Artificially Reduced LDL Cholesterol Levels Far Lower than those of Healthy, Young Individuals Appear to be Beneficial

Therapies such as statins, that aim to reduce circulating levels of low-density lipoprotein (LDL) cholesterol, are perhaps the most prevalent medical approach to cardiovascular disease. Indeed, when measured against the low bar set for past attempts to treat age-related conditions, they are one of the most successful forms of treatment to date. A sizable fraction of the reduction in cardiovascular mortality over the past few decades is attributed to the widespread use of statins and similar treatments. Still, this is only a delaying action, it is not a fix for the underlying problems.

How do reductions in LDL cholesterol slow the consequences of cardiovascular aging? The processes of interest involve damaged cholesterol molecules and cellular reactions to their presence. As the various causes of aging progress, there is ever greater inflammation and oxidative stress to produce damaged, oxidized cholesterols that find their way into the bloodstream. Once there, this mix of damaged molecules irritates blood vessel walls. In most cases unwanted metabolic waste of this sort is promptly cleaned up, consumed by the immune cells called macrophages, and disposed of. In some cases, however, there is an overreaction, or macrophages become overwhelmed by the damaged forms of cholesterol. A feedback loop is created in which the blood vessel wall becomes inflammatory, drawing in ever more macrophages that become dysfunction and die to add their mass to the creation of the characteristic fatty lesions of atherosclerosis. These masses narrow blood vessels and disrupt the structure of the blood vessel wall. They reduce critical blood flow, and eventually, as blood pressure rises due to other age-related issues, these fatty plaques rupture to kill or seriously injure the individual.

All of this can be slowed by interfering in any of the critical steps, even without preventing the underlying causes. It can't be reversed without forms of repair, however. So researchers could aim to make macrophages more resilient, could reduce the flux of damaged cholesterol by reducing the overall level of cholesterol, could dampen inflammation by attempting to adjust the regulation of the immune system, and so forth. All of these will slow down atherosclerosis to the degree that any particular implementation can produce change. But to turn it back, themedical community would need means of safely breaking down the problem compounds that irritate blood vessels and kill macrophages. Researchers associated with the SENS Research Foundation have investigated this class of treatment over the years, as their budget has permitted, and made some progress in targeting the problem compound of 7-ketocholesterol via adaptation of baterial enzymes.

Just how low can LDL cholesterol go, however? If less is consistently better, because it slows down atherosclerosis, does less ever stop being better? At some point, one has to presume that running out of LDL cholesterol has to be a bad thing, or else we wouldn't evolved to have it to begin with. With the advent of new and far more effective approaches such as PCSK9 inhibitors, a considerably more powerful intervention than statins, it is possible to reduce cholesterol levels to a fraction of what they would otherwise be. Normal healthy adults have LDL cholesterol measures somewhere below 100 mg/dL. The most severely impacted older people can be nearing or passing 200 mg/dL. The latest therapies can push LDL cholesterol in older people down below 10 mg/dL, far beneath that of normal, young, healthy individuals. The evidence suggests that this is beneficial, and for exactly the same reasons that smaller reductions are beneficial: it reduces the pace at which atherosclerosis progresses. This leads to a number of questions that researchers seem generally unwilling to state in print at this point in time, such as whether or not all adults should be lowering cholesterol throughout their lives, or whether to focus on gene therapies that can achieve this effect across the entire life span without the need for drugs.

How Low Should LDL Cholesterol Go?

A newer class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond current treatment targets. In a new analysis, researchers sought to explore whether there was "floor effect" in the lowering of LDL cholesterol - essentially, is there a threshold below which there would be no added clinical benefit? Additionally, researchers explored whether ultra-low LDL cholesterol levels would have any negative impact.

Using data from the FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), which found that patients treated with the PCSK9 inhibitor evolocumab and statin therapy had a 20 percent reduction in the risk of cardiovascular death, myocardial infarction, or stroke, researchers examined the efficacy and safety of very low levels of LDL cholesterol among 25,982 patients per the degree of LDL-C reduction following one month of treatment. Researchers found that the risk for cardiovascular events (including cardiovascular death, heart attack, and stroke) over 2.2 years progressively declined as LDL cholesterol levels decreased to below 20 mg/dL (0.5 mmol/L), and participants who achieved an LDL-C of less than 10 mg/dL (0.26 mmol/L) had a more than 40 percent lower risk of cardiovascular events than those with an LDL cholesterol equal to or greater than 100 mg/dL (2.6 mmol/L).

