Mankind has been on the lookout for centuries for the precious elixir of youth, but did it occur to anyone that it might have been laying all the time inside that 5 cent white pill, known as Metformin?
For long centuries, the active ingredient in metformin has been known and used for digestive health and treating urinary ailments. And since the beginning of the last century, it has been famous for treating diabetes due to its ingredients (guanidine) effects in lowering blood sugar and improving glucose metabolism.
Yet after a century of using it among prediabetic and diabetic patients, substantial evidence shows that Metformin regulates cellular aging via its influence on inflammation, oxidative damage, diminished autophagy, and cell senescence; 4 fundamental pillars that can arguably extend lifespan in humans. And hey, all biohackers out there, behold the newborn wonder drug.
How does Metformin do it? It turns out that Metformin mimics the biochemical pathways set forth by intermittent fasting, inducing calorie restriction and more efficient sugar handling via insulin receptor sensitization. A growing body of research supports the detrimental effects of accumulated glucose on aging proteins, a term now widely known as advanced glycation end products (AGEs). The downstream effects of these include oxidative stress and its many manifestations, notwithstanding an inability to remove cellular debris, otherwise known as cellular senescence.
A common factor among many age-related diseases such as diabetes, cardiovascular disease, dementia, and cancer, is a suppressed activity of the AMPK pathway. And what is that? It is an essential enzyme, a master regulator for cellular energy homeostasis. To put it simply, it is responsible for mediating an effective solution to advanced glycation end product (AGE) damage, thereby lowering cellular stress, inflammation, and diminished autophagy. Several studies found that our good friend Metformin can increase the activation of the AMPK's pathway, thereby having a profound effect on the body’s ability to resist cellular damage caused by lifestyle, environment, and even the DNA that we were handed.
With all the exciting data emerging about Metformin’s influence on longevity, caution should be held until more direct studies are done in non-diabetic patients. While many physicians will not block regulated, gradual doses of Metformin for non-diabetic patients, further human studies are needed to give a green light for broader safe usage of the drug. Suffice to say, though, that this topic has never been more clinically relevant than in this era of health & wellness. If a wide safety margin can be consistently demonstrated, then expect popularity to only explode with consumer awareness.
A Wrench In The Dietary Guidelines
Dietary recommendations continue to be one of the most confusing topics in modern medicine simply because of the paucity of good data and the complexity of randomization within these studies. It seems like every day something new comes out challenging the peaceful paradigm of what seems intuitive. The most widely accepted dietary regimen for the last 40 years is the Mediterranean Diet which advocated largely plant-based foods, unsaturated fats such as olive oil, and copious fruits and vegetables. As part of this, it is postulated that red meats should be limited to only a few meals per month; many prominent Cardiologists support this recommendation as part of the plant based diet, which has gained tremendous popularity.
An article published by Dr Daniel Dressler et al in the Annals of Internal Medicine October 2019, however, raises eyebrows to the data behind these recommendations. Because of the significance of this, this article was even highlighted as one 12 significant “guideline changing” articles within NEJM Guideline Watch 2020.
As part of the study, an independent research panel scoured literature underpinning associations between red meat consumption and multiple disease markers, and highlighted multiple concerning limitations: Most studies were observational studies with high risk of bias, poor statistical methodology, and inordinate amounts of cultural and population bias. Meta-analysis of 12 randomized controlled trials with over 10 year follow-up on all cause mortality (including cancer markers, heart disease, development of diabetes etc.) showed no statistical significance between patients who consumed high or low quantities of red meat. This difference was defined by greater than 3 servings reduction in red meat per week; does this mean that patient’s with even tighter reduction in red meats would yield the same result? What about outcomes from those consuming extremely high quantities in red meat? We don’t know! This article supports the ambiguity here, and highlights the need to perform more research prior to defining causation.
Nothing in the article argues harm from reducing red meat consumption, and personally I would recommend to continue to do so, but it highlights the need to question dietary regimens that seem too black and white amidst this enormously challenging and controversial field.
