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Mitochondrial Uncoupling: If You Want to Live Longer, Look to the Skies

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Over the years an enormous amount of both scientific and pseudo-scientific speculation has been aimed at explaining prevailing trends in the lifespan of animals,and how we might apply those lessons to humans.

Since clear, observable trends exist with respect to various groups of animals and lifespan, if we can understand the underlying processes behind those trends, we might be able to extend and maximize our own lifespans.  The most obvious trend is body size versus lifespan, which is robust and repeatable, yet has some outliers that offer tantalizing grounds for speculation.

Figure 1 shows the trend between size and lifespan.  The trend lines, both of which have significant scatter, clearly show two trends, with the data broken down to illustrate the difference between flying and non-flying species.  The striking difference between species who can and cannot fly will be immediately available to anyone who has ever kept a parrot – some species can reliably outlive their human owners.

sizeA number of theories exist to explain the differences between these groupings – and why bats and birds live so much longer.  The authors of the study behind Figure 1 [1] point to the differences in predation vulnerability and argue that flying reduces predation and vulnerability to food shortages.  In that respect, flight offers some of the same advantages as large body size, resulting in the anomalously longer lifespans enjoyed by bats and birds.  The only problem with this hypothesis is that a Malthusian distribution should ensue, and when these populations explode to the very limits of their ecological carrying capacity, one would expect that these advantages would be nullified.  Yet the differences persist.

An alternative view is that animals adapted for flight have a chemical advantage related to flying.  Their tissues express larger quantities of mitochondrial uncoupling proteins, which allow the “leak” of H+ without producing ATP in the mitochondria.  This means that they can “throw away” excess energy produced when they are at rest, necessary because their cellular machinery is designed to process huge amounts of energy during periods of flight.  Tossing the protons made by oxidative respiration has the side benefit that reactive oxygen species (ROS) are destroyed, preventing cellular damage that accumulates over time and causes aging.  Birds therefore age slowly and maintain their youthful function throughout the vast majority of their years.

Other animals, including humans, might be able to benefit from research that targets these proteins.  A growing body of research aimed at treating obesity has a similar goal, and gene therapies that are aimed at stimulating “brown fat” promise to kill two birds with one stone.   Brown fat, a vascular active form of adipose tissue, burns fats rapidly in the presence of oxygen and uncoupling proteins to generate heat.  This is the fat that allows long-lived walruses and cetaceans to keep warm even with wet skin in freezing climates by using fat as nothing more than fuel for the furnace.  Through gene regulation to stimulate brown fat we might be able to reduce obesity and inflammation caused by ROS.

Current research is promising, with the side benefits that gene therapies that increase the activity of the brown fat also cause marked increase in muscle mass and strength, at least in lab mice[2][3].  Scientists at Virginia Tech have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. The research of Santos and colleagues, published in Nature Communications on May 14, 2020, are especially promising for the treatment of obesity and diseases characterized by inflammation.

Although research on mitochondrial decoupling proteins is ongoing, recent progress is promising, and the implications for medicine are sky-high.

[1] Healy, et. al.  2014  Ecology and mode-of-life explain lifespan variation in birds and mammals.  Proc. Royal Soc. B.  DOI: https://doi.org/10.1098/rspb.2014.0298 or visit https://royalsocietypublishing.org/doi/10.1098/rspb.2014.0298.

[2] Weintraub, Arlene.  2020 Gene therapy cuts fat and builds muscle in sedentary mice on unhealthy diets.  Fierce Biotech. May 11. https://www.fiercebiotech.com/research/gene-therapy-cuts-fat-and-builds-muscle-sedentary-mice-unhealthy-diets.

[3] Tang et. al. 2020  Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet–induced obesity.   Science Adv. 08 May 2020:Vol. 6, no. 19. DOI: 10.1126/sciadv.aaz7492 or https://advances.sciencemag.org/content/6/19/eaaz7492.

[4]  https://www.sciencedaily.com/releases/2020/06/200608132539.htm?utm_content=131524119&utm_medium=social&utm_source=twitter&hss_channel=tw-463200485

Will Big Pharma Sabotage its’ Own Re-Shoring?

