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From the Townsend Letter
January 2017

Galectin-3: An Emerging Biomarker for Evaluation and Treatment of Cardiovascular and Kidney Disorders and Cancer
by Jerry Stine, CNC, and Nancy Faass, MSW, MPH
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Galectin 3 (Gal-3), one of the lectin proteins made in the human body, is now recognized as a significant biomarker for monitoring the progression of cancer, cardiovascular diseases, prostate conditions, accelerated aging, and inflammatory expression. Understanding of the importance of Gal-3 has developed over the past 20 years through both research and clinical experience. The PREVEND study, which evaluated approximately 8,000 patients for potential kidney disease, found a threefold increase in all-cause mortality in patients with elevated galectin-3. A study of CHF patients also found that higher levels of this biomarker correlated with a threefold increase in premature mortality from all causes. Elevated galectin-3 has been associated with a startling number of common, and frequently serious, health conditions:

  • Cancer, including prostate cancer
  • Heart disease and congestive heart failure
  • Coronary artery disease
  • Fibrosis of the heart, lungs, kidneys, liver
  • Diabetes
  • Arthritis
  • Parasitic disease
  • Sepsis
  • Compromised wound healing
  • Accelerated aging

It is now clear that measurement of galectin-3 levels should be routinely used to manage a wide range of health issues. Testing is not just a theoretical exercise. An important reason to test for this biomarker is the potential to inhibit over-expression of Gal-3. Elevated levels can be reduced with nutritional supplementation, thereby contributing to solid clinical improvement and risk reduction in degenerative disease.

Galectin-3: Friend or Foe?
What is galectin-3 and why is it involved in so many pathologies? Gal-3 is one of a number of carbohydrate-binding proteins evident in functions such as anti-bacterial and anti-fungal activity, tissue repair, kidney regeneration, and maintenance of lubricity in the joints. The binding action of these molecules is a key aspect of both normal function and pathological effects of Gal-3. It should be noted that Gal-3 is distinct from lectins occurring in food, currently a popular topic in food reactivity and obesity considerations.
Problems can develop when Gal-3 is over-expressed, with serum levels above the normal range. The precise reasons for this dynamic are not always clear, but at elevated levels, there appears to be a consistent association with processes such as inflammation, chronic infection, and hypoxia. Gal-3 feeds back to the macrophages, promoting the production of inflammatory cytokines and, through another pathway, increases collagen 1 synthesis, which encourages fibrosis and tissue injury. Over-expressed Gal-3 also drives fibroblast differentiation. These dynamics suggest that Gal-3 is inflammatory and that elevated levels of this marker may be an aspect of a feed-forward system that encourages additional, cumulative inflammation.
The strong binding characteristic of Gal-3 allows the formation of matrixes joining Gal-3 molecules with toxin compounds that can advance a number of pathological processes that include the following:

  • Immune dysfunction,
  • Reactive Oxygen Species,
  • Fibrosis,
  • Tissue damage,
  • Vascular damage.

Galectin-3 is not only a predictive marker. It is also an initiator and driver of these pathological processes in numerous health conditions.

MetalPulResearch and Testing
In-Depth Research:There are approximately 5,700 published articles on galectins, with about 3,000 on Gal-3, reflecting a marked increase in papers more recently. This research has looked at the value of Gal-3 in diagnosing and monitoring a wide range of conditions and in its prognostic value.
Studies on the importance of inhibiting Gal-3 activity have utilized experimental pharmaceuticals, none of which are commercially available at this time. However, a botanical supplement – modified citrus pectin (MCP) – has been available for clinical use in the management of Gal-3 for two decades. MCP has been evaluated in animal models, discussed in more than 40 articles on Medline, documented in a human study of prostate function, and currently is the focus of two clinical trials.

Laboratory Testing: Evaluation for Galectin-3 is FDA-approved and covered by many insurance providers and Medicare. It is widely available from LabCorp and from Mayo Medical Laboratories. Approximately 20% of the population demonstrate fluctuating Gal-3 levels over three-month intervals, apparently independent of obvious pathology. This suggests that regular monitoring of Gal-3 is important in initial clinical management until individual variations are identified and understood. This marker reflects inflammation; so, when a condition improves, Gal-3 levels frequently change. Data from the PREVEND study suggested keeping Gal-3 levels below 15 for lower risk. The group with the greatest longevity in that study had Gal-3 levels averaging 9.4 ng/ml.
Gal-3 elevation is common to a wide range of health disorders and is efficacious in monitoring the progress and severity of these conditions; however, this marker should not be the sole indicator or biomarker used to diagnose heart disease or any other pathology.

Immune Suppression
Gal-3 crosslinks and inhibits the function of T-cell receptors and CD-45 by binding glycans, resulting in a number of adverse effects:

  • Suppressed immune surveillance,
  • Blocked T-cell receptor activity,
  • Downregulated T-cell signaling,
  • Inhibited dendritic, T-cell, and NK-cell function.

It is possible that this aspect of elevated Gal-3 levels reflects a form of stealth immune suppression not detectable by the usual measurement of T-cell or NK-cell levels or activity.

Gal-3 has become an important biomarker in cancer management. Numerous forms of cancer and cancer pathologies have been associated with elevated levels of Gal-3, which has been shown to promote the following:

  • Cell adhesion,
  • Migration,
  • Invasion,
  • Aggregation,
  • Angiogenesis,
  • Tumor growth,
  • Inhibition of apoptosis,
  • Immune evasion,
  • Metastasis.

