The Next Recommendation on Lowering Cholesterol May be to Start Earlier
The clinical work on lowering blood cholesterol that has taken place over recent years has demonstrated that if there is a lower limit beyond which low cholesterol levels become harmful, then that limit is very low indeed. Certainly below 10% of the normal human level. There are a number of uncommon mutations that produce individuals with up to half of the normal amount of blood cholesterol, people who exhibit significantly reduced risk of cardiovascular disease as a result of this difference from the norm. This is all quite interesting: why did we evolve to have the blood cholesterol that we do, if we need only a small fraction of it?
The reason why lowering blood cholesterol lowers the risk of cardiovascular disease is that atherosclerosis is caused by the dysfunction of macrophage cells in an environment rich in oxidized lipids. Atherosclerosis is age-related because oxidative stress, and thus amounts of oxidized lipids, rise with age. A lesser degree of all blood lipids means a lesser degree of oxidized lipids in the blood stream, entering blood vessel walls to aggravate and kill macrophages. This in turn results in a slowed progression of atherosclerosis. Unfortunately it really doesn't help all that much to remove existing fatty lesions produced by the processe of atherosclerosis, and it doesn't do more than slow the progression of the condition. Lowered blood cholesterol only raises the odds of avoiding the consequences of atherosclerosis, meaning stroke and heart attack when a weakened artery or large lesion ruptures, because a few years of delay are enough to allow some other consequence of aging to kill the patient first.
The advent of new and very efficient tools for lowering blood cholesterol, such as PCSK9 inhibitors, present the medical community with something of a quandary. The technology for lowering blood cholesterol has reached its natural limit. One really can't go much lower, and yet it isn't enough. It still only slows atherosclerosis, and cannot meaningfully reverse the corroded state of arteries and their fatty lesions. The research community is investigating other avenues beyond the lowering of blood cholesterol typified by statins and PCKS9 inhibitors, but in the meanwhile what should the medical community focus on? The next logical step appears to be starting treatment earlier, with an even greater focus on prevention and target metrics in healthier individuals, rather than on treating the manifestations of clinical disease.
Cholesterol lowering: to live longer, start younger?
Cardiovascular disease, particularly coronary heart disease and stroke, is a major cause of death globally. Since older age is an independent predictor of increased cardiovascular risk, the global burden of cardiovascular disease increases as populations age. Lowering low density lipoprotein (LDL) cholesterol has become an important strategy for reducing the risk of atherosclerotic cardiovascular disease (ASCVD). Recent evidence has shown that the benefits of this approach extend to patients over 75 years. Though LDL lowering is beneficial across middle to older age, two questions still arise: how early in the disease process should LDL lowering be initiated; and, are the currently recommended LDL targets ambitious enough?
It has been estimated 10-year ASCVD risk for an untreated 50 year old Caucasian male with a systolic/diastolic blood pressure of 140/90 mmHg and LDL cholesterol level of 3.4 mmol/L, is 5.3%. A 60 year old male with the same risk factors has a 10-year ASCVD risk of 11.8%, which increases to 22.6% at age 70. Older age appears to be a marker of the cumulative exposure to LDL cholesterol, along with other traditional cardiovascular risk factors. Delaying treatment until the cardiovascular risk is above a certain threshold will lead to additional years of exposure to this cumulative burden. Initiating statin therapy at say, the age of 50 rather than 60 years old, will prevent an additional 10 mmol/L/year LDL cholesterol exposure, or in other words, provide an additional 10 mmol/L/year of LDL cholesterol reduction.
More complex and older atheromatous plaques only partially regress with LDL lowering therapies, which means delayed treatment will leave older individuals at considerable residual risk of ASCVD. It makes sense to advocate for a greater focus on the lifetime exposure to elevated LDL and the benefit of LDL cholesterol lowering over longer periods of time. A primordial prevention strategy would target the development of atherosclerosis rather than simply preventing its complications. This hypothesis is supported by cohort studies which showed exposure to elevated blood pressure and cholesterol levels during young adulthood is associated with a greater risk of ASCVD later in life, independent of later adult exposures.
Hi there! Just a 2 cents.