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The need to reshore American products has been recognized on a federal level for many decades, with legislation such as the original Buy American Act, dated to 1933.

The urgency has grown in recent years, with the burgeoning dependence of the United States on foreign medicines and medical equipment now constituting a huge strategic burden.  The issue has recently come to forefront because of  renewed distrust in supply chain stability thanks to Covid-19, however, and current legislation is upping the ante by including Big Pharma among the list of key players that need to be reformed.

The imperative to return American products home is primarily being addressed through legislation offering incentives aimed at making American businesses more competitive, imposing tariffs on foreign goods and offering tax benefits for American manufacturers.  Although 28% of registered worldwide pharmaceutical API manufacturing sites are located within the US, according to government statistics when we consider the sourcing of raw materials, various estimates suggest that the true foreign dependence is even higher.  Indeed, it is surprisingly difficult for consumers to determine the origin of their drugs and medicines, and many pharmaceutical companies are reticent about their suppliers given the proprietary nature of the information.

Figure2-2

President Trump’s proposed “Buy America” Executive Order, spearheaded by White House trade adviser Peter Navarro, was sidelined by the National Security Council before it could be signed last Friday.  Although the exact details of the order are under negotiation, it is clear that the future of the pharmaceutical industry is at a major crossroads: what happens when the order is signed will shape the manufacturing of pharmaceuticals worldwide.

While this situation underscores the necessity for re-shoring American manufacturing of pharmaceuticals, the biggest opposition to the movement is coming from pharmaceutical lobbyists on Capitol Hill.  Perhaps this is unsurprising, given the enormous disruptions that changing the system would cause, and the fact that many of the losers would be large, powerful corporations with pronounced sourcing from overseas.  Nevertheless, the Pharmaceutical Research and Manufacturers of America (PhRMA), which is the largest pharma lobbying group present, has proffered an argument that re-shoring proposals will “… not only overestimate the potential feasibility and underestimate the time and effort it would take to make such changes, but also misunderstand that a diverse pharmaceutical supply chain is precisely what enables the industry to respond quickly and make adjustments in its supply chain sourcing during natural emergencies and global public health crises.”

Some of this rhetoric is true:  the process will definitely be expensive and difficult.  Some of this is false: parallel supply chains increases the robustness of the worldwide supply.  In fact, redundancy is a key element to airplane safety, and by analogy, it’s plain to see that parallel sources are far more secure than relying on a potentially distant source in an emergency.  This resistance is troubling, since the truth is staring us in the face:  global supply chains are not always reliable.  Imports from China for critical medicines and pharmaceuticals are being cut off entirely due to Covid-19.  This dependence has placed lives at risk since 90 percent of the generic medications that Americans use daily are imported.

The reluctance of  Big Pharma to reduce an unhealthy and greedy dependence on cheap labor and materials will have serious consequences for American healthcare as well as national security.  China’s dominance of the pharma supply chain is highly dangerous to the United States.  Pharmaceutical production must be reshored and even expanded in order to develop secure and safe supply chains for medications, vaccines and medical devices. This crossroads brings us to a critical question: will the United States commit its financial might to developing American pharmaceutical manufacturing capabilities, or will pharma itself stand in the way?

Cow Hearts: Beefy Benefits for Humans

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heart2According to the CDC, heart disease is the leading cause of death in the U.S., killing more than 600,000 Americans each year.

  • More than five million Americans are diagnosed with heart valve disease annually.
  • Heart valve disease can occur in any single valve or a combination of the four valves, but diseases of the aortic and mitral valves are the most common.
  • Calcific aortic stenosis is the most common form of aortic stenosis (AS).
  • While up to 1.5 million people in the U.S. suffer from AS, approximately 500,000 within this group of patients suffer from severe AS. An estimated 250,000 patients with severe AS are symptomatic.
  • Without an aortic valve replacement (AVR), as many as 50 percent of patients with severe AS will not survive more than two years after the onset of symptoms.

