*In a grand gesture of gratitude to our dear readers, we're launching these inaugural editions of The Future Almanac and a first never-before-seen upgrade (UPG) with a price tag of zilch, nada, absolutely free! Usually, the TFAs’ biohacking enhancements are locked away like top-secret intel, and the crème de la crème of biohacks could set you back a pretty penny! But just so you can get a feel of how the TFA rolls, we'll give you a free sample on the house - santé! This UPG1 is a follow up of INT1. * Access to this entry is free, but feel free to mint a souvenir NFT to support the cause!

Palm wine, aloe pulp, hemp and crusades

C:\ Rise and shine, my fellow bio-wizards! Buckle up and join me on a wild ride in our trusty time machine and transport ourselves back to the good ol' Middle Ages, precisely to the year 1118... Picture the scene: The Knights Templar, a formidable religious military order, is taking shape on the Temple Mount in Jerusalem. These fierce warriors are destined to grow in power over the next two centuries, revolutionizing the world of finance by establishing the first bank-like services. Cha-ching!

Now, imagine the awe-inspiring sight of a Templar knight, standing tall and proud, well into his 60s. In a time when the average European barely made it to 40, these knights defied the odds and outlived their peers. They even surpassed the life expectancy of their monastic counterparts!

Ah, the enigma of their longevity! How did these medieval marvels manage to dodge the Grim Reaper 💀 for so long? Well, it all boils down to their peculiar lifestyle and culinary quirks. As we observe the grand finale of their order in 1314, with the last Grand Master, Jacques de Molay, quite literally going out in a blaze of glory at 70, we can't help but be awestruck by the extraordinary shelf life of these legendary knights.

In the whimsical days of the 12th century, a French abbot named Bernard de Clairvaux decided to spice things up by concocting a scrumptious set of guidelines for the Templars, dubbed the "Primitive Rule." Inspired by the culinary wisdom of saints Augustine and Benedict, the order whipped up their own delectable rules, featuring a mouth-watering medley of meat, fish, cheese, whole grains, fresh fruits, veggies, and the pièce de résistance - alcohol, primarily in the form of wine. To add a touch of panache, they'd mix the wine with aloe pulp, creating the oh-so-chic "Elixir of Jerusalem," and sipped it in style with standardized portions.

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Hopping from past pandemonium to disease detective chronicles

Why time travel to the Middle Ages for a health boost, when the elixir of life is right at the tip of our noses - or rather, our glasses? As reporter Dan Buettner so eloquently spills, "The world's longest-living folks are sipping their way to eternity, one delightful drink at a time." And it's not just a one-size-fits-all potion; from Italy's daily double dose (🍷🍷) of wine to Japan's centuries-old tradition of Awamori 🍶- a rice-based, distilled delight that's often mixed with water - it seems the secret to a high-quality life is to simply drink up, buttercup!

In the not-so-distant past of 2008, a group of curious minds at The University of Cambridge (EPIC-Norfolk) (6) embarked on a quest to uncover the secrets of longevity. A decade later, Harvard University's T.H. Chan School of Public Health (Nurses Health Study) (7) joined the pursuit, and together they analyzed 45 years of data like Sherlock Holmes on a mission. The result? They identified five habits that could potentially extend life expectancy by an impressive 12 years for men and 14 years for women. These five habits included:

1. bidding adieu to smoking,

2. maintaining consistent serum vitamin C levels throughout the day,

3. consuming at least one alcoholic beverage daily,

4. engaging in physical activity for a minimum of 30 minutes per day, and

5. maintaining a normal body mass index (BMI)

These intriguing findings were subsequently reported in the media, with the alcohol-related aspect summarized and translated as "Limit your alcohol intake." This demonstrates the unease surrounding the topic in contemporary society. However, the studies indicate that ethanol is one of the five habits that contributed to the subjects' extended lifespans, suggesting that individuals should, in fact, consume at least one alcoholic beverage daily to obtain the reported health benefits.

