There is no one single biological process test that is definitive for complex chronic diseases of aging. However, evaluating the results of many tests, with emphasis on those of the blood, help us paint a more comprehensive diagnostic picture and provide clues for treatments even in the apparently well.
This section covers the tests that will help you determine your risk for chronic disease. Some of these tests are routine, while others are seldom ordered. But all of them contribute to an understanding of one’s current and future chronic disease risk. (1)
Homocysteine. This is a metabolic by-product of methionine metabolism. Progressively elevated blood levels of homocysteine are a documented risk marker for cardiovascular events and Alzheimer’s disease. Curiously, the standard-of-care continues to raise the upper limit of normal for homocysteine. It used to be around 12.5 and now it is 15. Also interesting, the upper limit for cholesterol continues to go down. Homocysteine is a much better predictor of your future health compared to cholesterol but cholesterol has a simple drug treatment. And that treatment happened to be the biggest selling drug category of all time. What do you conclude from this?
C-Reactive Protein (hsCRP or CRP). This is one of a number of acute phase reactant proteins that increases in response to inflammatory stimuli. We refer to the CRP value as a measure of your chronic vascular (vessel) inflammation. No one parameter, like CRP, is accurate at assessing you chronic disease burden, but CRP is one of the most useful. In large epidemiologic studies, elevated levels of CRP have been shown to be a strong indicator of heart and circulatory diseases.
Complete Blood Count with Differential (CBC). Parameters obtained in this test tell a lot about immune system activity by measuring the levels of your health-defending while blood cells. The most useful data obtained from the CBC with differential includes:
- White blood cell (WBC, leukocyte) count. White blood cells are part of your immune system. White blood cells protect the body against infection. If an infection develops, white blood cells attack and destroy the bacteria, virus, or other organism. White blood cells are bigger than red blood cells but fewer in number. When a person has a bacterial infection, the number of white cells rises very quickly. The number of white blood cells is sometimes used to find an infection or to see how the body is dealing with cancer treatment or to determine if an immune system disorder exists. We discussed new “healthy” ranges in detail in Chapter 5.
- Neutrophil granulocytes. These are generally referred to as either neutrophils or polymorphonuclear neutrophils (or PMNs), and are subdivided into segmented neutrophils (or segs) and banded neutrophils (or bands). Neutrophils are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute inflammation. These cells also protect the body against infection by destroying bacteria, thus are also a hallmark for chronic inflammation.
Eosinophil granulocytes. These are usually called eosinophils or, less commonly, acidophils and are white blood cells that are responsible for combating multicellular parasites and certain infections. They also control mechanisms associated with allergy and asthma which are often tied to fungal infections.
- Lymphocytes and Natural Killer (NK) Cells. NK cells are a part of innate immune system and play a major role in defending the body from both tumors and virally infected cells. We are learning the virus are the cause of many cancer cases, so appreciating you lymphocyte activity is extremely important. NK cells distinguish infected cells and tumors from normal and uninfected cells by recognizing changes of a surface. NK cells are activated in response to a family of cytokines called interferons. Activated NK cells release cytotoxic (cell-killing) granules that then destroy the altered cells. They are named “natural killer cells” because of the initial notion that they do not require prior activation in order to kill cells.
- Basophils. They appear in many specific kinds of inflammatory reactions, particularly those that cause allergic symptoms. Basophils contain anticoagulant heparin, which prevents blood from clotting too quickly. They also contain the vasodilator histamine, which promotes blood flow to tissues. They can be found in unusually high numbers at sites of infection, e.g., by ticks. Like eosinophils, basophils play a role in both parasitic infections and allergies.
- Monocytes. Monocytes are a type of white blood cell that fights off bacteria, viruses and fungi. Monocytes are the biggest type of white blood cell in the immune system. Originally formed in the bone marrow, they are released into our blood and tissues. When certain germs enter the body, they quickly rush to the site for attack. Monocytes have the ability to change into another cell form called macrophages before facing the germs. They can actually consume harmful bacteria, fungi and viruses. Then enzymes in the monocyte’s body kill and break down the germs into pieces. Monocytes help other white blood cells identify the type of germs that have invaded our body. After consuming the germs, the monocytes take parts of those germs, called antigens, and mount them outside their body like flags. Other white blood cells see the antigens and make antibodies designed to kill those specific types of germs. This is called “adaptive immunity.”Vitamin D. This extremely important hormone promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults. Vitamin D also helps protect older adults from osteoporosis. Vitamin D works in concert with Vitamin K2 in the directing of calcium out of our vessels (where calcium is harmful) and into our bones. Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation.Vitamin D is a critical part of our immune system. It collects and is stored in our fat tissue. Like soldiers in their barracks, Vitamin D is always on the ready to protect us from “insults” like infection. When the immune system detects infection, like the soldiers who respond and grab their weapons, Vitamin D converts to the “activated” form. This activated form is now known to be antibiotic. The first hint of this “antibiotic” activity was noted over 150 years ago when people who took cod liver oil – that contains natural Vitamins D and A – were somewhat protected from the scourge of tuberculosis.
