The Cryo-Paleo Solution

Originally published as a Cryonics magazine web exclusive

Cryonics is an odd service. When you pay for a service—whether it’s having your car cleaned, your taxes prepared, or your dinner served—you typically want what you’ve paid for as soon as possible. Cryopreservation is unusual in that those who pay for it hope never to need it. If we do need it, we hope it will be later rather than sooner. (Of course it’s not unique in this; companies retain lawyers who they hope not to need.)

Those of us with arrangements for cryopreservation have a well-worn but deeply wise aphorism: “Cryonics is the second worst thing that can happen to you.” Both the uncertainty of the cryonics endeavor and the fact that we want to remain in direct control of our fate means that we should attempt to put off the need for cryopreservation for as long as possible. Extending maximum life span is tough. Calorie restriction might do it, although Aubrey de Grey and Michael Rose have argued that the effect in humans is likely to be modest.

We have many more options for reducing our chances of dying early—and for enjoying improved health, vigor, and well-being in the meantime. The subject of this article is a currently unfashionable option with a potentially huge health payoff. This is the paleo diet, also known as the caveman diet, the new evolution diet, and the primal diet. The plan is actually more than simply diet. It includes a perspective on exercise and other aspects of healthy living. The topic is complex. My aim here is merely to introduce and hopefully intrigue you to investigate further.

I’ll sketch out what the paleo diet is, its rationale, highlight some of the crucial ways in which it differs from standard dietary advice, and consider how a backward-looking paleo perspective fits with the forward-thinking typical for cryonicists, how it benefits health, how intermittent fasting can add to the benefits, and what a paleo approach to exercise looks like.

What is the paleo diet?

Answering this question is complicated by disagreements among its advocates and by the range of foods eaten by our Paleolithic ancestors. The basic idea is that the paleo diet is the only diet that ideally fits our genetic makeup. Our genes and the functions they regulate change very slowly, over many generations. The human genetic endowment was formed over millions of years of evolution. The genus homo is almost two and half million years old, and includes humans and species closely related to us. The Paleolithic era (or, more informally, the Stone Age) accounts for 99.5% of that human history.

During that time, our ancestors lived as hunters and gatherers. This changed dramatically with the advent of agriculture, a mere five to ten thousand years (really little more than two thousand years in most of Europe). We lived as hunter-gatherers for over a hundred thousand generations, compared to six hundred generations as farmers and ten generations living in the industrial age. Our genes have been almost entirely shaped by the conditions of the Paleolithic era.

Hunter-gatherers (HGs) consumed large amounts of animal food, some getting 100% of calories from meat or fish. The HG diet was higher in protein compared to today and higher in fat. Crucially, it was much lower in carbohydrates. Carbohydrates that were eaten generally had a low glycemic load. Even the fruits then were less sweet than today’s, because we have bred for sweetness over centuries. Refined, high-carbohydrate foods have been eaten only for the last few hundred years—just for the last thousandth of one percent of our 2.5 million years as humans. We did not evolve to eat easily digestible starches, refined carbohydrates (such as flour and white rice), and sugars. Paleo advocates also prefer to eat grass-fed beef and free range chickens because of their superior fatty acid profile (a higher omega-3 to omega-6 ratio) as compared to factory-farmed, grain-fed animals.

Probably the leading paleo advocate (and perhaps the most scientifically grounded) is Loren Cordain. In his book, The Paleo Diet, he condenses the paleo approach to food into six ground rules: All the lean meats, fish, and seafood you can eat. All the fruits and nonstarchy vegetables you can eat. No cereals. No legumes. No dairy products.  No processed foods. (Other paleo writers dispute the need for meat to be lean.)

Expanding on that highly compressed outline, Cordain also offers Seven Keys of the Paleo Diet: 1. Eat a relatively high amount of animal protein compared to the typical American diet. 2. Eat fewer carbohydrates, but lots of good carbohydrates—from fruits and vegetables, not from grains, starchy tubers, and refined sugars. 3. Eat large amounts of fiber from nonstarchy fruits and vegetables. 4. Eat a moderate amount of fat, with more monounsaturated and polyunsaturated fats than saturated fats and nearly equal amounts of omega 3 and omega 6 fats. 5. Eat foods with a high potassium content and a low sodium content. 6. Eat a diet with a net alkaline load. 7. Eat foods rich in plant phytochemicals, vitamins, minerals, and antioxidants.