''This is all quite interesting: why did we evolve to have the blood cholesterol that we do, if we need only a small fraction of it? ''
I believe this has to do with mitochondrial outter/inner membrane cholesterol incorporation. Cholesterol is a strong fluidizer, as such, just like long chain DHA/EPA Omega-3 incorporated in membrane for fluidization it helps to make membrane structure more fluid and less viscous. It also helps to decompact it a bit, because thight lipids make membrane packing/compaction and rigidification. While, chiolesterol, makes it more loose and fluid/watery-like, by being a fat that is less compact/ridig/viscous. Plus, the brain is very rich in cholesterol and needs it for function; because mitochondrias. Mitos having the cholesterol in membranes, in brain mito membranes for brain functioning/thoughts (which DHA/EPA also end up doing similarily and are in high amount in brain. They had compared small chain fatty acid and long chain fatty ones; the small one did not affect fluidization of membrane, only the long chain ones (DHA mainly)). Neurons need fluid mitomembranes for fast impulse sending/communicating through neuron network (or else we be 'slow thinking/vegetable). Now, why would we need So much more of it;
I think this is 'fail-proof' mechanism; to make sure we Don't Lack any. So More of it. But then, this can cause atherosclerosis because too much of it; the LDL specie one which triggers whole cascade and commands macrophage behaviour change & invasion into atherolesion.
Our brain needs rich/high cholesterol, thus higher blood levels make sure we don't lack any for brain function is critical to rest of body as central tower command organ. But, it's not perfect, so the complication of too much of it/not enough excretion fo it by the liver is atherosclerosis. We are forced to reduce it to compensate this excess.
And then. People go eat cholesteroly food On Top of that. Error, huge error. I made it. Played the russian roulette. And survived it to tell you to not do it like I did. Some people are Very Lucky and did not develop anything despite splurgin in ultrafatty cholesterol foods/junk and whatnot; it's not because you do exercice that you stop this, espeically if have family/herited 'genetic cholesterol', it comes anyway and Even when you are Thin, very thin. Obese people are accelerating the problem but the people who have the Worse is thin people because, thin people should not get atherosclerosis yet They Can. Your fatty blood levels may be wack, thin or obese. You may have fatty depots around organs, thin or obese. You may have diabetes type II, thin or obese. Obese people can be exen healthier - but only for so long until they aren't and 'it catches up to you' because obesity causes health problems down the line by excess fat depots all over and ends up contributing to accelerated aging/global demethylation of epimethylome clock.
Very few Centenarians are/were obese ever. Of if they were, it was short bout because if you were obese at one point and 'became thin again' - you left epimark on you and that lowers your lifespan/longevity - down the line later. Thus, you have Double the effort later to make sure to 'counter' the negative effects you put your body through in your long ago past. Every thing that happens left epimark on body and 'changed the (methyl) trajectory' of your lifespan, decades later. I hope that your business you built with help people like me and to defeat/end atherosclerosis by new means of destroying plaques and completely reversing the whole process/start of it to never have the single thought of having/possibly atherosclerosis in life (or again) later in life. Beause that is a scary thought I had everyday, thinking I would die of it and be a statistic on your fightaging.org website.
Just a 2 cents.
Maybe, but going after healthy younger people sounds more like a great way to increase statin profits to me......
Why do the medical community have the blinkers on when it comes to slowing the rate of damage accural vs damage removal?
Thank you again Reason for starting Repair Bio to try the second approach by giving macrophages the ability to digest damaged low density lipoprotein in their lysosomes.
It boggles my mind that billions were spent by big pharma on a race to develop PCSK9 antibodies, yet this second approach is largely ignored.
I don't get it why people want to have very low TC when there is enough data to assume that it increases all-cause mortality.
You reduce the risk of artheriosclerosis but have an impaired immunity as a result on the other hand. How is that working out.
The most logical life style choice would be to have a normal TC and avoid fatty acids high in peroxidation potential (MUFA) like the plaque to reduce the oxidation of lipids.
Hi Chris! Just a 2 cents.
You're absolutely right, I should have nuanced and meant, keeping 'normal/normo/homeostatic' levels of cholesterols (instead of reducing it until no more of it...we need it, just the right amount and right combination/ratio of species). Because it is true (and 2-faced) that going Too low is dangerous. And it's true you can weaken the immunity system too from cholesterol imbalance.
Yet, I went through OverlyExcessive Immunie system (I think I got this from maternal side, my grand-ma (maternal) died of lupus (autoimmunity disease) quite young at 55); thus, atherosclerosis can lead to Both Overly active macrophaging invasion (that's the immune system in overdrive) or well, dysfunction, because too little cholesterol; for cholesterol is crucial for function (espeically, in mitos needing it ot else be sluggish -> Low ATP -> cell death -> endothelial cell death -> CVD and many others). Thus, I have the 'type' of 'hypersensitive' immune system which Reacts/Explodes by 'overk*lling' whatever its attacking/exterminate and in doing so can even 'Attack itself' by error. IT's the old ''Using a Tank/Hammer to destroy a fly''.
