we derive from food comes from its visual appearance, so the color of food ingredients is extremely important. We offer products that allow consistent delivery of precisely-pigmented egg yolks, poultry and fish.

Carotenoid levels vary from one plant to another, and unless poultry and fish diets are provided with supplements, the result will be variation in the appearance of food products.

Our CAROPHYLL® range of carotenoid additives allows producers to deliver precisely-colored and pigmented food reliably and consistently. We have combined our quality products, our unique beadlet technology and our many years’ experience to provide a great method for improving product quality and increasing consumer confidence.”

Without the food additive, farm-raised salmon would have white flesh. According to Don Read,47 CEO of West Creek fish farm,48 this would not appeal to their customer base.49 Time magazine reports salmon is the second most popular seafood item sold in the U.S. and most aquaculture farmers are adding pigment compounds to get the same deep color found in wild-caught Alaskan salmon.50

The color compound is the most expensive part of salmon feed, costing nearly 20% of the total price of the feed. Some farmers add the carotenoids since it supports more normal growth, but they use just enough to meet the nutritional requirements.

Read said if customers would buy white salmon, he would use51 “significantly less” of the color compound in the feed. He went on to say,52 ”We’d be very, very happy if we didn’t have to use it. But that’s not the way it works.”

Remember, it is not only the astaxanthin levels in your salmon that are important. Wild-caught Alaskan salmon is a powerhouse of nutrition, while farmed salmon may have more in common with junk food than health food.53 A combination of exposure to pesticides, sea lice, antibiotics, dyes and PCBs contributes to this analogy.

In addition, farmed salmon may also be genetically altered. Mandatory labeling of bioengineered fish will not take effect until 2022.54 So, while farmed salmon may be a bright pink color, it is better to seek out wild-caught Alaskan salmon that won’t create a burden on your health.

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Lipid Accumulation in Microglia Contributes to Neuroinflammation and Neurodegeneration

Lipid Accumulation in Microglia Contributes to Neuroinflammation and Neurodegeneration

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Researchers have found that microglia in the aging brain have a tendency to accumulate lipids, and that those that do are harmful. This is a fascinating discovery, given that microglia are essentially the central nervous system version of macrophages elsewhere in the body, and lipid accumulation in macrophages leading to senescence and inflammatory behavior is an important mechanism in atherosclerosis. Further, it is well established that microglia in the brain become inflammatory, senescent, and dysfunctional in later life, and this behavior contributes to the progression of neurodegenerative conditions. It has been demonstrated that removing senescent microglia can turn back Alzheimer’s pathology in mouse models of the condition, for example. This lipid accumulation might be an important aspect of dysfunction in microglia, though it is anyone’s guess at this point as to where it sits in the web of cause and effect.

Microglia in the brain assume a dizzying array of states. Now researchers describe a new one: lipid droplet-accumulating microglia (LAM). These lipid-stuffed cells resemble the foamy macrophages seen in atherosclerotic lesions. They accumulate in the hippocampus of the aging brain and appear to be bad news, hiking inflammation and reactive oxygen species while having little ability to phagocytose debris. Notably, inflammatory stimuli induce LAM, as do some genetic variants associated with neurodegenerative disease.

Previous studies have identified a smorgasbord of distinct transcriptional profiles delineating subtypes of microglial states. A handful of these have been correlated with neurodegenerative disease. These include disease-associated microglia (DAM), which cluster around plaques in mouse models of amyloidosis, and the similar microglial neurodegenerative phenotype (MGnD) found in multiple mouse disease models. A recent study characterized human Alzheimer’s microglia (HAM), which were isolated from the Alzheimer’s brain. It is still unclear how all these types relate to each other and what they do.

While examining hippocampal sections from aged wild-type mice by electron microscopy, researchers were struck by the accumulation of lipid droplets inside microglia. These microglia resembled cells first described by Alois Alzheimer, who reported lipid-stuffed glia clustering around amyloid plaques in the Alzheimer’s brain more than 100 years ago. Researchers quantified the phenomenon in mice, finding that more than half the hippocampal microglia in 20-month-old wild-type animals contained from one to three lipid droplets. Droplets were rare in other brain regions, and nearly absent in 3-month-old mice.

To characterize these LAM, the authors isolated microglia from aged mouse hippocampi and sorted out those with high lipid content. Transcriptional profiling revealed 692 genes that were differently expressed between cells with low and high lipid content. In particular, genes involved in the production of reactive oxygen species, lipids, and pro-inflammatory cytokines were up in LAM, while genes responsible for phagocytosis were down. Notably, this transcriptional profile was in many respects the opposite of DAM, which turn up phagocytotic genes.

Functional studies of LAM reinforced these transcriptional findings. When the authors injected myelin debris into aged mouse hippocampus, microglia without lipid droplets engulfed it, but few LAM did. LAM isolated from brain produced more reactive oxygen species (ROS) than did low-lipid microglia, and they secreted higher levels of several pro-inflammatory cytokines such as CCL3, CXCL10, and IL-6. How do these cells arise? Because many of the LAM genes are regulated by inflammation, researchers speculate that they are products of an inflammatory response.


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