Aortic valve stenosis — or aortic stenosis — occurs when the heart’s aortic valve narrows. This narrowing prevents the valve from opening fully, which reduces or blocks blood flow from your heart into the aorta and onward to the rest of your body.

heart picRecent advances in the treatments for aortic valve stenosis[1] seem to be tipping doctors and patients increasingly towards xenografts for treatment.  Traditional treatment regimes have involved open heart surgery, focused on the replacement of the damaged aortic valve with a mechanical replacement.  The move away from these highly invasive operations has been prompted largely by a single, increasingly attractive development: Transcatheter Aortic Valve Replacement, or TAVR.

The new method of TAVR was only approved as recently as August 2019 for low-risk patients, as new research began to overturn the idea that mechanical heart valves were superior for patients with significant post-operative life expectancy.  The old thinking went like this: since mechanical heart valves do last longer, these valves could provide patients with a lower risk of failure, complications or repeat surgery.  The problem is that some of these assumptions are no longer true, and in many cases, “biologic valves are better even in the young patient.”[2]

The only true representation of the above claims is the fact that mechanical heart valves last longer.  That’s absolutely true; a valve made from titanium or other high-strength, highly impervious material can last for decades.  Unfortunately, these materials increase the risks of blood-clots since platelets have an affinity for collecting on non-biogenic surfaces.  These blood clots can result in thromboses, heart attacks and strokes.

The current treatment regimen is at best an uneasy compromise, because patients are assigned a life-long regimen of anti-coagulants that must balance the risks of clots against the risks of fatal bleeding, hemorrhagic stroke and other complications from the anti-coagulants.  The mortality and morbidity due to surgical complications and failure of the mechanical valves are complicating factors as well.

TAVR addresses some of these problems with short-term mortality by significantly reducing the risks of open heart surgery.  The minimally-invasive procedure begins by inserting a catheter into the femoral artery (or another blood vessel) and threading it up into the aorta.  Once there, in the increasingly common valve-in-valve (VIV) procedure, a collapsible replacement valve can be delivered right inside the aortic valve and then expanded.  Once it’s inside the valve, the new valve holds everything open during systole, meaning output resistance drops and the heart doesn’t have to work as hard.  The new valve will also close more effectively, so blood doesn’t continually wash back and forth, which further eases stress on the heart.

TAVR heart valves are typically made from cow pericardium[3], which also eliminates the platelet adhesion problems seen with mechanical valves.  Some people can go off of blood thinners, and not have to worry about their potential side effects.  The primary disadvantage of TAVR valves is their limited lifespan of 10 to 12 years.  New refinements are addressing this problem: recent studies have shown the chances of having problems with repeat surgeries and TAVR for failed bio-prosthesis valves are either the same, or slightly better for redo TAVR[4].  In another study of approximately 50 patients who had redo TAVR due to failing bio-prosthetic valves, every patient survived to discharge, with only one serious bleed and one minor, non-disabling stroke[5].  In fact, the lower risk of early- and mid-term morbidity associated with TAVR means that for many people, the procedure offers the best chance to live their best lives – living with the highest quality and lowest risk of disability.

[1] Source for stenosis diagram: Michigan Medicine, Frankel Cardiovascular Center.  https://www.umcvc.org/conditions-treatments/aortic-stenosis.

[2] Expert Analysis. 2015 Surgical Aortic Valve Replacement: Biologic Valves Are Better Even in the Young Patient. American College of Cardiology.

[3] Source for TAVR diagram: TCTMD.com

[4] Maxwell, Y.R. 2018.  Valve-in-Valve TAVR: Mortality, Adverse Events Similar to Redo Surgery at 30 Days. TCTMD/the heart beat.  < https://www.tctmd.com/news/valve-valve-tavr-mortality-adverse-events-similar-redo-surgery-30-days>.

[5] Barbanti, et al. 2016. Circ. Cardiovasc. Interv. (9):e003930.  Outcomes of Redo Transcatheter Aortic Valve Replacement for the Treatment of Postprocedural and Late Occurrence of Paravalvular Regurgitation and Transcatheter Valve Failure.  < https://pubmed.ncbi.nlm.nih.gov/27578840/>. DOI: 10.1161/CIRCINTERVENTIONS.116.003930

Thanks for the Plague, California!