This is a recipe for atherosclerosis because Too Much (overactivity/scavenging/forring entity scanning) immunity is a thing too. When I entered atherolsclerosis, I had high LDL and my immune system was compromised but was working Overtime and was Called way too much in my arteries (causing atherome formation from macrophages (to try to consume LDL) call by LDL and dying/ROS producing there in a futil circle that makes more LDL pockets until is plaque that can rupture). I 100% of the belief that are hyperactive immune system can also be a double-edged sword. But it can also become dysfunctional at the same time.
As such, I was Foreced to reduce the cholesterols/Total and improve my HDL one by doing specie production change (in liver).
Studies that showed low total cholesterol levels leading to higher total mortality demonstrate there is 'fine-line/gold mean' whereby you keep low LDL and high HDL; but have more than enough total cholesterol levels. Not too much just enough (thus not too low neither).
But, I think, when you get atherosclerosis, the imperativity of it means you cannot simply say/think '' things will get back by themselves if lower immunity system/activity''...it does not.
The most critical element is changing the blood composition of cholesterol, Only this, truly makes you survive such a tsunami/tidal wave/freight train coming at you (you can't stop it). It takes years to reverse atherosclerosis. IT is why the imperativity (to stabilize atheroplaques from rupturing later) to immediately reduce cholesterol; but more preceisely, to reorder the ratio to normal/proper low/high density lipoprotein ratio. After that, the immunity can be worked on more (if too low cholesterol due to statins...) and be resolved/can resolves itself.
I think that the danger is mitochondrial death from too low cholesterol; and thus can lead to brain death from cells dying 'membrane starved of cholesterol'.
Just a 2 cents.
PPS: MUFAS (like 16:1, 18:1, palmitoleic acid and oleic acid, like in cold-pressed extra-virgin olive oïl from greece/italy (yep...I took that...and nearly ended me, I used to splurge in that, it accelerateed things) they are double-edged, and a bit conflictual in studies.
From one side you read studies saying they reverse it like do MCT (medium-chain triglycérides), yet from other studies, they don't. It means that The Moment is crucial, when/how far (developped) you take this can affect the outcome (positive/negative). In my case I was too far and it just contributed to it (taking this MUFA rich fatty oils en masse). But, I took them for Years, before, and I would say the year or 2 before the event; I took more of them so they were ''the (bad) cherry on the sundae'' to top it off and make it (atherosclerosis) happen.
You read studies from centenarians saying : ''I am an centenarian consumed oliver oïl (MUFAs) all my life, just like Jeanne Calment, she ate bagigeonned all her stuff with this oïl, and live 122 years old...I am like her'/living proof'.. Except, the 99% rest of people (not genetically protected) who do the same and no, they do no reach 122 and die of atherosclerosis much younger.
Thus, for most people, excess fats intake can end up detrimental, from the Saturated Fatty ones up to the PUFA ones too (DHA/EPA) Only Controled Dose is benefitial, the minute you splurge all this turns bad. There were studies for example, done on macaques that were unhealthy (had CVD problems) and they showed atherosclerosis formation when they consumed diet rich in MUFAs (like they were fed extra virgiin olive oïl..and stopped Nothing; Contributed to it). They also died in the study.
MUFA (like 18:1, oleic acid, found from olives/oil), is a double-edged sword; it reduced Peroxidation index by making membranes more peroxidation resistant and it Improves Membrane Fluidization (the best one...with the lowest number of kinks possible; 18:1 - Mono, one kink only and very little ROS 'surface' to Attack; thus unsusecptible to lipoperoxidation.).