While these studies precluded excessive alcohol consumption (above two daily drinks), telling people to limit their alcohol intake is not ideal since each of the five habits progressively adds a layer of longevity. Even a person with an already healthful lifestyle can further increase their health and lifespan by starting a moderate drinking habit, represented here for convenience as the blue dotted line.

For the inquisitive minds craving extra tidbits, among the four habits reported in the Cambridge study, not smoking provided the most powerful benefit. However, drinking alcohol is associated with even more than the risk reduction observed for sufficient exercise, and this is applied to all-cause mortality, CVD, and cancer. Drinking alcohol daily increases lifespan, reduces the risk for cardiovascular disease, and significantly lowers our chance of getting cancer (30-35%) for both men and women. Ahoy! Abstaining from the ol' liquid courage might just ruffle one's health feathers, and the mysterious U-shaped curve shall unveil its secrets further down this scroll.

Because up until now, most of the evidence in the literature for the protective effects of alcohol had been done on young and middle-aged people, scientists published (13) a large-scale, long-term multi-center, bi-national study in 2021, specifically looking at subjects older than 70 years old. They discovered that, like their younger drinking buddies, these older individuals had a reduced risk of heart disease and death from all causes compared to their age cohort of alcohol abstainers

In 2021, an update of the most recent studies was done (22) and showed decreased CVD, decreased mortality, decreased diabetes, and decreased osteoporosis. Alcohol strengthens the effect of HDL, makes stronger bones, and generally, does not lead to increased body weight in individuals. In addition to reducing the incidence and severity of myocardial infarction, low to moderate alcohol consumption is associated with a lower risk for ischemic stroke, dementia, congestive heart failure, peripheral artery disease, intestinal and hepatic I/R injury, and frequency of Raynaud’s phenomenon (24). According to NIH-funded research alcohol of any kind is a dietary factor (along with cheese! 😀) that protects against Alzheimer's disease (27). And here's the “sherry” on top, because alcohol protects against the inflammatory mediators of adipose tissue, drinking alcohol is extra healthy for the pleasantly plump and doesn’t seem to lead to extra weight in this demographic (22). Of course, a calorie is a calorie and your daily intake should be accounted for.

We’re not alone, researchers have observed that moderate alcohol consumption provides cardioprotective effects across nearly all species, including mice, rats, guinea pigs, dogs, and rabbits. Would you like to know why that is? Read on, my curious comrade!

Intoxicating Perks: A Spirited Guide to Alcohol's Boons 🍸

✅ Microbiome

Multi-omics analysis shows that people moderately drinking alcohol have a healthier microbiome, these bacteria ultimately translate into improved circulating metabolites.

Oh, the microbiome - quite the party animal, isn't it? Producing a daily happy hour of about 3 grams of ethanol, courtesy of its carb-crunching fermentation fiesta! A variety of enzymes help process ethanol into acetaldehyde, which then transforms into acetic acid and acetyl-CoA. Some amino acid sequences in these enzymes have remained unchanged since the last common ancestor over 3.5 billion years ago. As a result, ethanol catabolic degradation is essential not only for humans but for all known organisms, as they all produce small amounts of alcohol.

✅ Immunity

Oh, wasn't it the grand decree to imbibe during our corona confinement?

In both humans and in experimental animals, alcohol strengthens the immune response and results in enhanced host defense. (Romeo, 2007). The natural function of ethanol is a preservative against bacteria and other microorganisms. It is plausible that the consumption could lead to a disinfecting effect in the body. Ethanol is able to inactivate human coronavirus on hard surfaces (Meyers, 2020). Drinking before getting a jab, is extra beneficial, it lowers inflammation and improves the response to vaccination (25) while simultaneously working as an anxiolytic.

