1) Initially researchers tested the molecules that they had the ability to test for, from the body parts; they had access to, which is mainly the blood of individuals.

2) Research started in earnest when the quantity of cholesterol, a large flat planar molecule in the blood correlated, to whether an individual got heart disease or not.

3) Problem was the correlation was not that good, the r value (connection) was only .29 out of one, and cholesterol has many beneficial effects like giving fluidity to cellular membranes.

4) Low density lipoprotein (LDL) was next looked at because it was the transport vehicle in the blood that took cholesterol to where it was needed, and yes it was better correlated to heart disease than cholesterol itself. High density lipoprotein (HDL) was then added because it took cholesterol away from cells, and yes that added to the correlation value over just LDL itself.

5) With the theory of Oxidation / Reduction (redox) in the field of aging, researchers noticed that LDL was only atherogenic (causing heart disease) if it was oxidized. This made sense since cholesterol was a cellular building block brought in on a vehicle (LDL) that was bringing in building blocks to cells and if these building blocks were not in pristine condition they would not fill their purpose and correct building would not be able to take place. Arteries are continually (through life) expanding, contracting and bending with blood flow pulses, this creates damage which then needs to be continually repaired while the arteries continue to be used to transport needed building blocks to cells. This is a difficult proposition as compared to repairing while sleeping when a cell is not being used as heavily. Fibrosis is basically the building of needed things under bad building conditions with bad building materials; yes it is better than nothing but not as good as repairing to pristine conditions with pristine building blocks.

6) Next was the question of where this oxidation, that was breaking building blocks and other things, was coming from. It was known that white blood cells could throw oxidation out of their cells (basically bleach) to kill invaders like viruses and bacteria. So inflammation was then assigned the blame of starting heart disease.

7) The next question was why inflammation was turned up in the individual’s body. This is where we are today and where the study of vascular disease merges with the study of aging.

8) The main four explanations of why inflammation is high in sexual organism’s (the thymus at puberty undergoes an evolutionary conserved “involution”) somatic tissue (sex hormones broadly affect immune cells quantity and quality as well as cytokines) and is causing aging and heart disease are:

1. 500 million years ago, vertebrates made an additional (adoptive) immune system, even though invertebrates do fine with only the old, innate immune system, to allow vertebrates to be “friends” with organisms in our microbiomes that help us get added energy via our digestive systems. The extent of human microbiomes and their connection to human health is now being researched extensively, but is yet to be easily understood or improved.
2. Invading (lytic) viruses and bacteria that mandate the us-vs-them necessity for an immune system which kills invaders with inflammation. SARS and West Nile (new/emergent) viruses are more serious in the elderly.
3. Endogenous viruses, that invaded a while back in human history or an individual’s life and that are still are being dealt with to keep them under control. Two examples below of families of problematic endogenous viruses.
• Retro Viruses It is guesstimated that retro viruses attacked human ancestors about 50 times during evolution, the latest being the HIV attack. 45% of human DNA is composed of transposable elements such as LINE 1 and Alu retro-elements and DNA transposons. 8% of the genome is derived from sequences similar to infectious retroviruses. These can be easily recognized because all infectious retroviruses contain at least three genes (gag-viral structural proteins, Pol1 –viral enzymes, and env—surface envelope proteins) as well as long terminal repeats. They are known as HERVs and they come in three classes. Some are human specific, so they are recent additions. Three pro-HERVs have complete open reading frames still to this day. Some are used by humans like in the formation of the placenta and use in centromeres that organize DNA replication. In the case of HERV-K111 that (it still is able) produces the Np9 protein, it is possible that this plays a role in evolutionary development of primates since Np9 stimulates notch and Wnt signaling pathways (Chen T 2013, Armbruester V 2004) suggesting Np9 might have a role in brain development. Np9 also stimulates ERK and Akt which are very important (in a pro-aging way) in aging biology pathways. Some seem to be a problem for health, and have been accused of being associated with cancer, autoimmune disease and neurological disease (Griffiths DJ 2001). HERV k18 T-cell antigen (Sag) is associated with diabetes type 1 (Marguerat S 2004). With experimental radiation one can activate HERV gene expression out from under epigenetic control (Lee JR 2012), which is the same effect as aging on epigenetics. Many of the effects of past retroviruses are in gene expression regulatory elements that change the activity of genes. The full extent of the effects, of these retroviruses, has not been worked out, but are thought to be substantial and keeping them under epigenetic control: which is lost with age and could be the key to deterioration with age, as well as onset of specific diseases.
• Herpes Viruses There are 9 known human herpes viruses. They all integrate into our nuclear DNA where they stay for the rest of our lives. Some are more problematic to aging than others. Human Herpes virus 5 (HHV-5) [also called cytomegalovirus (CMV)] persistent infection is known (which are associated with frailty) to nearly double cardiovascular deaths in healthy older adults (Savva GM 2013). T-cell senescence or exhaustion is often associated with CMV infections (Chou JP 2013, Lang PO, 2013, Pawelec G 2009) CD8+ T-cell subset for a single CMV epitope maybe nearly 25% of total T-cells. Because of these observations senescence markers may actually be indicators of an adaptive response required to keep persistent infections in check, and that in the terminal phases of life, the highest priority of the immune system is to control chronic infections, regardless of the collateral damage this may cause. (Moore SJ 2016) HHV-6 was previously noted to be associated with heart disease, now it has recently come back into view as a possible initiator of Alzheimer’s disease (Readhead B 2018). Varicella zoster (HHV-3) (chicken pox/shingles) vaccines need to be given at 14 times the dose to achieve immunity in the aged (Amanna IJ 2012 and Gagliardi AM 2012), showing the weakening of the immune system with age. HSV (HHV-1) and EBV (HHV-4) are known to be associated with diabetes mellitus (Haeseker MB 2013).
4. The original bacteria (mitochondria) that animals took in a long time ago in evolution incorporated it to use in being more efficient at getting energy. The breakdown of communication between the nucleus of the cell, that now has much of the mitochondrial genetics and functions, and the remaining machinery in the mitochondria itself, that still has some of its own genetics and machinery, happens with age. When this communication breaks down the mitochondria is malfunctioning and cannot produce the abundance of energy it was originally absorbed by eukaryotic cells for. Since it is the original successful invader of eukaryotic cells it is intimately connected to the original innate immune defense functions that were altered to accommodate it and thus weakened the defense for other invaders. Experimentally correcting this miscommunication, between the mitochondria and the cellular nucleus, reversed age in mice (Gomes A 2103).

