September 2014 Blog with Durk and Sandy

September 02, 2014

September 2014 Blog with Durk and Sandy

APPETIZERS

Every time you spend money, you’re casting a vote for the kind of world you want.
— Anna Lappe

The hardest thing in the world to understand is income tax.
— Albert Einstein

No man ever listened himself out of a job.
— Calvin Coolidge

If you want a guarantee, buy a toaster.
— Clint Eastwood

Your Physics Lesson for Today

Heisenberg and Schrodinger are driving, and get pulled over. Heisenberg, in the driver’s seat, is asked by the officer, “do you know how fast you were going?” Heisenberg replies, “No, but I know exactly where I am.” The officer looks at him confused and says, “you were going 108 miles per hour!” Heisenberg throws up his arms and cries, “Great! Now I’m lost.”

The officer, now more confused than ever, orders the two men out of the car, and proceeds to inspect the vehicle. He opens the trunk and yells at the two men, “Hey! Did you guys know you have a dead cat back here?” Schrodinger angrily yells back, “We do now, jerk!”

The Problem with Learning Physics from Jokes 
Is That Unless You Already Know the Physics, 
You Won’t Get the Punch Line

OK. The Heisenberg uncertainty principle shows mathematically that you cannot know both your momentum AND your location at the same time. The police officer did not know that. The Schrodinger wave equation shows that, in order to determine whether, in your universe, the cat in your trunk is alive or dead, you have to take a look, otherwise you don’t know. The cop didn’t know that, either. The moral of this story is: Never expect a dumb cop to have a clue about physics. Your best bet is to fail to arrive at the pullout at the same time as the cop. You can blame it on Heisenberg. The cop will have you point blank on the speed violation but won’t have a clue whether you were in the speed zone at the time. In the meantime, the cat has died and the stench will act as a cop repellant as the Schrodinger equation waives the cop’s authority out of existence.

NOW DO YOU GET IT??

HYDROGEN THERAPY NOW APPEARING IN LEADING JOURNALS!

Hydrogen-Rich Water Decreases LDL Cholesterol and Improves HDL Function in Human Trial

Papers on hydrogen therapy are now appearing more frequently and in leading journals. A paper published this year1 in the Journal of Lipid Research reports on the results of a small trial of human volunteers (12 men, 8 women equal to or older than 43 years), all of whom had one or more of the following conditions associated with metabolic syndrome: prehypertension (diastolic 80–89 mm Hg and systolic 139 mm Hg or lower; fasting serum glucose from 5.2 to 6.9 mmol/l (prediabetic), total cholesterol greater than 5.18 mmol/l and/or LDL cholesterol greater than 2.59 mmol/l; body mass index between 25.0 and 34.9 kg/m(squared); or waist circumference greater than or equal to 100 cm for men and greater than or equal to 88 cm for women. The subjects were considered to potentially have metabolic syndrome.

After 10 weeks of treatment with hydrogen-rich water, total cholesterol and LDL cholesterol levels were significantly decreased in 18, while 1 patient had increased total and LDL cholesterol and one other patient had no significant effects to either parameter. Interestingly, while 10 of the 20 patients were smokers and 10 were nonsmokers, treatment decreased serum total cholesterol and LDL cholesterol in both smokers (said to be occasional smokers) and nonsmokers.

We were particularly interested in the finding that the oxidative state and some functional properties of the HDL molecule were improved in the subjects treated with hydrogen-rich water. This is especially important because HDL can, especially under conditions of oxidative stress, lose its protective properties and actually become pro-atherogenic. One of the results, for instance, was that the ability of the isolated HDL particles to elicit efflux from cholesterol-loaded macrophages was dramatically higher after hydrogen treatment compared with the HDL particles isolated from the serum before hydrogen treatment. In addition, hydrogen was found to reduce the oxidation of LDL and LDL-mediated inflammation. Hydrogen also decreased apoB100, considered to be an antiatherogenic effect, while there was no change in ApoAI.

Although the criteria for having potential metabolic syndrome were relatively mild (only one of the above listed conditions needed to be present), this actually underlines the meaningful nature of these protective effects of hydrogen on HDL and LDL since it ought to be more difficult to demonstrate improvements in a less abnormal condition.

Reference

  1. Song et al. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J Lipid Res. 54:1884-93 (2013).

ONE OF THE MOST IMPRESSIVE EFFECTS OF HYDROGEN YET

Hydrogen Treatment Prevents Lipid Deposition in Descending Aorta in Rat Model of Periodontitis

As we have mentioned in this newsletter before (in the context of bacteria found in tooth decay being involved in the development of atherosclerotic plaques), the connection between periodontitis and atherosclerosis is becoming supported by more data (hypothesis under development). In this very interesting paper,1 scientists have shown in a study of rats with induced periodontitis that lipid deposition occurred in the descending aorta, but when a similar group of rats with induced periodontitis was treated with hydrogen (as hydrogen-rich water), those rats had a significantly lower level of lipid deposition in their descending aortas. Hence, the results of this study if verified in people could be of major importance to a great many people with periodontitis, who may be unknowingly vulnerable to a silent source of atherosclerosis.

The researchers propose that the reduced lipid deposition was a result of decreased serum oxidized LDL and decreased aortic oxidative stress. The periodontal tissue examined showed infiltration by inflammatory cells, which was reduced in the group receiving hydrogen water therapy. Importantly, results showed that “[l]ipid deposition in the descending aorta was observed in all rats in the periodontitis group and in none of the rats in the control or periodontitis + HW [hydrogen water] groups.”1

Reference

  1. Ekuni et al. Hydrogen-rich water prevents lipid deposition in the descending aorta in a rat periodontitis model. Arch Oral Biol. 57:1615-22 (2012).