Other versions of the paleo diet look more similar to the Atkins diet. But even these more fat-friendly versions differ from Atkins in that the latter allows any amount of processed meat, and can be more restrictive of vegetables and fruit (especially in the early stages of weight loss). Although the Zone diet shares some recommendations with paleo, the Zone is too high in carbs, too fat-phobic, too structured, and wrongly recommends soy.

Paleo Variations

Sometimes I prefer to talk of a “NeoPaleo” diet, to emphasize the point (often misunderstood) that we are not trying to exactly emulate a unique Paleolithic diet while rejecting all modern innovations in nutrition. Critics who point out that there was no single, universal diet over those 2.5 million years are right, of course. But I don’t know of any paleo advocate who argues otherwise. Clearly, ancestral diets varied significantly at different times and in different environments. A major difference exists between the Ice Age Paleolithic and post-Ice Age. Sometimes we were more hunters than gatherers; at other times the opposite. Sometimes (actually quite a lot of the time) Paleolithic people ate practically no fruits or vegetables, but in temperate times non-starchy fruits and vegetables became a larger part of the diet.

Anyone wanting to be a paleo purist will also run into the problem of disagreements among advocates. The good side to this is that it encourages you to examine the evidence for yourself rather than blindly following a unitary regimen. Some of the differences—such as whether any amount of salt should be used—are relatively trivial. We can find a more substantial divergence on the issue of the optimal level of carbohydrates, and on the related matter of whether glycemic index or glycemic load is important. While all paleo writers agree on throwing out starches, legumes, and grains, and refined sugars, that leaves fruits (and to a lesser extent vegetables and nuts) as a source of carbs. Is any amount of fruit good or not?

Cordain recommends a relatively high 22% to 40% of calories from carbohydrates. For a 2,000 calorie diet, that would amount to 440 to 800g. Mark Sisson, author of The Primal Blueprint, specifies  100 to 150g as the “Primal Maintenance Zone”, while 50 to 100g is the “Primal Sweet Spot for Effortless Weight Loss”. The paleo-compatible analysis by Gary Taubes, author of Why We Get Fat and Good Calories, Bad Calories, recommends 20g or less. Nora Gedgaudas, author of Primal Body, Primal Mind, agrees with Taubes’ view that there is no human dietary requirement for carbohydrates.

Views also diverge on the issue of the optimal amount or range of saturated fat. Cordain favors lean meat, whereas Sisson, Gedgaudas, and Taubes argue that higher levels of saturated fat are fine. Sisson allows modest amounts of dairy but most others rule out dairy other than eggs. Cordain used to be an exception in recommending canola oil, but no longer does. One point that probably all the authors would agree on to some degree is that the optimal amount of dairy and saturated fat will vary across individuals. Some can tolerate dairy better than others, and genetic differences (such as possessing the apolipoprotein E3 variant) may mean some people do well with a lower intake of saturated fat.

Among the other differences of opinion, Cordain and Taubes seem unconcerned about diet sodas and artificial sweeteners, whereas Sisson is less accommodating (without entirely ruling them out). Everyone agrees that being vegetarian and paleo is difficult and not a good idea from an optimal health standpoint but some take a harder line on the compatibility of the two. They would all agree it’s better to be a paleo-vegetarian than just a vegetarian.

Futurist-Paleo

Looking for health guidance by looking back, say, 40,000 years, may seem odd coming from a cryonicist, transhumanist, and someone known for thinking about the future. That impression might be reinforced by reading paleo proponent Mark Sisson’s book or blog posts, since he often rails against genetically modified foods and almost any kind of modern changes to our food. If the construction were not so clumsy, I might call my position “Futurist-NeoPaleo”. That would emphasize the point that old is not necessarily optimal, that modern doesn’t mean bad, and that paleo is an approximation that forms a good starting point but not the whole truth.