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black_death

Because if hiding dead bodies isn’t a conspiracy, we don’t know what is.The bubonic plague (and its’ siblings, the septicemic and pneumonic plagues) is alive and well in the Western United States.  In fact, in the most plague-stricken region in the United States (Northern New Mexico) several cases pop up every year.  Even with modern antibiotics, nearly 1 in 6 plague patients will die – which is still better than no treatment at all, since some forms are 99% fatal if untreated.

Thanks to horizontal gene transfers and other mechanisms, soon antibiotics may not even help: one recently isolated strain of the plague was found to be resistant to eight antibiotics, including all of the three primary treatments for plague.  Even more disturbing, a Nevada woman who eventually died was treated for a bacterial infection in early 2017 that was resistant to every antibiotic available in the United States.  Yersinia pestis typically hides out in long-term environmental reservoirs, which may provide more opportunities for horizontal gene transfer and makes eradication of the plague almost impossible in the Western U.S. (or other countries).  This makes the average 10 to 20 annual cases in the U.S. largely unavoidable.cycleThe plague is not native to U.S. soil and its’ presence here was neither inevitable nor even especially difficult to avoid.  The plague made landfall in San Francisco’s Chinatown, where deaths started occurring around 1900.  Under the direction of the governor of California, Henry Gage, the bodies of plague victims were hidden for at least two years.  In fact, over 100 deaths were concealed, and newspapers reported that the plague “Did not, nor ever did exist in California.”  The San Francisco Examiner even ran an article :Why San Francisco is Plague-Proof.”

Why hide such a deadly disease from the public?  Greed, pure and simple: Gage and his officials feared the loss of revenue during quarantine, and an even more significant loss of revenue if consumers stopped buying California produce, which was by then a burgeoning $25 million dollar industry.  Despite the attempts by the governor to silence the medical community and corrupt the media, a handful of champions of public health eventually succeeded in ridding the city of the plague.  Two of the city’s most prominent physicians, Wilfred H. Kellogg and Joseph Kinyoun, Chief Bacteriologist and Chief Quarantine Officer,  made valiant efforts to protect the public welfare that did not immediately come to fruition.  After discovering Yersinia pestis in the blood and lymph smears from infected corpses, these doctors made recommendations to contain the outbreak.  The response from California State officials was swift and merciless:  the doctors were fired and massive, devastating smear campaigns were launched against them in the local media.

Still, by 1903 the political tide started to turn against the Governor, and after repeated outbreaks in 1906 and 1908, the plague was eradicated from the city of San Francisco.  The same newspapers that had denied that the Black Death had ever descended on San Francisco now gleefully declared that it had been eradicated.

Unfortunately, while the cleanup-up was a win for San Francisco, lasting damage had been done to the Western United States.  Local populations of mammals, including rats and squirrels had already been infected within the first several years due to the critical delays in treating and containing the outbreak.  Over half of all plague related deaths in the United States now take place in a region that had nothing to do with the introduction of the disease.  Free-ranging animals have spread the disease, until at last, it found its’ greatest permanent reservoir in the United States: The Gunnison and black-tailed prairie dogs of northern Arizona, New Mexico, southern Colorado and Utah.

These regions overlap with the distribution of plague hotspots in the United States, and not just for humans either: over 90% of the inhabitants of an infected prairie dog town will usually die in a single outbreak.  Fleas jump from their dying hosts in favor of dogs (who seem to be plague-resistant) and enter homes where they kill both humans and cats (who seem to be especially vulnerable).  Thus, Henry Gage’s legacy repeats itself, claiming more lives every year, and reminding us that the consequences of inaction during a pandemic are severe, while the consequences of actions taken to deliver misinformation during a pandemic are abominable.

[2] Tansy, T. Plague in San Francisco: Rats, Racism and Reform.  2019  Nature. https://www.nature.com/articles/d41586-019-01239-x.

[3] Plague Ecology and Transmission. United States Center for Disease Control (CDC) webpage.  See infographic, vide supra. https://www.cdc.gov/plague/transmission/index.html.