Omega 3 levels. Omega-3 fats are a small group of molecules technically known as fatty acids. The key clinical omega-3 fats are EPA and DHA, which are found largely in cold water fish. It is well established in current literature that a higher blood level of these important fats may help to reduce the risk of Alzheimer’s disease, heart disease, and stroke. Neurons in our brains are formed with omega 3 fatty acids as part of their cell membrane. This is where electrical signals pass. Having too many omega 6 fatty acids or simply insufficient omega 3 fatty acids in your system can alter the electrical behavior of your brain.
Blood Glucose. Glucose is a type of sugar that the body uses for energy. An abnormal glucose level in your blood may be a sign of diabetes. Hemoglobin A1c is a more dependable way to determine your average blood glucose level. The red blood cells that circulate in the body live for about three months before they die. When sugar sticks to these cells, it gives us an idea of how much sugar has been around for the preceding three months.
Insulin. Abnormal fasting insulin, especially when combined with other risk factors, identifies patients at significantly higher risk for diabetes, heart, and circulatory diseases. Insulin is the most studied of all molecules in our bodies. Insulin rises before glucose or A1C in pre-diabetics and is thus a better biomarker for early detection of metabolic disorders.
Tumor necrosis factor alpha (TNF-α). TNF-α is a growth factor for immune cells and osteoclasts, the cells that break down bone. It has well know pro-inflammatory functions and may be elevated in chronic infections, certain cancers and Hepatitis C. TNF-α is another important marker of inflammation and elevated levels should be used for diagnostic purposes and a reason to dig deeper and find a cause for its elevation. TNF-α is not a direct treatment target despite what the drug companies are creating. Do NOT take one of their new TNF-α drugs. Instead ask your doctor why your TNF-α is elevated and treat that instead. This will help create a healthier you.
Fibrinogen. This is a plasma glycoprotein that can be transformed into a clot in response to injury. The combination of elevated fibrinogen with other cardiovascular risk factors such as CRP signals substantially increased disease potential. As with elevated tumor necrosis factor alpha, this does not imply that fibrinogen is a therapeutic target.
PUFA 6/3 Ratio. This is the ratio of polyunsaturated fatty acids, specifically Omega-6 fatty acids to Omega-3 fatty acids. High ratios (>5) are associated with chronic silent inflammation and compromised immunity. Our bodies need omega 6 fatty acids. In fact, they need more omega 6s compared to omega 3s, by a factor of about 3-to-1. Omega 6 fatty acids help cells grow, for example. However, in our modern agricultural society where most foods are derived from soy, safflower, sunflower and corn feed stocks, we are overloaded with omega 6 fatty acids. Toxicologists know that “the dose makes the poison.” That means anything can be toxic – it is just a matter of dose.
Interleukin-6 (IL-6). Elevated IL-6 may occur in different conditions including chronic infections, autoimmune disorders, certain cancers and Alzheimer’s disease. IL 6 tracks with CRP.
Ceramides. “Serum ceramides increase the risk of Alzheimer’s disease,” according to a Mayo Clinic group. 30 They may not increase the risk on their own, but their presence at a high level surely is an indicator of increased risk. “Compared to the lowest tertile, the middle and highest tertiles of ceramide were associated with a 10-fold and 7.6-fold increased risk of AD respectively.” Ceramides is an expensive test and there are other predictive tests of high value and lower cost. However, this test makes a value contribution to future Alzheimer’s risk.
- Testosterone. It is a hormone made by your body and is responsible for the normal growth and development of the male sex organs and for maintenance of other sexual characteristics. In men, testosterone is produced in the testes, the reproductive glands that also produce sperm. The amount of testosterone produced by the testes is regulated by the hypothalamus and the pituitary gland. Testosterone deficiency can also lead to a number of disturbing symptoms, including loss of stamina and lean muscle mass, reduced libido, anxiety, depression, and cognitive decline.