Grains may be bad for us (see below) but what if we could genetically modify our foods (or ourselves) to use them without any downsides? That may even be essential if we are to feed the global population in good health. Personally, I would be delighted if I were able to stop eating animals and instead eat animal nutrients grown in a vat. Only someone dogmatically committed to an absolute, a priori paleo position (one not entirely tied to the conditions of health) would reject these possibilities out of hand. At the same time, it’s crucial to acknowledge that until we can reengineer ourselves or have reengineered grains to work better with our biology, we should take into account the diet for which we are adapted.

Some modern additions to diet and health, while not available to Paleolithic people make excellent sense given the different conditions in which we live. (And due to our living, on average, much longer since we are far less susceptible to deadly infections and accidents.) It’s sensible to wear sunglasses, since we live a lot longer than paleo people and can accumulate more eye damage. It also makes sense to get flu shots, even though these were unavailable throughout almost all of our history.

It probably also makes sense to take some nutritional supplements. While Paleolithic people in many regions were regularly exposed to hours of sunlight, our modern life style keeps most of us out of the sun, perhaps indicating a need to supplement our diets with vitamin D. I don’t see any sensible paleo objection to taking a general vitamin supplement, and perhaps additional fish oil and probiotics.

Paleo is an excellent starting point. But we can’t be sure that it is optimal for health. We must remain open to direct evidence. For instance, the evolutionary argument behind paleo eating would suggest that we should consume no more than a very few grams of salt per day. But the body, being a complex system, might never have become optimized to that level. It’s possible that a higher intake is better. Paleolithic people may have eaten a lot of food raw, but that doesn’t mean it’s not better to cook moderately at least some kinds of meat.

Health benefits of going paleo

For thirty years I was a believer in the standard wisdom that a healthy diet is one low in fat and high in carbohydrates primarily from high-fiber sources. The shift to paleo (which took place last year) is therefore a major change of mind. If you hold the views I did (and hadn’t looked into the subject for many years), you may be skeptical, and you certainly won’t find the detailed evidence to change your mind in this article. I’m going to make naked assertions about the health of going paleo, leaving you to take a look at the sources provided at the end for the details.

The advent of agriculture was followed by a decline in human stature, bone density, strength, dental development, and health. There was an increase in birth defects, malnutrition, and degenerative diseases. Evolutionary biologist Jared Diamond has gone so far as to declare agriculture and the advent of grains as the “worst mistake in the history of the human race”. Despite improvements in medicine, numerous health problems have greatly expanded over the last century as we replaced animal fats with vegetable oils, trans fats, and carbohydrates (especially refined carbs including high fructose corn syrup).

Low-fat diets encourage us to load up on grain products (wheat, rice, bread, pasta, cereal, corn). Unfortunately, consumption of grains yields relatively poor nutrition but provokes a high insulin response. Grains (and legumes) also contain problematic anti-nutrients such as phytates, lectins, gluten, and goitrogens (thyroid-inhibiting substances). Lectins are natural plant toxins that can inhibit healthy gastrointestinal function and provoke an autoimmune response.

Gluten is a large, water-soluble protein found in most grains, including wheat, barley, and rye. Perhaps one third of us are gluten-intolerant or gluten-sensitive. The rest of us may suffer negative consequences (such as disruption of healthy immune function and inflammation) that are less obvious. Those who are gluten-intolerant can develop conditions including dermatitis, joint pain, acid reflux, reproductive problems, autoimmune disorders, and celiac disease.

The phytic acid found in grains inhibits the absorption of minerals by binding them and eliminating them from the body. Heavy consumption can lead to deficiency of minerals including calcium, iron, magnesium, and zinc. Legumes also contain lectins as well as protease inhibitors, which can damage the pancreas and reduce the body’s ability to digest and use protein. It’s true that phytic acid and other anti-nutrients can be reduced or eliminated if you take the trouble to pre-soak, sprout, or ferment these foods, but are you going to do that often?