Hydrogen Makes “the Big Time”!
Journal of the American Heart Association
Publishes New Hydrogen Therapy Paper

Hydrogen Gas Improves Functional Outcome Following Cardiac Arrest to an Extent Comparable to That of Therapeutic Hypothermia in Rats

The potential benefits of hydrogen therapy are beginning to appear in major journals. A 2012 paper1 reports that hydrogen gas treatment (via inhalation) was as effective as therapeutic cooling (hypothermia) in mitigating mortality and functional outcome following cardiac arrest in a rat model. The paper starts by introducing hypothermia for cardiac arrest as being “widely accepted as the gold standard method to improve survival and limit neurological outcomes in patients who achieve return of spontaneous circulation (ROSC) after CA [cardiac arrest]. Despite that, it is still underutilized.” The authors suggest that the treatment of cardiac arrest is an unmet medical need. They hypothesized that hydrogen gas inhalation, having been shown to be effective in ameliorating the damage caused by ischemia/reperfusion in heart and brain of different animal models, might be an effective therapy for CA. They also cite some papers providing preliminary human clinical data on hydrogen in various medical conditions.

In this study, rats were subject to cardiac arrest and treated with isotonic saline, hydrogen gas, therapeutic hypothermia, or hydrogen gas + therapeutic hypothermia. The researchers found the survival rate after ROSC was 43% (6/13) in the control group, 92% (12/13) in the hydrogen group, 77% (10/13) in the TH (therapeutic hypothermia) group and 100% (13/13) in the hydrogen + TH group, whereas 72 hour survival rates were 31% (4/13), 69% (9/13), 69% (9/13), and 77% (10/13) respectively.

The oxygen tanks carried in ambulances already contain a small amount of carbon dioxide to help stimulate respiration. It would be simple and inexpensive to include 1% hydrogen (which is below the minimum flammability threshold) in the oxygen; this might save a lot of lives and prevent much disability. Simple and inexpensive? Oh, sorry, we forgot about FDA regulations on medical oxygen … Unfortunately for heart attack victims, the FDA has declared that the oxygen they receive is a drug, which means that addition of 1% hydrogen would make it an unapproved new drug. Since this addition is unpatentable, no one is going to spend a billion dollars or more to obtain FDA approval. The Federal Death Agency strikes again!

Reference

  1. Hayashida et al. H2 gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc.1:e003459 (2012) doi: 10.1161/JAHA.112.003459.

Increasing cGMP Promotes the Expansion and 
Browning of White Adipose Tissue

A Brite Future for the Treatment of Obesity

A remarkable new discovery1 published this year reports that increasing cyclic GMP (cGMP) signaling can cause white adipose tissue to develop the properties of “brown-like” or “brite” (also sometimes called beige) fat tissue that, like brown adipose tissue (BAT), uncouple mitochondrial metabolism from ATP synthesis to the generation of heat (thermogenesis) via UCP-1 (uncoupling protein 1). Also, like brown adipose tissue, the browned white adipose tissue have larger numbers of mitochondria than white adipose tissue and also increased insulin sensitivity. The authors1 suggest (and we agree) that browning white adipose tissue is a potential treatment for obesity.

One way to increase cGMP is with phosphodiesterase 5 inhibitors (which inhibit the degradation of cGMP) such as those used in the treatment of erectile dysfunction. Some of the experiments in this paper1 tested the effects of sildenafil (Viagra®) as a browning agent. (Note: Cialis® is another phosphodiesterase 5 inhibitor, which however has a far longer half-life than sildenafil; we expect that it would have similar effects on browning white adipose tissue though the effect of the longer half-life is unclear but might be expected to be advantageous. Further testing will provide answers.)

The researchers studied the effect of cGMP signaling, focusing on cGMP-dependent protein kinase I (PKGI), which is expressed in white adipose tissue. By inducing overexpression of PKGI, there was a 4.3 fold increase in the abundance of UCP-1, uncoupling protein 1, the uncoupling protein found in brown adipose tissue (BAT) that is part of BAT’s thermogenic program. Importantly, “treatment of DC57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 days caused 4.6 fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype (“browning”) of WAT in vivo.”1 The basal expression of PKGI in white adipose tissue is negligible.1 “Our study clearly shows that activation of PKGI in adipocytes increases adiponectin expression and, in parallel, decreases gene expression of proinflammatory cytokines (MCP1, CCL3, CCL7, IL6, and TNFA).”1

The researchers also investigated the effects of a demethylating agent, 5-aza-deoxycytidine, on the UCP-1 gene promoter. They found that the treatment of 3T3-LI adipocytes with this drug increased basal levels of UCP-1 mRNA levels, which (they also report) were even further increased in cells expressing high levels of PKGI treated with cGMP. Moreover, the expression of adiponectin by the 3T3-LI adipocytes treated with cGMP was increased and this effect was also further increased in cells overexpressing PKGI. The expression of PGC-1alpha, a “master” regulator of mitochondrial biosynthesis, was also increased in the white adipose tissue of mice treated with sildenafil.

Possible Enhanced Expression of UCP1 With Curcumin or EGCG

In a separate paper,3 the UCP1 gene was demethylated by 5-aza-deoxycytidine that increased the expression of the gene. The natural substances curcumin4 and EGCG5have been found to be demethylating agents and might, therefore, have similar effects to that of 5-Aza-deoxycytidine by increasing basal levels of UCP-1 mRNA. If so, these substances may also act as “browning” agents. We expect to see papers published on these effects, should they be revealed in new experiments, following hot on the heels of these new findings on UCP1 demethylation.

The bottom line is that both cGMP and sildenafil promote browning of white adipose tissue. The effect, the authors say, can be induced by phosphodiesterase 5 or phosphodiesterase 3B inhibitors, via increase in cGMP or cAMP (cyclic AMP). The researchers cite a study in which 12 weeks of sildenafil (Viagra) treatment of normal mice fed a high fat diet reduced body weight and improved energy balance.2

In their “Discussion” section in the paper,1 the authors note that cGMP has been shown to regulate glucagon secretion (and, thus, gluconeogenesis by the liver), mitochondrial biogenesis, and the development of “classical” BAT (brown adipose tissue). Out-of-control gluconeogenesis, that is, excessive release of glucose by the liver (which is supposed to be suppressed by insulin following a meal), is a major cause of the hyperglycemia of diabetes.