Anti-Vaxxers a Top Health Threat

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A new threat to the health and safety of children has recently begun to take center stage: diseases that were once thought eradicated have reemerged into public consciousness.  These diseases have been aided and abetted by the irresponsible and dangerous behavior of people opposed to vaccines, otherwise known as anti-vaxxers. Read More

Toxoplasma Gondii: The Brain Hitchhiker

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kitty3Toxoplasmosis is a widely known disease that results from infection with the Toxoplasma gondii parasite, one of the world’s most common parasites. Infection usually occurs by eating undercooked contaminated meat, exposure from infected cat feces, or mother-to-child transmission during pregnancy.  Estimates suggest that about 1/3 of the entire human population of the Western world is harboring the parasite in the form of “benign cysts” concentrated mostly in the brain.

The parasite can form cysts anywhere almost: hearts, lungs and eyeballs are common hiding places, but the brain is the preferred hangout for this organism.  If you are a cat lover, chances are high you are already infected, courtesy of your cat.  Cat brains are a natural repository for the adult protists, which reproduce inside our feline friends and spread from cat feces.  This is not to say that won’t infect any warm-blooded animal that they are capable of, but the only hosts truly necessary for their continued survival are felids, according to the CDC website.  Once infected, they usually infect you for your entire lifespan, mostly asymptomatically.toxo

The most interesting thing about the infection, though, is that the cysts hijack our brains, producing subtle but measurable and influences on behavior.  Scientists have suspected that the success of Toxoplasma is due in part to its’ ability to change rats and mice behavior, and causing them to stop fearing cats.

In a now famous study, it was demonstrated that mice, which have a morbid fear of cats and a strong fear reaction to cat odor, tend to lose that fear and unequivocally show a preference for cat odor after being infected with the parasite.

Mice aren’t the only ones whose brains can be hijacked, though: there’s a good chance that the parasite in your head may be at least partly responsible for the shots you call, too.  A growing body of research indicates that the manipulation theory, as it is called in medical and biological journals, extends to human in several ways.  Latent toxoplasmosis in humans has been associated with serious neurological disorders, including schizophrenia, intermittent explosive (rage) disorder and suicide.

In addition, research shows infection by Toxoplasma gondii, directly affects the production of dopamine, a key chemical messenger in the brain.  Dopamine is a natural chemical which relays messages in the brain controlling aspects of movement, cognition and behaviour. It helps control the brain’s reward and pleasure centres and regulates emotional responses such as fear. The presence of a certain kind of dopamine receptor is also associated with sensation-seeking, whereas dopamine deficiency in humans results in Parkinson’s disease.

Infection changes the way that your brain processes information, slowing reaction times (more traffic accidents) and changing your preferences for a great many things, from risk aversion to tidiness to extraversion.  The effects of Toxoplasma infection on an individual depend on genetics, with some genotypes immune to infection and less likely to experience effects, and gender.  To take one example, the effect on personality has been summed up after analyzing multiple studies, each with well over a hundred (and often several hundred) subjects.

According to Effects of Toxoplasma on Human Behavior, significant differences in personality factors were found between Toxoplasma-infected and -uninfected subjects in 9 of 11 studies, and these differences were not the same for men and women. After using the Bonferroni correction for multiple tests, the personality of infected men showed lower rule consciousness and higher vigilance. Thus, the men were more likely to disregard rules and were more expedient, suspicious, jealous, and dogmatic. The personality of infected women, by contrast, showed higher warmth, suggesting that they were more warm hearted, outgoing, conscientious, persistent, and moralistic.

Even sexual characteristics and preferences might be affected.  In one photograph study, men who harbor infections are consistently rated as being more dominant and masculine looking then men who don’t have infections – on the basis of photographs alone.  Toxoplasma increases expression of the genes coding for testosterone in men, and the effect is large enough to be seen by the naked eye and borne out by physical measurements, including a noticeable 3 cm boost in average height.

Although the mechanisms by which this parasite seems to influence its’ hosts are still being elucidated, its’ clear that it touches our lives in ways we never before imagined.  How much of “them” is really “us”?

Anti-Cancer Gut Bacteria

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gut_2

The human microbiome is the subject of a burgeoning field of research.  The effect of gut microflora, and especially bacteria, has in the last few years been linked to anxiety, depression, gastrointestinal and autoimmune diseases, and numerous other disorders. Read More