And it wa showed that Longest Lived Mammals have reordering of lipid membranes towards Linoleic acid (18:2) Omega-6/PUFA and a bit more Oleic acid (18:1) MUFA/Omega-9; thus, centenarians have more of these MUFAs and Also more of the Very long chain PUFAS (Omega-3/DHA/EPA), they saw a reduction of Omega-6 *(which cause inflammation by prostaglandin formation via 20:4 (Arachidonic acid) and Omega-6 present in OVerabundance in Wester fatty junk foods); 20:4 PUFA O-6 makes peroxidation (4 kinks, plenty to attack) and inflammation. While 22:6/20:5 PUFA O-3 make Heavy peroxidation that many kinks; yet they command the mitos/cell to make Anti-inflammation; that is due to their fluidizing nature and 'configuration' which makes them be 'double-edged'; they help you (To think because lots of Omega-3 long chain in brain) but in the inverse they are peroxisusceptible by high long chain (it's why evolution did lipid reordering to Reduce DHA/EPA - Even - in brain..because peroxidation at mitomembranes is very causative of intrinsic aging (if it is/ROS 'quenched/consumed/Scavenged' by mito redox). Thus, if you are healthy and your cholesterol levels are ok, and you are taking MUFAS, all the better becaue you have a 'sturdier'/peroxidation resistant membranes...and that'S what centenarians have too and any other Long Lived Mammal. Saturated Fats (16:0, palm oïl..palmitic acid) is very toxic and very peroxidation resistnat (no kinks whatsoever toattack), there is also 18:0 (stearic acid from cocoa butter/chocolate), they contributed to my atherosclerosis; animals fed palm oïl die rapidly of atherosclerosis. The worse offenders: Trans-fat (this is Ultra-toxic and makes Ultra advancing of atheroslcerosis) and Hydrogenated/trans fast; they accelerate strongly. Total saturates fat intake has huge contribution on atherscleoris (I had to caught that strongly...your body needs saturates in Small quanity only and it burns some of it for energy) but otherwise, don't exaggerate when you see ''nuts with 100gr of saturates...'' nuts did Not improve ahterosclerosis, thus
Moderation is key and when you are sick/have atherosclerosis lots of this you must stop and change diet (become vegetarian wheich I became and saved me; now you hear stories 'vegetarians are sick and lacking proteins/vitamins...you must supplement to 'counter' the body vitamin/mineral lackings if turning vegetarian for health improvement purpose).
Just a 2 cents.
2017 "Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors".
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Healthy non-smoking people with no diabetes, no hypertension at 45 have sub-clinical atherosclerosis. even at LDL levels at 60-70 (low) and up to 60% at levels >160. So, probably, one should start treatment at their 40s or even 30s. On the other hand having cholesterol very low doubles risks of infection (why is that?).
I've been aware of your work for over a decade and my interest goes beyond that point to being a teenager learning about transhumanism.
Have you any interest or have you spent any time studying peer reviewed research involving "near death experience"? I would suggest the work of Sam Parnia as an entry point.
Sadly, its nearly impossible to have a rigorous study of experience at the point of the brain blood flow stopping. But if you are not aware of this research, here are some tentative conclusions that are non-controversial in the field:
1. near death experiences occur in people who are 'near death' and in those whose brains have not received any oxygen in a time period that makes supporting lucid experiences impossible according to current paradigms.
2. Lucid experiences require stable oxygen supply. A non-active brain cannot create memories, thus the memories must occur either before death or after regaining consciousness.
3. Its often claimed awareness of the operating theatre can occur while having a compromised brain due to the heart not pumping blood, but research comparing NDE (near death experiencers) to non experiencers show the non-nde group do not recall behaviors of people and tools used in the operating theatre, but the NDE group does.
The primary issue is explaining consciousness. There has never been a time when you were not aware of something and when we die it could be our minds instantly fill in the gaps with fantastic stories.
Or it could be that a new paradigm in science is slowly developing. In the mean time, cancer, alzhiemer's and many other problems vex humanity. I don't know if we are immortal, but I do believe this is worth more time than you may be giving it.
With all these anti-aging treatments as soon as they become available it should be the choice of the individual at what age they should start taking them.
PPPS: @dimza Hi dimza! Just a 2 cents. Thank you for this great study, it goes to show that 'it's happening' even in young people seemingly well and seemingly healthy; the ratio might say so but Atherolsclerosis accumulates over (the) years, you can have partial form of it 'Subclinical atherosclerosis'/pre-atherosclerosis, depsite healthy. Mainly people are seemingly healthy but artieres tell otherwise and you can See atheroplaques forming 'slowly but surely' (the debuts of it). Like you said, I suggest it too, to Start Young doing cholesterol check and if need reduction.
Very low cholesterol (may) cause cholesterol ratio imbalance which will affect cell/mito functioning and may affect immune system; with a weakened immunity/overdrive immunity/Dyfunctional immunity, you are bound (Open) for infections/vulnerable to pathogen/bacteroa/virus/cancer...any infections that the immune system is the first defense for and if low cholesterol created infeciotn, it means immune sys dysfunction. Even, immunosenescence is possible because cholesterol levels are so low, there is lack of it, which shows up as compromised immunity, then creating infections. Just a 2 cents.
@Hi Matthew! Just a 2 cents.
I agree, explaining consciouness is hard, very hard because ambiguous like that. I likie to think it (using my conciousness) that is a collection/(re)collection of memories and associations - that You yourself are not doing, but a Part of you; which is the collective neuron network in all the several parts of the brain and they act/communicate interdependetly and interindependently from/with each other; but studies showed there aer 'patterns' visible where such or such parts of the brain lead up to such types of behaviours/commands; there are patterns and for example motricity might be in the frontal cortex while the parietal and occipital parts might take care of emotions..but it is combination of them all acting intandem that gives Something/thinking and consciousness. It's egg or chicken coming first question? Neither, And, Both. Talk about catch22.