When people start to consume alcohol daily, after a period of 30 days, they can expect CD3+ lymphocyte counts, IL-2, IL-4and IFN-gamma to increase, which are all essential for the immune response. Alcohol activates the master regulator of immunity to infection; IL-10 (an anti-inflammatory cytokine). Unsurprisingly, drinkers, when compared to abstainers, are more resistant to the common cold virus. Alcohol improves both innate and adaptive immunity (25).

✅ Inflammation

According to Mandrekar (2006), moderate alcohol consumption has an anti-inflammatory effect on the body through multiple pathways, monocyte responses, and IL-10*.* Reductions are reported in factors implicated in inflammation like C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-alpha (24).

✅ Cardiovascular health

Ethanol increases endothelial nitric oxide synthase (eNOS) production (21), which declines during aging. Ethanol-induced vasodilation occurs as a result of 1) NO generation 2) increased nitric oxide synthase (NOS), and 3) via activation of transient receptor potential vanilloid 1 (TRPV1) channels on perivascular sensory nerve terminals, which release the potent vasodilator calcitonin gene-related peptide (CGRP). These mechanisms increase coronary blood flow (24) and lower blood pressure. In theory, the polyphenols from wine can in themselves stimulate NOS activity, but the ethanol seems to already pretty much max out production.

The effects of alcohol are similar to the effects of taking a blood thinner like aspirin (14), which clearly prevents heart attacks. It renders the blood (blood platelets) less sticky, so blood can flow more smoothly while the risk of clots is greatly reduced. Heart rate variability (HRV), a marker of autonomic imbalance, is also improved by the consumption of alcoholic beverages (24). In young men, the lowest systolic blood pressure was found in subjects taking 1-3 drinks per day (24).

✅ Cellular health

According to research sponsored by the Buck Institute for Research on Aging, ethanol has been shown to cause autophagy (recycling of cellular components) in mice, just as with exercise. Ethanol also inhibits mTOR and affects FOXO3a (20) which could lead to increased longevity, FOXO3A activity is associated with longevity in healthy older human populations. Alcohol protects the small intestine and the liver, it also protects the small bowel via the production of prostaglandins (24).

Alcohol seems to release heat shock proteins which is part of the hormetic response and helps the body correctly fold and refold proteins.

✅ Brain health

Alcohol doesn't kill brain cells, when properly dosed, alcohol actually creates new brain cells. Ethanol has been shown to promote neurogenesis in the hippocampus of rodents consuming moderate amounts of alcohol without triggering apoptosis. Indeed, a large Australian cohort study of 7,485 participants found that people drinking at a moderate dosage, had a superior cognitive function to those abstaining from alcohol altogether. Alcohol has been found to activate the murine glymphatic system (the brain's waste drainage system) and protect against many different diseases by doing so.

Alcohol consumption has been found to lower levels of anxiety. Alcohol consumption can improve foreign language skills in bilingual speakers (15) who received higher observer ratings for pronunciation, compared to controls. Evidence from the University of Exeter, also shows that drinking alcohol improves memory for information learned before, the day afterward, the drinkers remembered more of what they had learned (16). In 2021, using PET imaging scanners, researchers discovered that just like exercise, alcohol has effects on the brain that can help you relax, and reduce stress levels by decreasing activity of the amygdala (the part of the brain associated with things like fear) and dividing it by activity in the frontal cortex (the part of the brain involved in executive functions). In turn, these effects benefit our emotional state and cardiovascular health.

Alcohol is in fact, a rapid antidepressant comparable to the effect of ketamine. Alcohol seems to have the same neural and molecular changes as rapidly acting antidepressant drugs by affecting NMDA receptors and FMRP to transition the neurostimulator GABA from inhibitor to stimulator activity, a single dose of alcohol can elicit these biochemical changes and result in non-depressive behavior lasting at least 24 hours (19). The liquid therapist with a twist!