"Our findings demonstrate that there is essentially no floor effect, and that lower levels translated to a greater reduction in risk. Among high-risk patients, achieving a LDL cholesterol level far below the most common treatment target of 70 mg/dL (1.8 mmol/L) can further reduce the risk for an adverse cardiovascular event, with no major safety concerns."

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

27,564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25,982 patients (94% of those randomly assigned) 13,013 were assigned evolocumab and 12,969 were assigned placebo. 2,669 (10%) of 25,982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8,003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3,444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4,395 (17%) patients achieved concentrations of 2.6 mmol/L or higher.

There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.

Comments

I have a very good HDL level of 85, but my bad LDL cholesterol stays around 110 no matter what I do, cut out eggs, take more fish oil, etc. My doctor recommends statins, but since I have a very good HDL to LDL ratio and low Triglycerides of around 100, I have resisted the statin route so far. Also, the PCSK9 drugs are too expensive for me. There still seems to be a diversity of opinion among medical researchers as to what a good cholesterol level should be for longevity purposes, which is my personal goal.

Posted by: Biotechy at September 14th, 2017 8:06 AM

@Biotechy, there are numerous risk factors for heart disease as illustrated by this link. Although they specialize in nutritional supplements instead of research, Life Extension does offer comprehensive blood testing for all relevant cardiac risk factors and this would offer a better picture of your level of risk. http://www.lifeextension.com/Protocols/Heart-Circulatory/Atherosclerosis-and-Cardiovascular-Disease/Page-01
For example, http://www.lifeextension.com/Vitamins-Supplements/itemLC123810/NMR-LipoProfile-Blood-Test

Posted by: Morpheus at September 14th, 2017 10:45 PM

@Biotechy

Hi Biotechy ! I had the same problem (I suffer from atherosclerosis). I did the same as you, I avoided the statins. Long story into short story, I had this2 years ago, and was on my death bed. Anyway, I changed completely my diet and now it is 'manageable', I still sometimes have arterial ischemia bout attacks, this is generally due to lack of O2 in confined spaces indoors or eating too much crap (excess glucose/sugar). So, I cut my calories down to the gold number : 600 calories a day, at first it was not enough I needed more to rebuild arterial necrotic lesioned tissue from my LDL cholesterol-filled plaques and lesions. I learned that as an atherosclerostic arteries person, your body is forced to use whatever small amount of fat on you as second energy when your O2/ATP levels drop too low in your endothelial cells in arteries tissue (otherwise it becomes necrotic and you can feel intense stingy sharp pains akin to being stabbed by 8inch knife in your body - they freeze you tahat much it hurts and you know Inside of you 'it's dying', your artery thus not have sufficient oxygen and is going into ischemic bout Attack, it will, litterally, 'wobble' around as it tries to 'suck' air but can't). IT's pretty scary stuff and I lived it. After that, I did like you, I stopped - completely - eating anything with cholesterol. 0 cholesterol.

Now, with that said, cholesterol is important for you - the Type is important. HDL is good in higher level, but in atherosclerosis your LDL, LDL-ox, vLDL are skyrocketing - this is a recipe for death. And, as you said, thus your HDL:LDL ratio is changed (lowered), making the LDL much too present compared to the HDL levels.

Cutting Any cholesterol intake from from (cholesterol-laden food/Junk food) was the Most Major effect on my health, it was improved. Statins are not enough, you must cut out the cholesterol completely. That is the only way to reduce the LDL for good. Statins work by inhibiting the liver X-receptor thus block cholesterol uptake, and also reduce choleterol production (they block a liver choleresterol enzyme that helps in cholesterol synthesis).

Cholesterol is important, for your brain needs it. It is a glucose rich organ, but also cholesterol rich - not just that, cholesterol is found in every mitochondrial membrane as a fluidizer to increase speed of mitochondrial kinetics (this, in turn, accelerate RMR (resting metabolic rate) which depends on chemical reaction kinetics inside ATP producers like mitos).

Now, this took many many months, it is not an overnight thing; you need at least 1 or 2 years to give your body the chance to recuperate from this catastrophe; as I did, and still alive, to tell you about.