Gal-3 interference with normal immune response to solid tumors is related in part to the formation of the Gal-3 matrix, which can include toxic growth-promoting compounds that can surround and bind tumor tissue, blocking normal immune surveillance and tumor inhibition. As Gal-3 surrounds tumor tissue, not only does the tumor become less approachable by normal immune mechanisms, but the effectiveness of a number of cancer treatments is blocked. This fact is borne out by studies that document the inhibition of Gal-3 levels and subsequent improvement in the effectiveness of radiation therapy and chemotherapeutic agents such as Cisplatin (Platinol), Bortezomib (Velcade), Doxorubicin, Dexamethasone (Decadron), and Paclitaxel. When Gal-3 is inhibited, cancer treatment is enhanced; and inflammation and fibrosis are reduced.

The role of Gal-3 in obesity has not been explored extensively. However, study findings are suggestive, identifying Gal-3 as a possible component of obesity and a complicator of obesity recovery. Studies of pathology in which obesity is a factor reported elevated levels of Gal-3. Galectin-3 was consistently higher in patients with hypertension, obesity, and atrial fibrillation compared with levels of this marker in heart failure patients without atrial fibrillation – and much higher than those of healthy individuals.
An animal study on the effect of Gal-3 in remodeling adipose tissue in obese mice found elevated levels of Gal-3 and pericellular collagen. The obese mice exhibited higher adipose tissue inflammation and other changes in adipocytes. Treatment with modified citrus pectin, a Gal-3 inhibitor, blocked all these effects. This is a fascinating study, suggesting a mechanism for cellulite reduction in obese humans, which is a difficult-to-manage aspect of even mild obesity. We look forward to more research in this area.

Heart Disease
Gal-3 levels can be particularly important in many aspects of cardiovascular disease management. Levels of this biomarker are a general risk factor as well as an independent indicator of disease severity and the likelihood of success with certain treatments. In the PREVEND study (7,900 people observed) Gal-3 levels were positively correlated with all the common risk factors: higher systolic and diastolic blood pressure, percentage that were diabetic, rate of myocardial infarction, and higher stroke incidence. Gal-3 also demonstrated a positive correlation with higher levels of CRP, cholesterol, triglycerides, LDL, and inversely with HDL. Elevated Gal-3 levels appear to strongly affect atrial fibrillation (AF) and predict the following:

  • Success of catheter ablation in AF,
  • Mortality from all cause in chronic AF,
  • Success of pacemaker therapy,
  • Mortality in coronary artery disease.

Higher Gal-3 levels are a component of the degenerative process (referred to as remodeling) in congestive heart failure and coronary artery disease. In CHF the heart is not just enlarged and exhibiting reduced ejection fraction, but the heart muscle becomes stiffened as the fibrotic process advances.
Studies indicate that higher galectin levels at the time of pacemaker implantation are associated with poor therapy outcomes. During a recent conversation with a cardiologist, this author learned that his expectation for success of implanted pacemakers was the following: one-third experienced a very strong felt response, one-third had a moderate felt response, and one-third had little or no felt response. Testing for Gal-3 levels offers both an opportunity to evaluate relative likelihood of benefit from pacemakers and suggests that Gal-3 inhibition of treatment may improve outcomes in pacemaker therapy. Serial testing is now considered important in assessing and managing risk in cardiovascular issues.

Pulmonary Fibrosis
Data from the Framingham study tracking 2,596 patients looked at pulmonary function and Gal-3 levels. Analysis found that those in the highest Gal-3 quartile were twice as likely to have the following:

  • Interstitial lung abnormalities on CT,
  • Restricted lung function, including decreased lung volume and altered gas exchange,
  • Potential benefit from the management of Gal-3 in early stages of pulmonary fibrosis.

Clinical studies have found that Gal-3 levels in non-elite marathon runners increase during exercise but normalize following exercise activity. This suggests that Gal-3 testing on athletes should not be performed on days of intense training. Marathon runners, most of whom typically show substantial increase in Gal-3 post-exercise, have been studied to determine whether they are developing fibrotic changes in the heart. Most marathoners in these studies did not develop fibrotic patches. The Gal-3 increase was mostly in skeletal muscle (98% increase), with much lower increase in myocardium of the left ventricle (19.9% increase). However, some ultra-endurance athletes do tend to develop patchy myocardial fibrosis. Note that this particular study did not specifically looked at Gal-3 levels, so more research is needed to correlate levels of galectin-3 with cardiovascular pathology in ultra-endurance athletes.

There is a great interest here at Lifespan Institute and at other anti-aging practices in lab tests that go beyond disease risk, reflecting metabolic activity associated with the rate and degree of aging. The ideal test would provide feedback on both reducing risk and enhancing regeneration. Several studies indicate that Gal-3 can be highly useful in this regard.
Population studies have found that Gal-3 levels increase with age for both men and women, starting at about age 30. Levels increase steadily, tripling at about age 70, with levels slightly higher for women. This strongly suggests that Gal-3 increase is an aging mechanism or reflects increased tendencies to inflammatory complications with age. This is illustrated by a comparison of 81 “successful agers” (100 to 104 years old) to 46 healthy younger individuals (ages 70 to 80). The centenarians showed lower average levels of Gal-3 and more clustering at lower levels. The healthy younger elders showed overall higher average levels and a wider distribution, some participants having high levels suggestive of elevated risk of premature mortality. Increased levels of Gal-3 correlate with higher levels of inflammation and reduced tissue repair.

A Note on Mold-Related Illness and Candida Infection
The author found no human or animal studies showing levels of Gal-3 in chronic candida infections or mold disorders. Consequently, this is a request that practitioners consider testing for Gal-3 levels in such cases and sharing the data. Are Gal-3 levels increased in these situations? Does Gal-3 inhibition help these patients? This is possibly of great value to patients with these conditions.

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