We look forward to a “brite” future that may result from the treatment of obesity with compounds that increase cGMP.

References

  1. Mitschke et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27:1621-30 (2013).
  2. Ayala et al. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes. 56:1025-33 (2007).
  3. Shore et al. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 53:1164-73 (2010).
  4. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
  5. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-7570 (2003).

Protection Against Recurrent 
Strokes with Resveratrol

Having suffered a transient ischemic attack (a TIA, or partial stroke) or a minor stroke greatly increases one’s risk of having a more serious recurrent stroke. One paper1reports that 6–15% of these people suffer stroke recurrence within 90 days and in up to 21% of patients by one year after the initial insult. The researchers1 had found that an MCAO (middle carotid artery occlusion), a very common rodent model of a stroke, can after a short period result in scattered brain cell death (necrosis) and that a moderate stroke following this event had exacerbated damage. They note that damage from a TIA or minor stroke is not always detectable with standard diagnostic imaging techniques.

The researchers studied 42 rats that were subject to MCAO, which resulted in their suffering a greater than 90% reduction in cortical perfusion in the core region. They modeled a recurrent stroke by subjecting the rats to a mild ischemic stroke followed by another mild stroke, which resulted in a higher damage score than what occurred from just the initial stroke with more dead tissue. Treating the animals with oral resveratrol for three days (25 mg/kg/day) prior to a single mild stroke reduced the amount of damage detected as compared with animals that received vehicle (same as that carrying the resveratrol). Interestingly, resveratrol did not improve cerebral blood flow in the affected areas, but did improve blood-brain-barrier function, thereby reducing leakage and edema. “Rather unexpected was our finding that resveratrol-treated rats subjected to recurrent stroke had less ischemic injury than untreated rats with a single mild ischemic stroke.”1

The scientists also studied the protective effects of resveratrol in vitro in endothelial cells. “… we found that pre-treatment of brain endothelial cells in culture with low doses of resveratrol improved their viability following oxygen glucose deprivation which could also explain improved BBB [blood-brain-barrier] following cerebral ischemia. The improved viability observed in their study was, the authors point out, consistent with the resveratrol-mediated protection of cerebral endothelial cells against apoptosis induced by oxidized low-density lipoproteins, as well as protection against high-glucose induced damage or death from oxidative stress as reported in other studies.

These results suggest a possible means of reducing the damage of a recurrent stroke in those who may have already had a minor stroke. As the authors sum it up: “Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature.”

Reference

  1. Clark et al. Protection against recurrent stroke with resveratrol: endothelial protection. PLoS One. 7(10):e47792 (Oct. 2012).

Beware of Falling Dinosaurs: 
A Continuing Saga of Corruption and Revolution

The article “FDA’s Changing Culture: What Every Food Company Needs to Know” in the April/May 2013 Food Safety Magazine, came as quite a surprise. Trade publications, as a rule, defer to regulatory agencies. A food industry publication would never call the FDA personnel that inspect food plants “thugs” for example. This deference may be coming to an end as we approach levels of FDA (and other regulatory agency) corruption that makes such attempts at industry politeness as you are hit over the head by agency gangsters simply futile. The new article is a warning to the food industry by a food industry trade publication of what to expect from FDA operating under the new Food Safety Modernization Act (FSMA).This article is a continuation of the talk we gave at Life Enhancement Products’ symposium in Las Vegas on preparing for an oncoming economic collapse which, among other things, will require planning ahead for your medical needs. Here we explore how food prices will slowly increase, then soar, as a result of taxes and regulations, including new FDA authority over the food industry. Stockpiling food may also be an important part of planning ahead to avoid falling dinosaurs.

The article explains that “the agency [FDA] is quietly becoming much more inspection-oriented and enforcement-minded, even before FSMA is fully implemented.” The article notes that “[t]he demeanor of FDA personnel during inspections has changed as well. Inspectors (or ‘investigators’ as FDA refers to them) are much more assertive, often insisting on access to records before the new legal authority becomes effective and asserting their ‘right’ to take photographs even without express legal authority.” “Moreover, instead of simply collecting product samples for laboratory testing of finished product, inspectors are increasingly conducting extensive environmental testing throughout facilities. Environmental testing is more likely to detect a problem than finished product testing, making it an important tool for the agency during inspections. Such testing can be so extensive that some have dubbed this practice a ‘swab-a-thon.’” For an agency seeking to increase its power, a testing regime that is able to magnify the appearance of danger is simply made to order.

What the article is saying here, in plain English, is that FDA inspectors are often thugs who make demands for which they have no legal authority. The inspection of every detail of a food plant is not the most cost-effective way to establish safety. Most economists agree that the inspection of final products, which are after all the source of any potential health and safety risks to the public, is far more cost-effective than examining everything in a manufacturing facility. It is, however, much easier for the FDA to identify supposed safety problems when every feature of a food plant is examined rather than just the finished products, giving the FDA the opportunity to milk companies by assessing large fines. And unsurprisingly, bullies are the type of people who fit in well with an agency culture of enforcement.

The cost of protecting a food plant from such intensive searches (all without a search warrant), requiring extensive lawyer assistance, plus the costs of the fines that the FDA can demand for the slightest deviation from the myriad and often vague rules and regulations will increase the price of food. Moreover, the practice of defensive food production, just as in the case of doctors practicing defensive medicine,* piles on costs to production that eventually are passed on to consumers. When you see food prices go up, you might give a thought to how much of that the FDA is responsible for. The failure of the TSA to improve airline safety despite their “inspections” (tests have found it easy to sneak prohibited items, even guns, past these inspections) suggests that the FDA’s intensive food plant inspections are performed at a heavy cost. The TSA, in fact, frequently violates the First Amendment free speech rights of “inspected” passengers by arresting those that complain of mistreatment. Would it come as a surprise if we see the same from these more aggressive FDA inspectors?