- Estrogen. Estrogen is probably the most widely known and discussed of all hormones. The term “estrogen” actually refers to any of a group of chemically similar hormones; estrogenic hormones are sometimes mistakenly referred to as exclusively female hormones when in fact both men and women produce them. Estrogens act on the central nervous system (CNS) both through genomic mechanisms, modulating synthesis, release and metabolism of neurotransmitters, neuropeptides and neurosteroids, and through non-genomic mechanisms, influencing electrical excitability, synaptic function and morphological features. Therefore, estrogen’s neuroactive effects are multifaceted and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protecting against a wide range of neurotoxic insults.
- Other hormones. Pregnenolone, testosterone, estrogen, cortisol, and DHEA, are members of a family of natural hormones that are essential for human survival. Scientists have discovered that pregnenolone also can be manufactured in the brain from cholesterol instead of being transported through the blood-brain barrier from other parts of the body. This supports recent findings showing that pregnenolone is involved in a variety of brain- related functions such as memory, concentration, and mood. 31Apolipoprotein E (apoE). This is an inherited trait. ApoE genotype predicts lipid abnormalities and responsiveness to different dietary fat intake. The e4 version of the APOE gene indicates an individual with increased risk for developing Alzheimer’s and macular degeneration. However, we offer a unique view on this. We actually believe the e4 version is actually protective of your health to some degree. The typical profile of an e4 carrier with Alzheimer’s is someone who has lived beyond the median age of life expectancy.Magnesium. Magnesium plays many vital roles in preventing heart disease, controlling blood pressure, and maintaining healthy cholesterol levels. This test is placed low on the priority list because serum levels probably do not accurately portray the true balance of magnesium. Are you taking magnesium supplements? There is almost no downside to taking excesses of this mineral. If you have constipation, take magnesium rather than some artificial compound.
Adiponectin. This is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism. Adiponectin is exclusively secreted from adipose tissue into the bloodstream and is very abundant in plasma relative to many hormones. “Adiponectin is an adipocytokine released by the adipose tissue and has multiple roles in the immune system and in the metabolic syndromes such as cardiovascular disease, Type 2 diabetes, obesity and also in the neurodegenerative disorders including Alzheimer’s disease. Adiponectin regulates the sensitivity of insulin, fatty acid catabolism, glucose homeostasis and anti-inflammatory system through various mechanisms.” 32
Cholesterol (total)/HDL ratio. Many studies have sought to show the benefit of high HDL levels and the results remain mixed. However, the ratio of total cholesterol to HDL is physiologically important. A ratio of <4 is preferred. However, it is also clear that we are actually healthier and live longer the higher our cholesterol is, in most instances. This is discussed in detail later in this book.
Calcium. Women beware! Although this is an important mineral in the body, abnormal calcium levels in the blood may be a sign of kidney problems, bone disease, thyroid disease, cancer, malnutrition, or another disorder. Excess calcium is connected with hardening of the arteries and dementia. The “calcium hypothesis of dementia” is an emerging theory on one of the potential root causes of accelerated vascular and brain aging. 33 Again, the dose makes the poison. Our recommendation is to NEVER supplement with calcium. We get enough in our diet. Instead, supplement with magnesium, Vitamin D, and Vitamin K2, to make sure that the calcium you do intake through food goes to your bones and not into your vessels where it causes significant long-term harm.
β2 microglobulin. This substance is a measure of the activity of the acquired immune system and can provide information about infection and inflammation.
Urinary Albumin. Studies have shown that elevated levels of urinary albumin in people with diabetes or hypertension are associated with increased risk of developing cardiovascular disease.
Kidney Tests. Blood tests for kidney function measure levels of blood urea nitrogen (BUN) and creatinine. Both of these are waste products that the kidneys filter out of the body. Abnormal BUN and creatinine levels may be signs of a kidney disease or other disorders.
Myeloperoxidase (MPO). Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease. It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable. “Alzheimer’s patients showed significantly increased plasma levels of MPO, which could be an important molecular link between atherosclerosis and AD.” 34
NT-proBNP. This is a progressive heart health risk marker with powerful independent prognostic value for detection of clinical and subclinical cardiac dysfunction. 35 Elevated levels indicate the presence of ongoing myocardial stress and potentially an underlying cardiac disorder.