Dressler, Daniel MD et al. Guideline for Consumption of Unprocessed Red Meat and Processed Meat. Annals of Internal Medicine, Oct 1 2019.
Covid fatigue is real. As the pandemic continues to overstay its welcome it’s more important than ever to disassociate science from politics. By addressing the 4 following myths about covid we can keep the numbers low in the community of Santa Barbara.
Myth: Masks don’t work:
Truth: They do! They do what they’re intended to do, which is to limit the quantity and distance of droplet transmission; this is the method of transfer in the majority of cases of Covid 19. This goes beyond the obvious examples, such as coughing or sneezing: Masks limit the droplet spread that’s been demonstrated via natural speaking as well. Its more important than ever to wear a mask whenever the 6 foot social distance principle is compromised.
Myth: Masks cause harm by preventing proper oxygenation:
Truth: Masks have NO bearing on oxygen delivery into the body, nor do they impact carbon dioxide transfer out of the lungs. We demonstrate this daily in the office when we measure arterial oxygenation (pulse oximetry) on each and every patient, and it invariably holds steady. I postulate that this myth has gained popularity simply because of covid fatigue, and that masks can be uncomfortable for extended times. This can be overcome with training. Remember, our colleagues in the hospital and operating room wear masks for 12 hours or more daily to protect all of us.
Myth: Increased testing accounts for the spike in cases we’re seeing in Santa Barbara:
Truth: I wish this were true. Increased covid case identification can account for higher numbers, of course, but the math doesn’t add up for 2 reasons: 1. The rate of infection rise significantly exceeds the change in testing. If testing alone accounted for the increase in cases, then the infectivity rate would be the same, and unfortunately, it’s seen a marked increase this last month. 2. The number of hospitalized covid patients has increased significantly since the reopening of Santa Barbara. Just a month ago Cottage had 4 covid patients hospitalized, as of July 10 this number was 31. The 7-fold increase in hospitalizations supports that we’re not simply identifying asymptomatic cases.
Myth: Social distancing is doing harm by delaying “herd immunity”.
Truth: False. Orders of magnitude more harm would result by ignoring social distancing and “hoping” for natural development of immune defense. Herd immunity is defined by natural disease mitigation through antibody development via exposure. Unfortunately, this is playing with fire when the virus is not even completely understood. Imagine if this is how HIV was handled in the 1980s? What we’re learning is that Covid is extremely infectious; it enters cells with very little effort, and has shown to overwhelm any healthcare system within weeks if left unchecked. Infectivity is the term used by Virologists, and its strongly linked to its ability to mutate and continue to cause disease despite antibody production. This is why its so important to develop a vaccine, but equally important in the interim to wear masks, keep distance, and take control over the terms of engagement.
What Inspires Doctors?
Many perseverate on why they chose medicine, but I can’t seem to find much commentary on why doctors continually choose Medicine. One of my most influential mentors once said that the connections we make with patients keep us going, and I couldn’t agree more. In other words, the academics that we spend decades laboring over sets forth a plan for the patient in the first 5 minutes. So what happens next? Well then patient care actually begins. I feel fortunate every day that my practice has this longitudinal care built in. What keeps you engaged?
Obesity Epidemic 201
201 funny sounding words to scare you into cleaning up your diet, courtesy of Heymsfield et al featured in this week’s New England Journal of Medicine. It’s quite astounding how much havoc an innocuous fat cell can wield on the human body! Some of these pathways are obvious, such as excess weight and osteoarthritis (right?), but some of this article is truly eye opening, less intuitive, and therefore warrants a 200 level course title.
First is the pro-inflammatory response to fat. Adipose cells are a sack of cytokines that, in effect, create a standing army of immune cells ready to attack something. That something tends to be your own body per emerging literature. This mayhem may even play into overstimulation of your “sympathetic nervous system” which clamps down on blood vessels, offering yet more insight into why obesity correlates to higher resting blood pressure, and either directly or indirectly, higher incidence of heart disease, stroke, and chronic kidney disease. Note also how preferential deposition of fat in the throat lends to sleep problems and consequent cardiopulmonary stress, while central deposition increases abdominal pressure and forces gastric acid up. A concerted New Year’s resolution to tackle the cause of all these problems is surely worth its weight in bitcoin.