* Defensive product production involving testing excessively in order to catch even unlikely sources of FDA inspectors’ attention, simply adds costs to production without benefit to customers but of course customers will have to pay the extra costs. In addition, whereas those doing a good job of producing food products for the public should feel a sense of achievement as benefactors of the general public, the threat of FDA demands and punishment hanging over your head and determining much of what you have to do in your daily work will rapidly change that to a culture of defensiveness and hostility. 

† This reminds us of the time that Sandy sat down in a commercial airliner to find that the very intoxicated and scruffy looking guy next to her had taken out a very large (9" long) switchblade knife from his carryon and was attempting to impress her with it. She was impressed all right and, claiming she needed to use the toilet, had warned the plane personnel just before takeoff in time for airport security to come in and remove the guy from the plane. Every passenger on this plane as well as the crew owes Sandy a thanks for performing the real security check on this flight. Oh, and how did the knife get by airport security? Easy. The knife was made of titanium. 

‡ We heartily recommend Emord & Associates as a source of legal advice on FDA inspections. (202-466-6937) (This is an entirely unsolicited endorsement for which we receive no payment of any kind. We have used the legal services of Jonathan W. Emord in our FDA lawsuits and other legal representation for over 20 years and recommend him and his firm without hesitation. The firm offers classes for how to deal with FDA inspections.)

The article goes on to explain how the FDA plans to expand implementation of the Park doctrine, where company executives can be held responsible for criminal misdemeanors for which they had no responsibility or knowledge, with personal fines of up to $100,000 if no deaths are involved, $250,000 if a death occurs, and up to 1 year’s imprisonment. The Park doctrine is considered a type of strict liability, where you don’t have to have had anything to do with the criminal act to be held responsible, hence, fined or imprisoned. And interestingly, if you are charged with one of these criminal misdemeanors, you are allowed no right to a jury trial! Whatever happened to the Sixth Amendment, which says, “In all criminal prosecutions, the accused shall enjoy the right to a speedy and public trial, by an impartial jury of the State and district wherein the crime shall have been committed …” The Sixth Amendment, like much else of the Constitution, has been made a nullity by power-lusting politicians and bureaucrats and by Courts unwilling or unable to defend the Constitution.

Corruption and the Cause of Revolutions

We highly recommend Alexis de Tocqueville’s The Old Regime and the French Revolution (Anchor Books, 1955§) for understanding how corruption in governments is a major forerunner of revolution. It starts with the loss of legitimacy fostered by corruption. Remarkably, the Chinese communist party, concerned about rapidly spreading government corruption in China and the possibility of a revolution as a result of it, is now recommending this Tocqueville book and even giving out copies to major party officials to attempt to warn of the consequences of increasing government corruption.

Free Speech Update

U.S. Dept. of Justice and Dept. of Education Mandate Unconstitutional Speech Codes at Virtually All Colleges and Universities

The Foundation for Individual Rights in Education (FIRE) (www.thefire.org) has sent out a press release warning that on May 10, 2013, the U.S. Dept. of Education joined by the U.S. Dept. of Justice have mandated a speech code concerning “sexual harassment” that is so broad in its scope that virtually every student would be in violation of its provisions. The mandate will apply to any college or university that receives federal funding or where even one student receives a federal scholarship or loan, thereby including nearly all such institutions.

Continuing on a trend of ignoring Constitutional prohibitions on government actions, the new speech codes will now mandate punishment for such student actions as (these are just examples):

  1. Any expression related to sexual topics that offends any person.
  2. Any sexually themed joke overheard by any person who finds that joke offensive for any reason.
  3. Any request for dates or any flirtation that is not welcomed by the recipient of such a request or flirtation.

Lest anyone misunderstand, the Executive Branch of the federal government is running totally amuck by making laws on what you can say (in violation of Article I Section 1 which grants all lawmaking powers to Congress) as well as ignoring the First Amendment’s prohibition (“Congress shall make no law … abridging the freedom of speech …”) denying the federal government’s legislative body the authority to limit free speech.

We can hardly wait for the backlash to come, both from the Courts and from the general public. The media, in the meantime, may find themselves stuck in the trap of their own political correctness. Attempting to extricate themselves from the authoritarians at the Obama White House should make for an amusing spectacle.

For more on the incredible details, see FIRE and The Volokh Conspiracy (posted 13 May 2013):

http://thefire.org/case/925

http://thefire.org/article/15767.html

http://thefire.org/article/15835.html

http://thefire.org/article/16050.html

We donate to FIRE and encourage you to do so, too.

https://secure.commonground.convio.com/FIRE/generaldonationform/

http://www.volokh.com/2013/05/13/the-administration-says-universities-must-implement-broad-speech-codes-2/

See also:

http://www.openmarket.org/2013/05/10/federal-title-ix-enforcers-effectively-define-dating-and-sex-education-as-sexual-harassment/

And finally for something beautiful that touched our hearts:

http://www.volokh.com/2013/05/13/space-oddity/

 

Progress Slow in Developing an Overall 
Model of the Aging Process

A recent paper1 proposes some reasons why progress has been slow in closing in on a comprehensive explanation of aging. As the authors note, “over 300 mechanisms have been proposed in the literature to explain the underlying molecular and physiological processes of the aging process.”

They suggest two particular problems in pulling all this diverse data together:

1. “Limiting an open communication between different investigators and diverse disciplines. Investigators involved in the exploration of one single pathway might be unable to adequately appreciate advancements in other aspects of the very same phenomenon under study. Also, some fields of research are extremely far from each other (for what concerns backgrounds, methodologies, and measurements) to easily develop effective and successful collaborations.”