✅ Hormonal health

As we age, both men and women experience an increase in Sex hormone-binding globulin (SHBG) levels, this pesky protein binds to sex hormones in the bloodstream - so much for the fountain of youth! In men, this translates to lower free testosterone, in women this leads to symptoms of menopause. Next to exercise and meat intake, alcohol seems to lower SHBG levels leading to better hormonal health, greater insulin sensitivity, and more free testosterone (28). A decades-long global decline in male fertility, but alcohol saves the day, as it is shown to increase fertility in men (31).

✅ Glucose tolerance

Dr. James O’Keefe, chief of preventive cardiology; "Solid gold-standard kind of research confirms beneficial effects of moderate alcohol intake (32)"

This was a 2-year randomized controlled trial (RCT) with wine consumption leading to improvements in HDL, and glucose metabolism in diabetics. Genetic interactions imply that ethanol significantly contributes to glucose metabolism, and the effects of red wine also include nonalcoholic components.

✅ Sleep

A slumber did my spirit seal. Up to two drinks, a day will not decrease melatonin production by the body. (which is good!) and alcohol shortens the time it takes to fall asleep, and increases deep sleep, moderate amounts do not reduce REM sleep (17). Overall, there is good evidence for sleep quality improvements, including from an RCT (32). There are other compounds in both beers (hops) 🍺 and wine (melatonin) that lead to improvements in sleep onset and quality via GABA receptor stimulation. Sipped the barley nectar, I declare, slumber in whimsy!

✅ Antioxidant

Just like fruits and vegetables do, alcohol raises the antioxidant capacity of the blood (11)(23), and in doing so benefits the redox status. This is one of the reasons why drinking protects against cataracts and against Type II diabetes. Alcohol also improves insulin sensitivity. Alcohol actually stimulates a major endogenous antioxidant in the human body superoxide dismutase (SOD) (24).

✅ Pretty much any conceivable human disease

In 2017, researchers developed a computational framework using System Level Interactomics Analysis and Network-Based Inference to establish diet-disease associations (34). They mapped the gene expression signature of disease alongside the gene expression signature of food, identifying 485 diet-disease pairs.

Interestingly, the gene expressions associated with alcohol (both wine and pure ethanol) counteracted the gene expressions of most of all the diseases among the 266 foods charted. This means that alcohol could potentially and uniquely, help reverse or lessen the effects of many possible diseases. This discovery highlights the fundamental genetic link between ethanol and our body's chemistry.

As the old saying goes, "where there's smoke, there's fire," and it seems our dear friend alcohol is the toast of the health town.

UPG1: The Principles Of Hormesis: Dosing

"Poison's potency lies in the dosage, my dear."

Behold the human superpower: alcohol immunity! Thanks to our ancestors' love for alcoholic fruits and nectars, our genes mutated to boost ethanol metabolism. Sip, but don't chug, and you'll unlock the hormetic effect, a positive buzz. Fruit flies are in on the secret too, with alcohol granting them longer lives and more babies. It's all about finding that sweet spot on the U-shaped curve, where we can toast to our "evolved normal" state.

Here Hayes elegantly describes a dose-response relationship. Not drinking ethanol, while not lethal and not considered a nutrient in and of itself, could in fact be plotted as a human nutritional deficiency on this curve.

"Sip or Sup: The Eternal Conundrum."

Since we usually drink alcohol, we should exercise caution because our bodies absorb liquid more quickly, certainly when compared to how as primates we mostly ate ethanol from foods. This fact reduces our safety threshold, indicating a very small margin between healthy and unhealthy ethanol consumption through drinks. A prime example is an RCT (26) that demonstrates HRV & HR remains stable with just one glass of wine but deteriorates with two glasses when consumed during a single session. Different studies seem to suggest that alcohol may become a pro-oxidant when consumed as 2 drinks within 30 minutes, this could also eventually shrink the brain (30).