9) It is looking that all four inflammation explanations are important.

10) What, you might ask, are my cholesterol lowering statin drugs (the largest selling drug in human history now a $19 billion per year market) and my blood pressure lowering ACE-inhibitors ($11 billion market) then doing for me. The answer is, in short, the same, they are helping you (thank you: evidence based human outcome medicine), but the explanation on how they are helping you is now different. This new explanation also now includes how statin drugs are hurting you as well, an explanation that the suppliers of statin drugs could not afford (-; to tell you about for the last 45 years.

1. Statin drugs:

   Statin drugs came from the research of CM Brown and J Goldstein and were originally reported in a scientific journal article in 1973. It was known then that HMG Co-A Reductase inhibitors, (which statin drugs, from a fungus, are) partially blocked the mevalonate synthetic pathway which makes (after the point of blockage) Cholesterol, Co-enzyme Q10 (ubiquinone/ubiquinol), dolichols. There are effects as well on: Heme-A, Sex steroids, corticosteroids, bile acids, vitamin D, Nuclear factor-kappa Beta (NfkB), selenoproteins, rho, and several other biochemicals (Golomb BA 2008).

   • Cholesterol besides being used to a) build cellular membranes which are the basics of life and b) allowing for the development of synapses which are the building blocks of memory and thinking goes on and is c) the basis of steroid hormones that determine sexuality. Cholesterol is transported on LDL. Of note here is the fact that asexual organisms (e.g. sea anemones) do not age. Men without testicles, thus without sexual hormones, live an average an extra 9 to 13 years.
   • Co-Enzyme Q10 is the actual molecule that carries electrons across the inner membrane of the mitochondria. An increase in electrons on one side of the membrane from the other made possible by the physical transport of electrons by Coenzyme Q10 forms a gradient of electrons which is the basis of potential energy and power in the mitochondria. This energy from the TCA cycle of the mitochondria is more efficient and makes more energy from fats than the evolutionary more primitive glycolysis which is the making of energy from tearing apart the carbon-carbon bonds of sugar. Glycolysis beneficially does make less oxidation as a byproduct. Co-Enzyme Q10 can also acts as an effective antioxidant. As aging occurs, the cell tends to use more glycolysis and less of the TCA cycle. Co-Enzyme Q10 (like cholesterol) is transported on LDL. In one study Simvastatin 80 lowered Co-enzyme Q10 from 1.26 µg/ml to 0.62 µg/ml (measured in plasma) in one month. Calorie (energy and building block) restriction was the first and still is the main concept for therapies to slow and stop aging. Taking away Co-Enzyme Q10, which statins do, takes away energy by the most basic means. Presently it is very difficult to get Co-Enzyme Q10 back into the inner membrane of the mitochondria where it makes energy for you. There is extremely low absorption of Co-enzyme Q10 supplementation.
   • Dolichols are involved in cellular messaging, neuropeptide formation in the brain and mitochondrial DNA error correction. Both cellular messaging and mitochondrial dysfunction is at the heart of aging, and we know you care about your brain.
   • Nuclear factor-kappa Beta is a key switch that turns on immunity. Statins inhibit the binding of NfkB (as well as AP-1, an anti-proliferation mediator) to nuclear proteins thus deceasing (down regulating) their transcriptional activation of their targets. This switch is either (if Nrf2 is on and NfkB off) towards anabolism / construction / synthesis / reduction (anti-oxidation) or (if Nrf2 is off and NfkB is on) towards catabolism / breakdown / digestion / oxidation. The cell is usually doing one of these or the other. This switch tends toward the latter (higher basal levels of inflammation and oxidation) with aging. It is proposed that a higher basal rate of inflammation is the underlying cause of aging.
   • Selenoproteins are proteins that use selenium on a cysteine amino acid. They make up many proteins used as antioxidants enzymes. Selenium is used in biology much in the same way as sulfur, which is also very important to health and aging. These proteins are a part of the thyroid pathway, insulin pathway, and heat shock / chaperone pathway which are all basic pathways that are important in aging. The most noted defect concerning this with statin use is the decrease of glutathione peroxidase, the backbone of the anti-oxidation defense system.
   • Statins take 19 months to show statistical beneficial outcome based lifesaving effects in large studies, compared to control groups. Heart attacks are lower due to the removal of inflammation from the 70% of heart attack causing plaques. These are “vulnerable” plaques because they have more soft lipid. These plaque are structurally unsound because of the soft lipid and thus more likely to break (pop like a pimple) with stress.