2. “Driving the development of interventions too narrowly focused. In other words, experts of one specific mechanism of aging are more likely to exclusively explore preventive/therapeutical protocols for that selected target.”

These problems were the reasons why we wrote our book Life Extension, a Practical Scientific Approach (Warner Books, 1982) that became a #1 bestseller, selling over 1,000,000 copies. We realized that there were many diverse areas of science (for example, food science, petroleum science, animal husbandry, toxicology, etc.) that were developing work that was very relevant to the study of aging and, yet, workers in one of these scientific fields could be entirely unaware of what researchers in another area were doing. We felt that it was extremely important to help bring out the relatedness of much of this important work in order to speed up the development of aging research and, according to feedback we got from many other scientists, we succeeded in doing so. That’s why Life Extension, a Practical Scientific Approach became a classic. It wasn’t because we were doing all this work. It was because a lot of people were doing work that added up to considerably more knowledge of the aging process than the scientific community (and, indeed, the public at large) realized we had. In the process, of course, it became clear that there was an awful lot more left to be learned (still is) which pointed in a number of directions that hadn’t received much attention before.

Reference

  1. Cesari et al. The stress of aging. Exp Gerontol. 48:451-6 (2013).

How You, Too, May Benefit From the 
New Research on DNA Methylation and 
“Browning” of White Adipose Tissue

As we have been writing in recent newsletters, DNA methylation is a widely investigated way that gene transcription (expression or non-expression) is regulated. DNA hypermethylation seems to generally (but not always) suppress gene expression, whereas DNA hypomethylation generally (but not always) increases gene expression. Both EGCG and curcumin have been discovered to act as hypomethylation agents, that is, to decrease DNA methylation and to possibly increase gene expression. (See, for example, references 4 and 5 in the article above.)

A recent paper1 reports the good news that methylation of the UCP1 enhancer is responsible in mice adipose tissue for the regulation of UCP1 gene expression. This could be important because UCP1 (uncoupling protein 1) is a major genetic factor that is responsible for regulating thermogenesis (energy expenditure) in brown adipose tissue (brown fat). The fact that methylation controls the expression of UCP1 suggests that the use of demethylating agents such as EGCG or curcumin might increase its expression, at least in brown fat or “browned” white fat. The researchers1 found, in fact, that demethylation of the UCP1 promoter by the demethylating agent 5-aza-deoxycytidine increased UCP1 expression while methylation of UCP1 promoter-reporter constructs decreased expression.

It has been discovered that it is possible to cause white adipose tissue to become “browned,” (as discussed in the article above) that is to change its properties to more closely resemble brown adipose tissue. One of the most important of those changes is for adipocytes to become able to express Ucp1 and to engage in thermogenesis. We anticipate additional publications on the use of demethylating agents for the browning of white fat.

Reference

  1. Shore et al. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 53:1164-73 (2010).

Closing In On Exercise In a Pill? Maybe. 
Decreased Methylation in Muscle Genome 
Turns On Exercise-Induced Gene Expression

Researchers have identified many of the skeletal muscle genes that are triggered by exercise and contribute importantly to the benefits of exercise. A new paper1 now identifies an important role played by DNA methylation in exercise-induced gene expression. DNA methylation is an important process for determining when genes are expressed (turned on) or silenced (turned off) and much has been learned about natural products that are able to trigger increased DNA methylation (which generally decreases gene expression) or decreased DNA methylation (which generally increases gene expression). With these discoveries, we are moving ever closer to pharmacological control of enhancing genetic expression that would otherwise require exercise as a trigger. Here’s the latest story:

A recent paper1 found that DNA methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after they performed acute exercise. “Exercise induced a dose-dependent expression of PGC-1alpha [an important regulator of mitochondrial biogenesis], PDK4, and PPAR-delta, together with a marked hypomethylation on each respective promoter. Similarly promoter methylation of PGC-1alpha, PDK4, and PPAR-delta was markedly decreased in mouse soleus muscles 45 minutes after ex vivo contraction.” “Promoter methylation of PGC-1alpha, Tfam, Mef2a, and Cs, but not PDK4, decreased prior to gene expression changes.”1 “Conversely, reactive oxygen species (ROS) production (induced by H2O2 [hydrogen peroxide]) elicitated hypermethylation.” The authors suggest, therefore that “DNA hypomethylation is an early event in [muscle] contraction-induced gene expression.”

In other recent work, EGCG1A and curcumin1B have been identified as natural substances that act as hypomethylating agents, e.g., they decrease DNA methylation. In light of the above study,1 this suggests (we speculate) that taking proper doses of EGCG and/or curcumin shortly before exercise might enhance the hypomethylation induced by muscle contraction, increasing the beneficial effects of exercise. Mild exercise might be able to provide the benefits that would otherwise require more energetic exercise. (The latter has not been demonstrated but we hope to see studies published in the near future testing this hypothesis.)

The authors1 suggest, however, that DNA methylation does not exclusively control exercise-induced gene expression as they have found that ionomycin, AICAR, or ROS production increased mRNA expression without altering promoter methylation. Thus, they propose that DNA methylation “may serve as a selective mechanism to orchestrate the activation of a subset of genes but, clearly, other mechanisms, such as transcription factor activation and recruitment to the chromatin, are likely to be involved.”

Exercise Alters Epigenetic Parameters in Rat Hippocampus

In a second paper on exercise and DNA methylation (an epigenetic process),2researchers found that exercise can alter DNA methylation in the hippocampus of 3 month and 20 month old Wistar rats. As it is known that exercise can improve cognitive processes, DNA methylation is an interesting link that suggests a possible mechanism for the effect of exercise on cognition.