UPG1 In a nutshell

• Limit alcohol consumption to 1 or 1,5 standard drinks during the same hour,

• If you are a female AND you get tipsy easily, limit yourself to 1 drink per hour,

• It's advisable (not necessary) to drink before or during a meal to hinder absorption,

• Drinking during meals also offers protection against oxidative effects of eating,

• Conserve dual-beverage rendezvous for [convivial congregations](https://convivial congregations),

• Have at least 1 standard drink per day for at least 3 days a week,

• But, 1 or 2 standard drinks every day are better, and doing up to 2.5 is still fine

Considerations.

Around 30% of Chinese, Japanese, and Korean people have a mutation in their genes that makes them deficient in the enzyme, responsible for metabolizing ethanol (ALDH2). They should avoid alcohol consumption or limit it to levels below natural exposure.

Women's different body compositions, enzyme, and hormone levels could cause alcohol to remain in their bloodstreams for longer periods of time. Seeing that we’re working with small margins, it is possibly “safer” to adjust to 1 standard drink per sitting. While variation in absorption rate might occur individually, the benefits of alcohol consumption are not sex-specific

For athletes, if consumed in moderation, body composition and strength qualities like VO2Max seem largely unaffected (8). Seeing the systemic benefits of ethanol, drinking is very suitable for athletes. Studies on mice show that the inclusion of vitamin C prevents the decline in exercise performance seen during acute drinking (2). This would be in line with how ethanol appears in the wild being part of vitamin C-rich fruits. Overall, it would be more interesting to drink after performance though.

When on the Planet of the Apes, do as the simians do? 🦍🌳

Most species of primates will consume alcohol when presented, even at rates producing "pharmacological effects" when the drink has a palatable taste and is under 15 to 20 percent alcohol by volume (33). Interestingly, the maximum theoretical alcohol production, before the substance starts inhibiting yeast’s biochemistry, is below 15%. It took the invention of distillation to produce harder liquor, and these animals were not taking shots. But while the animals seem to select for alcohol volume, there is nothing stopping voluntarily drinking monkeys from consuming alcohol at toxic levels (34). So be advised, in species like us, there don’t seem to be any natural breaks!

But ah, we humans possess a sly ace up our sleeves - our ever-expanding prefrontal cortex! This cerebral sorcery grants us unparalleled impulse control and decision-making prowess, leaving our primate pals in the dust. Chin up, simian friends!

In 2015, scientists observed wild chimpanzees in Guinea voluntarily drinking fermented palm sap (using leaf sponges) over an extended period (35). Some even got visibly tipsy (one chimp reportedly downed the equivalent of a bottle of wine and passed out). The 17-year study revealed that these chimps had a preference for naturally fermented palm wine from raffia palm trees. Genetic upregulation of ethanol genes likely improved access to sugar sources and offered protection against alcohol's harmful effects.

Fast forward to 2022, the "drunken monkey hypothesis" was confirmed (29), proving that monkeys don't just accidentally consume alcohol in fruits but actively choose ripe, fermented specimens for the calorie bonus. And, of course, there's always the pursuit of fun—by 2023 (36), researchers found that great apes enjoy spinning themselves around to alter their consciousness. Who knew?

*Ah, cherished perusers, we've reached the grand finale of our jaunt through the simian spirits sanctuary. We trust you've relished this borderline obsessive labor of adoration. Fear not, for we pledge to shower you with a plethora of biotechnological shenanigans in the days to come. After all, what better way to kick things off than with a frothy pint of ale? Thus, we wrap up UPG1, also known as "upgrade one," for the KOBE-SUITS.

Non nobis, Domine, non nobis, sed Nomini tuo da gloriam. (Not for us, O Lord, not for us, but for the sake of Your name, let the glory flow.)

The Templar knights, TFA (Ta-Ta For Now)

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Bonus Content: deleted scene’s

*a) People living in the Blue Zone of Sardinia drink wine, but this does not specifically associate with their increased longevity, at least not when compared to the rest of the Italian population who also tend to drink. (Michel Poulain).*

Well, this does indeed make sense, the health effects of alcohol intake would already be reflected in the drinking general population, and it also makes sense that there is no longer an extra association in the Blue Zone because any increased intake above moderate levels would not translate into additional health or longevity.