When you make a decision (in your thoughts and 'come up' with a decision) it is not Really You doing it; it's your brain/neurons/the parts of it; now you might say :'Yeah That's Me, The My Brain...thinking..my soul is in these neuron cells and when I decided something, I made that decision''...I meant that things happen out our control, even your decisions...for example, this hapepned to me several times (And continues happening, likewise for pretty much forevery one else/any human); say you looked at Something and Then, Suddenly, a thought comes to your mind - You, yourself, Never thought of that...but it Came to you without you Even thinking about that..The neurons are independent body and 'communicate to you' Something, they do associdations and memory recollection (scant the memory neuro network of billions of memories) and 'Come Up' with a Result...your decision/thought/idea...this happens Before you make that decision/idea...whatever...it is Extrmely rapid, in micro-fraction of second, your Brain/neuron...not you...has decided what Is your answer/decision/idea. Not you might say, but my brain/neuron are me...true, it's you...but they Independent and Also Dépendent, they can have Their say...about whatever you saw and then They will come up with a decision/association. I even noticed this, like D*mn...how come I am Thinking of that - Suddenly...I Was NOT thinking of that At All 2 Seconds Ago...and it was Not on My Mind..and Then BOOM it is in my mind, from One instant to the Next/in a fraction of second - I NEVER thought of that..who do you think made this happen...it's not who...it's What...that's your neurons that did this - For you. But not you your self. Anyhow, consciousness and unconsciousness are so deep (shades of grey) that is very hard to say what they are, Truly. The brain is so elusive, still, even after 20some centuries of medical research of it.
I understahdn your point that there should more thoughts given to 'loss of consciouness' and near death experience (I lived that,..and even before younger, several times), I did not reach the tipping point of loss of consciousness but Almost; that, as you said, it was to make sure to Never lack brain oxygen/stroke because that is Deadly and you may end up in this 'near death dexperience' and see the 'white light tunel' as seen by some who said they were floating and 'outside their body' experience after/near death; Don't ever want that,...the whole purpose of fghting aging and fightaging website is stop this completely; so that death is not feared anymore for it is cured; right now, people tell you ''don't fear it...we die anyway so 'be more ready for it' and not scared (of it/of dying). '' almost embrace it/don't fight it...give in...which is sad because if I had Given Up/Givin'in...I'd be dead.
Just a 2 cents.
@Hi TJ! Just a 2 cents.
Absolutely. Choice, it should always bem personal. Still, Lots of statistics coming in and the unsurprising of it is that starting earlier is (onftely) better than later(too late/too old). Because there is a thing as too old; they say 'it's never too late, never too old'..which is kind of true because we want to save all, including older. Time is Counted, we may die from one day to the next (be it of aging/old/accident)..that Truth is almost blind in people; like it's agiven and people think/resolve themselves to (in then end).. 'we die anyway'...which I agree/is a fact (up until now, until rejuvenation happens and comes out of fiction state) but must do Something of it. But, Late is Late. Even, sometimes, too late. Hoping the new treatments can really reverse the age/aging in older people quickest and then we save the yougner ones who have more life ahead. Priority/imperativity of it.
Just a 2 cents.
The reasons for high cholesterol are probably two fold:
1) Evolutionary selection for bolstering immunity through unclear mechanisms.
2) Diet switch from low cholesterol food sources to high cholesterol sources without enough time to evolve compensatory reductions in natural cholesterol synthesis.
I believe early humans were probably 90% plant based with the other 10% being mostly insects. With the rise of animal agriculture, our cholesterol levels rose as well. Because atherosclerosis mostly kills people past reproductive age, it probably didn't have much selective pressure to change nor time to change in.
Hi Anon112! Just a 2 cents.
That's a solid explanation and would explain why atherosclerosis continues still to this day. Our ancient diets were better until, much later, they weren't and just not enough time to adapt this/or won't be adapted on this at all/no selection presusur. Maybe it is 'inconsequential/rare' - back then ,as such it was not a problem; today it is unfortunately; maybe in 10,000 years we will (gone that is near 100% sure but our very far future descedants might be) atherosclerosis-proof.
We can't wait this long, we have to defeat the disease now (while progress happening) and save the people living, now not in 10K years. If we want us living people to be there in many centuries, perhaps millenias (don't hold breath), then we defeat aging/death, today.
Just a 2 cents.