The authors first point out that epigenetic mechanisms have been shown to affect cognition in earlier studies where histone deacetylase (HDAC) inhibitors improved memory in aged rodents.2 Moreover, exercise has also been shown to ameliorate age-related cognitive decline in rodents. Other studies have reported that exercise modulation of histone deacetylase status in the brain enhanced transcription of genes in the brain related to cognitive function.

The researchers therefore studied the effects of exercise on epigenetic changes as a consequence of aging. They followed the effects of two exercise regimens, a single session of treadmill exercise or chronic treadmill exercise, on changes in DNA methylation in the hippocampus.

The findings included that methylation changes as a result of exercise differed in 3 month old (young) and 20 month-old (aged) male Wistar rat hippocampi. They report decreased DNMT1 (DNA methyltransferase 1) activity in senescent human fibroblasts and suggest that this is correlated with a genome-wide tendency to DNA hypomethylation in multiple vertebrate organs during the aging process.2 Aged hippocampi were found to have lower levels of H3-K9 methylation levels. As the researchers explain, histone methylation can cause either gene activation or gene repression.

The single exercise experiment in young adult rats resulted in significant decrease in both DNMT1 and DNMT3b, two methyltransferases, which could reduce DNA methylation and, consequently, affect gene expression. In contrast, the single exercise test did not have an effect on DNMT1 or DNMT3b levels in the hippocampi of the 20 month-old (aged) rats. Other details reveal considerable complexity to the pattern of epigenetic changes in the hippocampus in conjunction with exercise in young and old rats. It is interesting to note that EGCG inhibits methyltransferases.

It appears quite plausible (but not proven) that DNA methylation changes in the hippocampus as a consequence of exercise may play a role in the improved cognition resulting from exercise but that these effects are different in young vs. old rats. Exercise in a pill? We aren’t there yet, but come back in five years or so.

References

1. Barres et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 15:405-11 (2012). 
1A. Yang et al. Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds. Nutr Rev. 66 (Suppl 1):S18-S20 (2008). 
1B. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009). 
2. Elsner et al, Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: a preliminary study. Exp Gerontol. 48:136-9 (2013).

Reducing the Risk to Male Humans of 
Making Excessively Generous Economic Offers to 
Physically Attractive Females

Continuing our reports on new findings in the biology of economic behavior, we offer the following humdinger. A new paper1 reports that minocycline, an antibiotic in the tetracycline family, reduces the risk to men of making excessively generous offers in economic exchanges with very attractive females, what is called a “honey trap.”

Recognizing that this sort of behavior can be a risky, costly form of bias in economic exchanges, this information may be quite beneficial to those inclined to the “honey trap.” The description of a number of past studies showed that in economic exchanges, minocycline pretreatment resulted in less of a “high” feeling in economic transactions with very attractive women and induced more sober decision-making. In the experiments reported in the new study,1 98 healthy men played a trust game with 8 photographed young females after four days of treatment with either 200 mg/day of minocycline (usually used as an antibiotic at this dose) or placebo. The photos of the women’s faces formed the basis for a decision on the part of each male participant of how much out of 1300 yen (about $13 at that time) they would give a woman.

As the authors explain, “[r]ecent studies with human subjects show that minocycline, a commonly used tetracycline antibiotic, may facilitate focus on appropriate environmental cues for social decision-making, possibly by reducing noise and other factors (e.g., personality and arousal) that can obstruct decisions.”1

It is not clear how the females “betrayed” their benefactors or expressed untrustworthiness, but the results clearly showed that men in the placebo group offered more money to the females that were more attractive, while the men in the minocycline group did not. For the most attractive women, the difference between the amounts of money offered by the men in the placebo group was statistically significantly greater than that offered by the men in the minocycline group, but the difference was not significant for the less attractive women.

There was some discussion of possible neurological mechanisms to explain these effects. In rodent models, minocycline is reported to reduce microglial activation (inflammation*) in certain areas of the brain, including the putamen, thalamus, and frontal cortex. The researchers also report that, in some studies, minocycline may link microglia with glutamate and dopamine interaction. It appears that the effect on “honey trap” behavior is, at present, though, poorly understood.


* The phrase “inflamed by lust” may be literally true! We hope that this experiment will be repeated with gay men viewing photos of other guys. Although we expect a similar result, you can never tell …


Reference

  1. Watabe et al. Minocycline, a microglial inhibitor, reduces “honey trap” risk in human economic exchanges. Sci Rep. 3:1685 DOI: 10.1038/srep01685.

It’s a NAD+, NAD+, NAD+, NAD+ World

[CAUTION: This article is unusually complex. Life can be like that.]

There is growing interest in the nucleotide NAD+ (nicotinamide adenine dinucleotide) because of recent research revealing it’s regulation of diverse pathways controlling lifespan.1 A paper by Belensky et al2 in the same issue of Cell as a commentary on it1found that a precursor of NAD+ (nicotinamide riboside) extended yeast life span via activation of pathways that respond to increased NAD+, such as those that depend upon the SIR2 gene. Moreover, the beneficial effects of caloric restriction appear to be NAD+ dependent, as well as mediated by the NAD+-dependent SIRT1/Sir2 activity.3,4

The ratio of NAD+/NADH regulate many aspects of metabolism, including DNA repair, stress resistance, and cell death.4

“Changes in NAD+ metabolism have been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disease, and normal ageing.”4 In fact, the authors of paper #4 suggest that, “NAD+ synthesis through the kynurenine pathway [de novo synthesis of NAD+ from tryptophan] and/or salvage pathway [from nicotinamide] is an attractive target for therapeutic intervention in age-associated degenerative disorders.”