I also stopped eating the bad fats : Trans fats and saturated fats - this has major impact on atherosclerosis. You suggested omega-3, it's true DHA EPA fluidizes membranes and improves ATP production which increases arterial ATP thus reduces inflammation from ischemia in atherosclerosis. I took Omega-3 for a long while, but it was unsatisfactory and did not help :

I even learned that Omega-3 I took was cholesterol-laden, the fish oil had trace amounts of cholesterol - after that, I did not take it anymore. It was self-defeating. Everytime I took Omega-3, only the smallest of smallest dose was helpful : I think I know why, oxidized DHA and EPA in capsules; it can backfire and be damaging than help. If I took too much DHA or EPA, it Increased Oxidation/Perodixation in my arteries - I felt it, again with the sharp sting and terrifying stabbing knife pain-feeling.

That means, I cut out fish too, fish was all great Before I had it, after I cut all types of meats - and became a vegetarian (sort of where I might add whole pasta here and there to get enough minerals, glucose, proteins). Fish is cholesterol laden, stop that if you have Advanced atherosclerosis - I stopped eatting 'oils' like Olive Oil - the worse of the bunch, I stopped eating 'Perilla oil/Flaxseed oil', stopped all fats altogethere greatly improved health and reduced 'cholesterol LDL production load'. EXtra-virgin olive oil, has benefits because it contains olive phenols, only eating the olive leaf is better for you avoid the oil. One study showed that extra-Virgin olive oil fed to apes increased their LDL levels and atherosclerotic lesion score - they died Quicker on the fatty oil diets. I was not surprised, monounsaturates in this oil improve against peroxidation but they dramatically increase Liver X and Stearoyl/stearic receptor activation in the liver. Which translates as LDL production, triglycerices and uptake/intake.

I also took many vegetables or certain low-fructors fruits - that did not help that much; it had to be constant. Polyphenols in these foods help in atherosclerosis such blueberries antocyanin whom 'mop up' the ROS in the atherosclerotic lesion and reduce TNF, stabilizes plaques that rupture and can cause Deadly clot (I know I had more than one, a Deadly clot yet I am still here). You have to reduce fibrinogen/thromboxane level, I took serratiopeptidase for a while and that helped in reducing fibrotic arterial plaque creation, not that much.
But, being Truthfull, before any of these Work to Save You from death, it Takes Time; and you will suffer ischemicpain as your body attemps 'To save itself' and repair the lesions; all the while stabilizing the plaque and it would become smaller with time.
Polyphenols are great at reducing plaque size with time and improving blood flow/circymference of the atherosclero-lesioned artery. Thus, reduce arterial ischemia/angina/embolism. I had all of these many times. I never thought I would see death so close, now I know what it feels like and that is why I believe in SENS and curing diseases on ce for all.

I also took aLot of vegetable/plant stearols - that counteract cholesterol. Stearols like Beta-sitosterol, Gamasitosterol, etc...have given me COnsistent benefits and are the Best; I keep them always close. They act by Directly inhibitng Liver X -receptor LDL cholesterol/uptake and produciton. And do a great job that is equal to stating or better (minus the bad side effects of statins). Along with many doses of minerals, such, as especially, Magnesium; magnesium levels too low, as such redox is weak and vasodilation weak too (too much vasoconstriction in the constrict atherosclerosed arteries; I aslo avoided very Hot ir COld temperature - cold was absolulely Killer to me, anything below -5 is absolutely Deadly because the arteries constrict upon detecting temperature change). Because you have lower ATP levels inarteries, your body tries to compensate by buring glucose faster to provide enough energy; this is why I would suffer eiter intense hypoglycemia or after 'binge-glucose' feeding intense hyperglycemia; it was not easy to find the middle; 600 calories with about 150 gr of glucose a day was the exact target and least mortaliy (From a study that showed 600 cal with 150gr glucose as lowest mortality on bell-sharped curve stats graph). EVen then, sometimes it was not enough because I burned it too quick I such I tried adding more fiber to slow down digestion (but digestion was very hard and then, I could actually Lose weight while I was on fiber diet; I would become thin and 'insufficient' in my artery; I would lose the important small 'fat layer' that is needed to provide a 'back up' in case the artery goes to low in ATP levels during a ischemia bout; this is provided by the adipocyte cells whom improve insulin and can give ATP/energy to the surrounding tissue. In fact, if I became too meager it was absolutely Havoc - you cannot be Too Frail or your will die; a small layer of fat is needed when glucose is become short of; the body switches to ketotic ketones formation just like in CR; it burns that fat layer Very Quickly in a ischemia bout and you become skeletic).