Lp-PLA2. It is a marker for vascular-specific inflammation and also plays a causal role in the vascular inflammatory process, leading to the formation of vulnerable, rupture-prone plaque. Elevated levels have been shown to be powerful predictors of ischemic stroke and heart attack risk. 36
Lp(a). Lp(a) is an inherited abnormal protein attached to LDL. Lp(a) increases coagulation and triples cardiovascular disease risk. Lp(a) is also implicated in brain diseases. “It is suggested that increased Lp(a) serum concentrations, by increasing the risk for cerebrovascular disease, may have a role in determining clinical Alzheimer’s. 37
ESR or SED rate. SED rate is a nonspecific test that measures how fast red blood cell platelets settle and is used to detect chronic inflammation associated with infections, autoimmune disorders, and cancer. Healthy blood cells hold a negative charge. SED rate is a way to estimate the relative charge on the cell platelets. Fast sedimentation implies low (poor) charge on the blood cells and is associated with higher levels of inflammation and early mortality.
F2-Isoprostanes (F2-IsoPs). They are the ‘gold-standard’ for quantifying oxidative stress. Increased free radical-mediated injury to brain is proposed to be an integral component of several neurodegenerative diseases. F2-Isoprostanes derived from arachidonic acid (omega- 6 fatty acid), are especially useful as biomarkers of lipid peroxidation.38
Ferritin. Checking your iron levels is done through a simple blood test called a serum ferritin test. The study of iron in the human brain is particularly important in the context of Alzheimer’s disease. Iron is both essential for healthy brain function and is implicated as a factor in neurodegeneration. The chemical form of the iron is particularly critical, as this affects its toxicity and disrupted iron metabolism is linked to regional iron accumulation and pathological hallmarks, such as senile plaques and neurofibrillary tangles. 39 Men should (almost) never supplement with iron.
Haptoglobin. This is a marker for inflammation and is known to protect against reactive oxygen species (free radicals). It also aids in wound repair by stimulating growth of new blood vessels. 40 More recently, haptoglobin has shown prognostic significance in patients found to have ovarian cancer. 41
Serum amyloid A (SAA). The level of this protein increases in the blood in response to various forms of assaults on our bodies. Concentrations may increase by 1000-fold during inflammation. It is potentially involved in several chronic inflammatory diseases by way of amyloidosis. 42 Amyloidosis frequently affects the heart, kidneys, liver, spleen, nervous system and digestive tract. Severe amyloidosis can lead to life-threatening organ failure.
Transferrin. The blood transferrin level is tested for diverse reasons: to determine the cause of anemia, to examine iron metabolism and to determine the iron-carrying capacity of the blood. Low transferrin can impair hemoglobin production and so lead to anemia. Low transferrin can be due to poor production of transferrin by the liver (where it’s made) or excessive loss of transferrin through the kidneys into the urine. Many conditions including infection and malignancy can depress transferrin levels.
Uric Acid. Uric acid is a risk factor of cardiovascular disease, as well as being a major natural antioxidant, prohibiting the occurrence of cellular damage. According to some research, “Notwithstanding the associated increased risk of cardiovascular disease, higher levels of uric acid are associated with a decreased risk of dementia and better cognitive function later in life.” 43 However, other research suggests that the correlation does not exist. 44 Uric acid remains an important test that should be performed routinely to measure health and health trends. It is a key marker for systemic hypoxia (lack of oxygen). Athletes often have high uric acid after exercise as do mountaineers.
Vitamin B6. Low circulating Vitamin B6 is highly correlated to markers of inflammation that contribute to Alzheimer’s disease. 45 This marker, taken together with other inflammation markers, help strengthen the case for inflammation and associated conditions, when all are pointing at an increase in inflammatory body burden.
Many markers of inflammation are elevated for acute (sudden) conditions, like trauma, but are also elevated for chronic conditions. These markers tend to be very high in acute conditions but often are just barely above “normal” in chronic diseases. Figure 3.1 below shows the behavior of some of these markers of inflammation in the blood after an acute event, like trauma. Notice that C-reactive protein goes down quite rapidly after the acute event. If your CRP is elevated day one, month one, and year one, it is elevated due to a chronic condition, not a one-time event.
Many markers of inflammation are elevated for acute (sudden) conditions, like trauma. These same markers tend to be very high in acute conditions but often are just barely above “normal” in chronic diseases.
Figure 3.1. Changes in inflammatory markers with time after an acute event.46
have just listed over 2-dozen tests, most of which involve drawing blood, and few will be reimbursed by insurance. Indeed, having these tests done raises the usual issues of insurance reimbursement, doctors catching up with emerging data, interpretations, and interventions based on the results. The biggest hurdle you face is that the best use of these tests is on the apparent “well person.” Insurance companies will not pay for most, if any, of these tests for prevention, but this is exactly where they provide the most value.