NAD+ is also reported to play a critical role as part of cellular respiration during the process of oxidative phosphorylation and ATP production.4 “Therefore, ATP synthesis and redox potential is directly proportional to intracellular NAD+ concentration.”4 The NAD+/NADH ratio is a measure of the metabolic state because of its importance in regulating intracellular redox state.4

Sirtuins are deacetylases that regulate large numbers of genes by removing acetyl groups from DNA. The function of the longevity gene SIRT1 has been shown to depend on the availability of NAD+. “Not surprisingly, the life-enhancing properties of sirtuins go hand in hand with those of NAD+ metabolism, suggesting a causal relationship where SIRT1 translates alterations of NAD+ levels into transcriptional events.”4 Interestingly, the DNA repair enzyme PARP (poly(ADP-ribose) polymerase) uses large amounts of intracellular NAD+ and is thereby in competition with sirtuins for the limited supply of NAD+. Under conditions of excessive expression of PARP, cellular NAD+ can be depleted, killing the cell. “Hyperactivation of PARP1 following DNA strand breaks can rapidly consume intracellular NAD+ pools, resulting in a loss of ability to synthesize ATP, and the cessation of all energy-dependent functions and consequent cell death.”4

The authors of paper #4 note that over-activation of PARP1 has been reported in the brains of Alzheimer’s disease patients, as well as in those with diabetes, MTPT-caused Parkinson’s disease, shock, and other conditions. It has been suggested that PARPs may play a role in aging by promoting NAD+ depletion. One study5 reported that PARP-1 activity in mononuclear blood cells increases with aging in at least thirteen mammalian species. In another study,5A researchers reported that “[o]ur results suggest that oxidative stress induced NAD+ depletion could play a significant role in the aging process, by compromising energy production, DNA repair and genomic surveillance.” The latter study5A examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female Wistar rats, reporting that “[o]ur results are the first to show a significant decline in intracellular NAD+ levels and NAD/NADH ratio in all organs by middle age (i.e., 12 months) compared to young (i.e., 3 month old) rats … The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.”

The authors of one paper5B write that “… when cells are subjected to oxidative stress by exposure to H2O2 [hydrogen peroxide], PARP-1 is activated and SIRT1 activity is robustly reduced, as PARP-1 activation limits NAD+ bioavailability. Treatment with PARP inhibitors in these circumstances allows the cell to maintain NAD+ levels and SIRT1 activity. … these observations indication that PARP-1 is a gatekeeper for SIRT1 activity by limiting NAD+ availability.”

The authors of paper #4 report that “[p]revious work from our group has shown for the first time that resveratrol induces a dose-dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT1)” but that this is unpublished data.

Interestingly, a very recent paper found that “enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models [of breast cancer], increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model.”6

Mitochondrial Biogenesis Induced by SirT1 Depends on Availability of NAD+

A very recent paper,6A in explaining how exercise or SirT1 activates PGC-1alpha, a master regulator of mitochondrial biogenesis, points out that the activity of SirT1 relies on NAD+ as a necessary coenzyme. The paper6A goes on to describe how, in its study of exercise in mice, chronic contractile activity (exercise) has a robust effect on mitochondrial biogenesis and that resveratrol acted synergistically with exercise to increase mitochondrial content when SirT1 was activated. “[T]he maximal effect of RSV [resveratrol] requires both SirT1 and a condition of energy demand in muscle that would be high in NAD+ and AMP, cofactors which activate SirT1 and AMPK, respectively.” 6A

Precursors That Can Be Taken As Supplements to Increase NAD+

There is (so far) remarkably little information on ways to increase NAD+ with natural products that are commercially available. There are three main physiological precursors: tryptophan, niacin, and niacinamide. It is reported that, “the administration of radiolabeled nicotinamide and nicotinic acid [niacin] has clearly shown that nicotinamide is a better precursor of NAD+ and that nicotinic acid is rapidly cleared by being converted to nicotinamide and excreted as nicotinuric acid.”6B Resveratrol was reported in paper #4 (but only as unpublished data) to dose-dependently increase the activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase. In another paper,7 quercetin was reported to oxidize NADH to NAD+ in rat liver, thus increasing the availability of NAD+. However, as the researchers also explain, “direct measurements of NADH/NAD+ are very difficult to perform.”7 This was as of the paper’s publication in 2005. The researchers inferred the NADH/NAD+ ratio from the ratio of beta-hydroxybutyrate to acetoacetate. Quercetin has also been reported to be a PARP-1 inhibitor.7B Niacinamide is known to be an inhibitor of PARP, thus may prevent the decrease in NAD+ that results from PARP activity. There is a salvage pathway of specific enzymes that converts niacinamide to NAD+.

Niacinamide (NAM) As a PARP Inhibitor May Explain NAM’s Antiviral Effects

Interestingly, PARP is reported to be critical for the integration of foreign DNA, as absence of the PARP enzyme interrupts the HIV life cycle.7C An early study published in 1996 on the effects of niacin reported that a daily niacin (combining niacin and niacinamide) intake in AIDS patients that equaled only 3–4 times the U.S. recommended daily allowance (at that time) of 20 mg/day experienced slower progression and improved survival.7D That was, of course, well before the current multidrug cocktails were developed that enable HIV infected individuals to survive 20 years or more, but still demonstrates the anti-viral effects of the vitamin.

Other natural PARP inhibitors include the flavonoids fisetin and tricetin8 and flavone.9

More About PARP Inhibitors

Keep in mind that PARP is an important enzyme for DNA repair and transcription. Hence, PARP inhibition has to be limited so as to avoid excessive impairment of DNA repair. “Impaired SIRT1 activity due to PARP mediated NAD+ depletion allows increased activity of several apoptotic effectors such as p53, therefore sensitizing cells to apoptosis. Adequate NAD+ levels are therefore critical to maintaining Sirt1 activity which can delay apoptosis and provide vulnerable cells with additional time to repair even after repeated exposure to oxidative stress.”5A

PARP inhibitors are now being incorporated into therapy for diseases such as cancer and diabetes.10–12 This cripples the DNA repair ability of cancer cells, which generally have deficient DNA repair to start with, further limiting their ability to repair DNA and making the cancer cells more vulnerable to apoptosis. In diabetes, moderate PARP inhibition can help maintain cellular NAD+ availability for ATP synthesis. In fact, as mentioned above, overactivation of PARP1 has been reported in diabetes, Alzheimer’s disease, traumatic brain injury, shock, and other conditions.4 A recent paper5C reported that PARP is hyperactivated by oxidative stress induced by beta amyloid; this PARP overactivation (and depletion of NAD+) could be an important source of cell death in Alzheimer’s disease.