*b) Alcohol consumption is only beneficial for people who already suffer from cardiovascular disease. (Michael Greger).*

The argument suggests that if ethanol benefits those with compromised cardiovascular systems, it would likely be even more beneficial for healthy individuals. Studies like the Alpha Omega Cohort (Esther Cruijsen, 2021) support this idea, showing that moderate alcohol intake in individuals with a history of CVD (MI) was associated with reduced all-cause, CVD, and IHD mortality compared to abstainers and heavy drinkers. This evidence highlights the potential fundamental health effects of ethanol on cardiovascular health. Moreover, observational studies on healthy young subjects also show a reduction in all-cause mortality, further supporting the potential health benefits of moderate ethanol consumption.

c) The benefits of alcohol intake are merely a fluke from nutritional epidemiological research, which is always prone to error due to the inability to perfectly adjust for confounding factors.

Experimental evidence from animal and human studies, along with epidemiology, supports the potential benefits of moderate ethanol consumption. While some specific epidemiological meta-analyses might argue against alcohol consumption, they don't necessarily align with the majority of research conducted over decades or with fundamental evolutionary biology. It's important to note that wild fruit naturally contains ethanol, highlighting its biological significance in the natural world.

d) Reported health improvements are being caused by nutrients in certain drinks like polyphenols or melatonin, (which can function as antioxidants), and are unrelated to the ethanol itself which is bad for health.

In 2013, a well-executed randomized trial on humans (5) established that; "both ethanol and nonalcoholic compounds in red wine have potentially protective effects that may reduce the risk of vascular disease, the phenolic content of red wine may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of red wine may modulate soluble inflammatory mediators in patients at high risk of cardiovascular disease." The result of this trial is reflected in studies that observe populations of people; all alcoholic drinks are linked to reduced diabetes and cardiovascular risk when consumed in equal quantities. (9) This seems to suggest that the alcohol itself, not the specific compounds found in each type of alcohol, has a much greater impact on health benefits. The ethanol brings in most of the benefit and any other healthy chemicals are a smaller bonus aka. "drinking alcohol-free beer is bad for you" (it's not, but you get the point). In 2021, a randomized, single-blind, controlled, three-arm parallel intervention study showed that alcohol was equally effective to lower inflammation when compared to a wine group (22).

*e) Scientists shouldn't promote alcohol because some people are prone to addiction. (WHO, etc).*

WHO and other organizations often equate the risks of alcohol consumption to smoking, but there is no evidence supporting benefits of moderate smoking. Public health institutions sometimes simplify complex truths for the sake of clear, population-wide advice, occasionally leading to more harm than good. For instance, advice to avoid sun exposure might cause more deaths than it prevents, despite sunbathers living longer (4). Discussions about addiction should belong to psychiatry, not nutritional science. Public health institutions and media often present anti-alcohol arguments, sometimes obscuring the truth. In 2016, the Department of Health revised its guidelines, stating no safe level of alcohol consumption exists, despite previous J-shaped curve observations.

British philosopher Julian Baggini notes that people prefer clear categories of good and bad, making complexity undesirable for some institutions. Governments may withhold the truth about alcohol due to intoxication-related deaths. This willingness to obscure the truth for an agenda is evident in warnings against sun exposure, despite people spending over 93% of their lives indoors.

*f) Ethanol is a powerful carcinogenic, associated with 7 different kinds of cancer. (AIRC).*

The American Institute For Cancer research specifically talks about alcohol intakes above moderate levels. One would almost forget that alcohol intake not only decreases all-cause mortality and cardiovascular risk, but also lowers the overall cancer risk by an equally impressive amount. This once again ties into the subject of how public health instances (like the AIRC) prefer to sacrifice informing people about basic biological truths (and its "small" benefit to an individual's health) in favor of reducing the costs and consequences of alcohol intoxication on the level of society.

SOURCES

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Published on April 03, 2023.