All in all, I suggest a positive Outlook and No Stress, Stress = Killer for atherosclerosis. Stress increases TNF, cortisol, hypertension and vasoconstriction. This makes for ischemic attacks. Also, I always have small Cayenne spice close for improving vasodilation; Cayenne just like Vanilla, both can activate the CRGP vasodilator peptide (Calcitonin-Gene Related Peptide) via the nerve Cayenne-receptor channel and vannilloid-receptor and it makes for a long lasting vasodilation and improved blood flow. As for diabetes (diabetes creates atherosclerosis increase), I use cinnamon; a great reducer of diabetes. Cinnamon's main component is hydroxi-cinnamaldehyde; it blocks glucose uptake very well. One study showed that most of the negative effects of hyperglycemia in mice were blunted by cinnamon intake before meal and later, post-prandial and fasting glucose came back much quicker; demonstrating that it improves beta-cell in pancréas. It does this because it reduces 'fat' that accumulates atroun d the pancreans and 'cloggs it'; its beta-cells literally become asphyxiated by this layer of fat that layers on the pancreas as you become hyperglycemic. In fact, one study showed that reduction of glucose or CR worked by reducing 'fat' content surrounding the pancreas itself.

I hope this can help in any way and give better understanding.

Just a 2 cent.

Posted by: CANanonymity at September 15th, 2017 4:52 PM

Just 2 cent.: I always take a 200mg Mixed Vitamin E capsule with my fish oil to neutralize any rancidity in the fish oil. Luckily, I have no atherosclerosis problem, or plaque in my carotids, or other arteries as I have had them scanned. My best longevity gene SNP is the UGT1A GG alelles that result in Gilbert's Syndrome (GS) which is a genetic condition that is very, very protective of atherosclerosis and many other diseases of aging. About 5-10% of Caucasians have GS which results in bilirubin levels 2 to 3x higher than normal (mine is 2.3). Bilirubin is a very strong antioxidant (10K stronger than glutathione peroxidase normally considered out best internal antioxidant) that protects the endothelial lining of the entire vascular system, greatly reducing any oxidant particles of LDL, and thus largely eliminating atherosclerosis with aging. GS has another benefit for anti-aging in that platelet counts are reduced about 40% over normal, mine platelet count number is about 103K. This low level of platelets reduces internal clotting and thus greatly reduces risk of heart attacks and strokes. GS also benefits the immune system because leukocyte telomeres are longer with GS, and inflammatory cytokine levels from IL-6, IL-1beta are lower than normal. GS has an all cause mortality risk of 0.5% as shown in research studies. Perhaps in the future with CRISPR technology, you could have the right GS SNP alleles transplanted to your genome. I am lucky I inherited GS, and hope to make 120.

Posted by: Biotechy at September 16th, 2017 11:01 AM

Thank you greatly for this detailed information and wishing to share/to help others less lucky ! I wish you 120 and more ! (Life is like that, it hands you a 'hand', and you have to play it - whatever is in that hand. Thank goodness, in the near-future (close(r) I hope), we will have SENS and other types of genetic alleles insertion therapies that will allow to finally get that great genetic that people who live to a 120 get upon birth (and, most likely, inherited from their centenarian grand-parent. But, this is just the 'basics', the next step is ending aging/curing death altogether (and diseases too) and possible LEV. It's a tall order but is Worth it in every way; our life depends on it because it has an end (120); and people accept that like 'aging/death' is 'all ok and we die anyway'...they should not. That we die, ok, but why not die MUCH later, like 120...220, 320 you know, why 120 or less. Is there some special 'limit' that we must Abide By and that is Sacred and Unviolatable. No. It is simply that people have never heard a human live above 120-140. As such, we are, now, there; and We Should make it happen and make believers out of unbelievers (I am not on some mission to convert' the people; only, to tell them what is to be and they can judge and see it is not a fluke; lifespan as we know it (120 year max) is about to be transformed into Something else because death (itself) will be stopped - dead).

Posted by: CANanonymity at September 16th, 2017 12:24 PM

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