Another recent paper “provided quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD+ catabolism in human tissue. The resulting NAD+ depletion may play a major role in the aging process by limiting energy production, DNA repair and genomic signaling.”13 In this paper, the authors note that other investigators have linked PARP1 hyperactivity to diseases such as diabetes, MPTP-induced Parkinson’s disease and injury induced brain disorders. They further reported for the first time, in this study,13 that PARP activity increases with age in human skin, correlating with both age and NAD+ depletion (in males, but not in females). Consistent with the regulation of SIRT1 activity by NAD+ availability, they found a significant decline in SIRT1 activity with age in post-pubescent males but, again, not in females. The authors suggest that one possibility is that females have a greater capacity to recycle NAD+ from the PARP metabolite nicotinamide; however this remains to be determined.

References

1. Denu. Vitamins and aging: pathways to NAD+ synthesis. Cell. 1293):453-4 (May 4, 2007). 
2. Belenky et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 129:473-84 (2007). 
3. Wolf. Calorie restriction increases life span: a molecular mechanism. Nutr Rev. 64(2):89-92 (2006). 
4. Massudi et al. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Rep. 17(1):28-47 (2012). 
5. Grube and Burkle. Poly(ADP-ribose) polynerase activity in mononuclear cell lines of 13 mammalian species correlates with species specific lifespan. Proc Natl Acad Sci USA. 89:11759-63 (1992). 
5A. Braidy et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLoS One. 6(4):e19194 (Apr. 2011). 
5B. Canto and Auwerx. Interference between PARPs and SIRT1: a novel approach to healthy ageing? Aging. 3(5):543-7 (2011). 
5C. Abeti and Duchen. Activation of PARP by oxidative stress induced by beta amyloid: implications for Alzheimer’s disease. Neurochem Res. 37:2589-96 (2012). 
6. Santidrian et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 123(3):1068-81 (2013). 
6A. Menzies et al. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem. 288(10):6968-79 (2013). 
6B. Imai. The NAD world: a new systemic regulatory network for metabolism and aging — Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys. 53:65-74 (2009). 
7. Buss et al. The action of quercetin on the mitochondrial NADH to NAD+ ratio in the isolated perfused rat liver. Planta Med. 71:1118-22 (2005). 
7B. Milo et al. Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. FEBS J. 179(2):332-6 (1985). 
7C. Murray. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 36:453-60 (2003) 
7D. Tang et al. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. [a study of the Multicenter AIDS Cohort Study] Am J Epidemiol.143:1244-56 (1996) 
8. Weseler et al. Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive disease or type 2 diabetes. J Nutr. 139:952-7 (2009). 
9. Geraets et al. Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression. Eur J Pharmacol. 573:241-8 (2007). 
10. Peralta-Leal et al. PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med. 47:13-26 (2009). 
11. Soriano et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res. 89:684-91 (2001).
12. Du et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 112(7):1049-57 (2003). 
13. Massudi et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 7(7):e42357 (July 2012).

Climate Models Deal Poorly With Clouds and Vegetation 

State Of The Art Model Couldn’t Simulate Known Droughts

The latest report in the 18 April 2013 Nature on climate models indicates continuing difficulties in dealing with environmental factors affecting the climatic influence of water (as in clouds, vegetation, precipitation, and droughts). Indeed, the test discussed in the Nature news article1 showed that the model couldn’t figure out what had actually taken place using data on large droughts (those lasting several decades each), which is far easier to do than to start from now and project into the future to predict the occurrence of droughts where you don’t have any data on when and where such large drought events may take place. And when you add to that the fact that water vapor is a vastly more important greenhouse gas than carbon dioxide, it would appear that current, even state-of-the-art models are unlikely to provide usable projections on what future climate will be doing.

The article was based on work done by Sloan Coats of Columbia University’s Lamont-Doherty Earth Observatory in Palisades, New York and his colleagues. Although the simulations did “find” a number of droughts lasting several decades each, these droughts didn’t happen when the real mega-droughts happened. In fact, the article said, “drought occurrences were no more in agreement when the model was fed realistic values for variables that influence rainfall than when it ran control simulations in which the values were unrealistically held constant.”1 One of the study participants, Jason Smerdon, was quoted as saying “The model seems to miss some of the dynamics that drive large droughts.” The group also tested other models, which did no better, even failing to reproduce a series of multi-decadal droughts that occurred in the southwest U.S. during the Medieval Climate Anomaly (until recently known as the Medieval Warming).

Finally, the article reported that a projection prepared for the Colorado Water Conservation Board revealed that models even disagreed on the direction of regional changes, with disagreements on whether mean precipitation in Colorado will increase or decrease.

After telling us this, the last paragraph assures us that these failures “don’t change the larger picture.” We should feel pretty confident, “scientists” say, that the southwest will warm and that water will become scarcer. Yes indeed. We would have to be downright mean and nasty skeptics (or, gasp, “deniers”) to doubt the “big picture” (of human-caused warming disaster presumably) when the models deal poorly with the dynamics of water, which in a climate model (for planet Earth, in any event) is surely the biggest factor affecting the overall picture.

Reference

  1. Schiermeier. Climate models fail to “predict” US droughts. Nature. 496:284 (2013).

 

It is in the nature of a hypothesis, when once a man has conceived it, that it assimilates everything to itself, as proper nourishment; and, from the first moment of your begetting it, it generally grows stronger by everything you see, hear, or understand. 
— Laurence Sterne



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