We have not listed these tests in any particular order because every test provides useful information. The more tests you can obtain the better.
An appreciation for the necessity of inflammation to protect our health is slowly emerging among researcher, but not so with clinicians. However, even the most astute researchers are still somewhat trapped in the dogma that inflammation can backfire and cause harm. There are scant few who recognize that our most serious diseases start through some event or events that suppress or degrade our immune system followed by growth of opportunistic pathogens or action by toxins – and increase in inflammation.
Reference and Precision Notes
(1). Microbiologists estimate that only 10% of bacteria species that exist have been identified. This heightens the need to test for inflammation because finding an offending pathogen may be challenging. New interpretation of a few of the “gold standard” tests are in order when evaluating their predictive power on your good long-term health. We are defining “new normal” values for some old tests – to help you better define and protect your health. Also, some of these tests are considered “non-specific,” but disease, by the way is also non-specific. . We confront this “non-specific” argument all the time. Consider this simple example. C-reactive protein is elevated in the case of trauma – for example it a stub my toe. In a couple of days, the value settles back down to baseline. It is also elevated slightly, but chronically, in someone with vascular inflammation. Vascular inflammation is connected with hundreds, if not thousands of so-called diseases. This means, elevated C-reactive protein is non- specific. Wouldn’t you like to know if a marker, tied to hundreds of diseases is elevated in your body? Of course, the drug companies have not develop a neat little drug to lower C-reactive protein. Now you know why this is NOT a common test – while cholesterol, for example, is. In the case of C-reactive protein and other markers that go up with an “acute” event, like trauma, it is important to obtain more than one value over a period of weeks or months. This eliminates the confusion in diagnosing a one-time event or a chronic, persistent, underlying problem. If the marker is up well beyond it’s “acute phase” behavior, it implies a chronic conditions. Later in this chapter we present the life cycle of many of these markers when there is no chronic underlying condition.
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4 Ravnskov, Uffe, and Kilmer S. McCully. “Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies.” Annals of Clinical & Laboratory Science 39.1 (2009): 3-16.
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14 Neumann, Franz-Josef, et al. “Treatment of< i> Chlamydia pneumoniae</i> infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial.” The Lancet 357.9274 (2001): 2085-2089.
15 Mitchell, William M., and Charles W. Stratton. “Diagnosis and management of infection caused by Chlamydia.” U.S. Patent No. 6,664,239. 16 Dec. 2003.
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17 Grayston JT, Jackson LA, Kennedy WJ, et al. Secondary prevention trials for coronary artery disease with antibiotic treatment for Chlamydia pneumoniae: design issues. Am Heart J. 1999; 138: S545–S549. CrossRefMedline
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19 Campbell, Lee Ann, Cho-Chou Kuo, and J. Thomas Grayston. “Chlamydia pneumoniae and cardiovascular disease.” Emerging infectious diseases 4.4 (1998): 571.
20 “Tuberculosis Fact sheet N°104”. World Health Organization. November 2010. Retrieved 26 July 2011.
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24 Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
25 Clayton, Paul. “Out of the Fire, Why chronic Inflammation is the root of all disease and HOW to put out the flames.” PharmacoNutrition Press, 2013
26 Panda, Alexander, et al. “Human innate immunosenescence: causes and consequences for immunity in old age.” Trends in immunology 30.7 (2009): 325-333.
27 Fagiolo, U., et al. “Increased cytokine production in mononuclear cells of healthy elderly people.” European journal of immunology 23.9 (1993): 2375-2378.
Chapter 3 – Inflammation
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32 Song, Juhyun, and Jong Eun Lee. “Adiponectin as a new paradigm for approaching Alzheimer’s disease.” Anatomy & cell biology 46.4 (2013): 229-234.
33 Disterhoft, John F. “Calcium hypothesis of aging and dementia.” (1994).
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46 Gabay, Cem, and Irving Kushner. “Acute-phase proteins and other systemic responses to inflammation.” New England journal of medicine 340.6 (1999): 448-454.
48 http://www.sciencebasedmedicine.org/inflammation-both-friend-and-foe/, December 27, 2011.
49 Lee, Jaemin, et al. “p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis.” Nature medicine 17.10 (2011): 1251-1260.
50 http://www.t-nation.com/free_online_article/most_recent/the_shocking_truth_about_inflammation. April 26, 2013.
51 http://healthletter.mayoclinic.com/editorial/editorial.cfm/i/163/t/Buzzed%20on%20inflammation/, October 25, 2014.