   • All of the above statin effects are intimately involved in the biology of aging, thus statins should be recognized as the first anti-aging drug. After reading about these drug affects from statins, you might well have been prompted to say to yourself: “I do not want to take these drugs, look at all the negative effects they cause” although you saw that they could prevent death itself. The drug companies, selling these statin drugs, and many well-meaning doctors, as well, actively stopped this information from coming out because of this negative purchasing effect on individuals. They believed potential patients could not weigh the benefit and negative effects of these drugs. Because of the deleterious effect on mitochondria energy production by statins, statins are seen by many to (after saving you from vulnerable plaque rupture thus heart attack) to be a cause of heart failure which normally happens later on if you prevent death from heart attacks. One in five individuals, who reach 40, will ultimately develop heart failure and the rate doubles every decade after 65. The question is: is there, a better way to fight heart disease and aging? The answer is yes. The good effects can be obtained, without the bad effects. Of course it takes time and a lot of money to show this in an outcome based study with humans. This is what EGA® from Egaceutical Corporation purports to do.
   • The good effects of statins have been reviewed (see Collins R 2016) by world class statistician Richard Peto, (who previously first told you cigarettes cause cancer) very-very basically the benefits are: if you have had a heart attack or stroke, statins (if you take them) will decrease your chances of having another by 10%, if you have not had one but have risk factors, statins will reduce your chances of getting a first one by 5% (some of you might be wanting closer to 100% reduction of chances).
   • The bad effects of statins include: Mitochondriopathy, metabolic vulnerability, glucose intolerance, fatigue, muscle weakness, myalgia, exercise intolerance, neuropathy, cognitive problems, cognitive loss, irritability, depression, aggression (decrease in males-increase in post-menopausal woman) sexual problems, sleep problems, hepatic dysfunction, pancreatic dysfunction and general oxidative stress (Glomb BA 2008). These problems (when studied specifically) in studies went away with disuse of statins and came back again if and when re-use started. Initial onset (when they happened) of bad effects was normally 3.5 months after starting statins.
   • To test your knowledge consider this: The FDA recently approved a cholesterol drug based on monoclonal antibodies (the new fad in pharmaceuticals) [that bind to and thus take away cholesterol] simply because the drug company showed their drug lowered cholesterol in individuals. Should the FDA have done this? Is the effect of Statins (that do save lives) based on cholesterol lowering? If this antibody drug company did an evidence based study with testing on meaningful outcomes would this product save lives?
2. ACE inhibitors:
   • Angiotensin Converting Enzyme (ACE) II inhibitors inhibit ACE. ACE activity (the making of the Ang II protein) markedly increases in both the endothelial cells (EC)s and the vascular smooth muscle cells (VSMC)s with age in the arterial wall of humans. The Ang II receptor also increases in old arterial walls. This stimulates Aldosterone (Aldo) hormone secreted by the adrenal gland which binds to the mineralocorticoid receptor (MR). MR is increased in aging as well. This system regulates (did you guess it?) inflammation in the cardio-vasculature. This inflammation can be seen and measured by increases in Il-6 and TNF-α with blood testing.
   • Connection to aging research includes: ACE II inhibition is also known to lead to defects in amino acid absorption (Hashimoto T 2012) and amino acid malnutrition (Singer D 2012). Amino acid starvation is known to work (via mTORC1 assessment) to effect calorie restriction thus elongated life. ACE inhibitors are sold for controlling hypertension / blood pressure (because scientists saw they did that first) and their real benefit and the reason they show, in outcome based medical tests, lifesaving properties is because they turn on calorie restriction and reduce inflammation. These are both key pathways involving aging. And yes, blood pressure and inflammation are connected in the vasculature, through physical stress.
   • Demonstrated benefit of ACE inhibitors: Very-Very basically if you have not had a heart attack or stroke and you take and an ACE inhibitor you will only have a 9% chance of having a heart attack or stroke instead of the 12% chance you would have had if you were not taking an ACE inhibitor, so a 3% benefit for you (for more precise information see Borer JS 2007). In conclusion compared to statins, ACE inhibitors have a more understandable mechanism of action, a slightly lower benefit but lower negative side effects including a probable benefit to heart failure patients instead of a detriment.