The answer is yes and no, but it’s important to distinguish acute from chronic blood pressure changes. The immediate manifestation of a 600lb leg press is a profound spike in blood pressure. In fact, clever real-time hemodynamic monitoring shows that systolic blood pressure can spike to over 400 mid “push”! The physiology of this is astounding, and in part due to “bearing down” and clamping the major blood vessels in the abdomen. The scariest part is that the heart must actually generate a pressure higher than this to move blood forward, and it does because we see that cardiac output is in fact maintained throughout the movement. It’s brief, transient, and reaches baseline when you rest. Phew, cerebral aneurysms can’t be cured with pre-workout drank.
The long term effects of resistance training are extremely positive though. The following figure is from a meta-analysis from the Journal of the American Heart Association showing sustained blood pressure lowering in response to resistance training of greater than 4 weeks. How this happens is less clear but I suspect the answer lies within expression patterns of circulating vasodilators, #genomics. Even more interesting, but not necessarily surprising, is that combining weights with cardio (ie “dynamic” training such a CrossFit etc.) seems to yield a synergistic effect on blood pressure! Gone are the days of 3min rest between sets.
The Holy Grail?
Assuming weight loss isn’t governed by a mystical deity it should be something we can elucidate with a cup of coffee and a napkin. Lets do just this!
Let’s start with a fundamental tenet of nutrition (and thermodynamics!): Calories in = calories out. It’s very true that energy cannot be created nor destroyed, but it can shift form! How about cankles or a muffin top? Our body operates in a steady state and either stores or removes the excess. Now the “intake” side of the equation is fairly straightforward. The calories we take in are the calories we take in. But note the quotient; the “digestibility” of our food dictates what percent of nutrients gets absorbed and what [expensively] adorns poop. R-squared is something I created to sound fancy but I do think it holds truth. The rate of ingestion and the digestibility (think fiber..) determines how cells lining the digestive tract see these nutrients. Grazing on a bag of potato chips throughout the day is more damaging than shoveling down a bag in minutes because the latter overloads our absorptive apparatus! I squared it for effect, and placed it in the denominator to yield a LOWER net caloric intake on the left side of the equation.
The right side of the equation is considerably more complex because calories are burned in multiple ways. Moreover, none of these is static! Many know that basal metabolic rate (BMR) is an intrinsic determinant of how we burn calories. But it’s governed by hormones (cortisol, thyroxine, insulin etc) that are in constant flux in time and space. Food ingested at 10am is processed differently than at 10pm. Similarly, the temperature of food correlates to the rate of enzymatic activity! SPA = calories burned with physical activity; but it’s cleverly weighted against the term NEAT, non-exercise activity thermogenesis, because multiple studies have validated that hard exercise is often accompanied by negative post workout behavioral changes! For some this equates to an extra episode of Property Brothers afterwards; for some this equates to an ice cream to reward all that hard work. The unfortunate ones choose both and effectively cancel out any change in output while increasing input!
This is a fun topic that gets very confusing very quick. We use weight as our primary end point but as we all know muscle weighs more than fat. Does burning 3500 calories per week really equate to a 1 pound weight loss? Where does this come from? And how does water-weight factor into the equation above? Wrestlers, boxers and the Real Housewives of the OC have long exploited the diuretic effect of salt wasting to drive weight down quickly. I’ll touch upon all of these soon.
Glycemic Index 101
Glycemic index is an important concept in nutrition. It provides a method for comparing and “normalizing” sugar moieties in food items, akin to an exchange rate for currency comparison or a 1-10 scale for attractiveness. The number that you hear is a ratio of the sugar spike at T2hrs when normalized to that of pure glucose. If you imagine the sugar spike when eating 50g of a strawberry pop tart and subtract out the sugar spike when consuming 50g of pure glucose you’ll still notice a high rise up the Y-axis; this is a high glycemic index food item. Now let’s imagine 50g of Fiji apples (note the standard quantity); if we see a sugar spike that barely rises above that of glucose we note a very low glycemic index food item. That’s it.
So why should we care about it?
1. It drives decisions! Or it should. High glycemic index food items cause insulin release from the pancreas and a multitude of physiologic side effects ranging from fatigue (“sugar high”) to obesity and type 2 diabetes when the pancreas calls it quits. Preliminary epidemiological studies even suggest higher rates of heart disease, colorectal cancer, infertility, and macular degeneration. More will come from this in the near future.
2. It’s modifiable. Increasing fiber content with higher glycemic index foods helps delay absorption spikes which overload the liver. Similarly, refinement of grain removes the bran and germ layers which are important to slow absorption. Simple dietary choices can make a big difference.
3. You’ll lose weight. And get more hits on Instagram. High fiber low glycemic foods are the cornerstone of weight loss because they dampen insulin, stretch the stomach, and feed into the hormonal regulation pathways of the brain to dictate satiety.
Food For Thought..
Sometimes a picture paints a thousand words. So here are 2000 words to illustrate the physiologic differences between pepsi and, say, honey. My disclaimer is that isolated biochemistry is quite weak to prove ultimate causality; but more than sufficient to disprove similarity between two cohorts.
The first image comes from the University of Wisconsin published about 10 years ago in The Journal of Biological Chemistry. Mice were fed fixed diets of either 60% glucose or fructose for 7 days and then sacrificed to the life forces of science. The livers were isolated and the “expression” pattern of multiple proteins paramount to fat synthesis was determined by “Northern Blot” analysis. The relative darkness of the splotches correlates to the degree of activity. Lipid formation goes through the roof in mice who challenge the liver with preferentially high fructose diets, qualitatively shown on the left and quantitatively illustrated on the right.
The second image is from a clever retrospective study published in 2008 in the Journal of Hepatology. 49 biopsy proven patients with fatty liver disease had “realtime PCR” analysis, a more sophisticated quantitative representation of DNA synthesis, from human liver tissue. Fatty Acyl Synthase (FAS) and phosphofructokinase (PFK), the latter being the key gateway enzyme in fat production from my prior post, are again highly expressed in these patients. Now one should never use such biochemistry studies to prove causality. But if they show physiologic differences between sugars at a basic level then one should be extra suspicious at a higher level.
Are All Sugars Created Equal?
Absolutely not. And one primary (albeit not exclusive) explanation lies in the physiology of the liver. When food gets digested it gets absorbed into the portal system, a fancy network of veins that drain into the liver. This is the body’s primary detox hub and a gateway into the arterial system. The distinction is important: If I squirt 1mg of epinephrine into my mouth I might shake for a moment then go about my day because absorption is heralded by regulation. If I inject the same amount into an artery my heart would [metaphorically] blow up. Poof.
This concept governs carbohydrate physiology because the liver buffers the foods we eat. Lining the cells of our digestive track are enzymes that both break down large complex sugars and facilitate movement into the body. This is called diffusion, and it happens either passively or when the body decides it wants to invest energy into pulling them into the venous circuit as above. What happens next is the premise of this story: Enzymes in the liver recognize and attack simple sugars uniquely. Glucose gets funneled down the full cascade and gets converted into ATP/energy or glycogen for storage based on relative needs. Fructose, by virtue of its diminutive carbon count, bypasses a key regulatory brake in the system (phosphofructokinase) and gets shunted into fat production with enhanced rapidity at high levels. Has anyone heard of a fatty liver? Fat deposition begets insulin resistance which is the primary mechanism of type 2 diabetes. We can thank Mother Nature for this because our bodies are simply less capable of handling certain sugars. This basic concept will become paramount in upcoming discussions on diet/nutrition.
Dr Viglione is a concierge medicine doctor in Santa Barbara, CA