Going paleo means avoiding grains and legumes, thereby avoiding a major cause of numerous maladies, that are thought to include allergies, food sensitivities, auto-immune disorders, colon cancer, pancreatic disorders, mineral deficiencies, celiac disease, epilepsy, cerebellar ataxias, peripheral neuropathies of axonal or demyelinating type, and myopathologies, autism, and schizophrenia. Obviously we vary greatly in how we react to grains, but I don’t know of any tests that reliably tell you how well you handle grains. You might eat grains and thrive, but that doesn’t mean they aren’t doing you some harm nor that they aren’t a bad bet: some people smoke and live long, healthy lives, yet smoking remains a bad bet.

Eating paleo-style can help avoid or reduce many health problems. Again, it would take up far too much space to support these claims with the relevant evidence (which you will find in the source below). The evidence I’ve seen leads me to believe that eating paleo reduces your chances of insulin resistance, diabetes, obesity, celiac disease (and the combination metabolic syndrome), high blood pressure, cancer, many disorders linked to inflammation, including auto-immune disorders such as arthritis, and improves your blood lipids, reduces your hunger and raises your energy level.

It’s important to note that you can expect a transitional period of adaptation of a few weeks to a couple of months. Your body needs time to switch from primarily burning carbohydrates for fuel to burning fat, especially if you adopt the more carbohydrate-restricted forms of paleo (which I believe to be the healthiest). You might want to take supplemental magnesium, calcium, and zinc during the transition.

While the caution about a transition period is standard in the paleo literature, in my own case I experienced no dip in energy at any time, despite continuing intense workouts (both aerobic and muscular). Nor did I find the restrictions to amount to a significant sacrifice. The almost immediate loss of craving for carbohydrates surprised me. I’ve found the new types of food—especially the highly colorful salads that are now daily treats—to more than make up for the foods I’ve let go of.

Start now or later?

Another wrinkle was added to the paleo story for me last year when I listened to a talk by evolutionary biologist Michael Rose. Professor Rose is a strong proponent of the paleo diet, but only for people over the age of 35 or 40 (earlier if you’re not Eurasian). In his talk (to which you’ll find a link below), he argues that most of us have adapted well to an agricultural diet at earlier ages. But as we get older (a little past the usual age of reproduction) those adaptations begin to fail. I don’t think Rose would disagree that even young people might be healthier on a paleo diet, but he only strongly urges making the dietary switch after the first three to four decades of life.

Intermittent fasting

We’ve become used to eating three square meals per day (and Taco Bell is pushing a “fourthmeal”). Paleolithic man certainly didn’t eat this way; nor do animals in the wild. More likely, after a kill they would eat a lot then rest. They would become hungry and have to go out and hunt or gather more food. They would have been used to going without food for longer periods than we do today. Although not by design, they practiced intermittent fasting (IF). Abundant evidence exists to suggest that IF generates major health benefits, even when it doesn’t lead to a lower total calorie intake.

Intermittent fasting can be done in a variety of ways, although skipping only one meal is probably insufficient to reap significant benefits. One popular, low-level approach is to fast for sixteen hours, leaving yourself an eight-hour window for eating primally. Even better is to fast for a full twenty-four hours occasionally—as often as once or twice per week. This might sound difficult and painful, but it’s much easier to skip meals when your regular diet is relatively low-carb, leading to stable blood sugar and insulin levels. If IF sounds appealing as a health measure but you’re not yet eating paleo or low-carb, it’s probably best to wait for a few weeks until your body has adapted to use fat stores for energy rather than carbohydrates.

What are the likely health and longevity benefits of supercharging paleo with IF? While being considerably easier than permanent calorie restriction, it appears to have many of the same benefits. These include increased insulin sensitivity, stronger resistance to stress, improved cognitive clarity, improved blood lipids (such as healthy LDL particle size and distribution), better neurological health, lower risk of cancer, reduction in risk of metabolic syndrome, and improved autophagy (the cellular recycling of waste material and repair processes).

Paleo exercise

Our Paleolithic ancestors didn’t go to the gym to run on treadmills or bicycles. They didn’t play football or go rollerblading. Yet they certainly got plenty of exercise. Both modern exercise science and our evolutionary history suggest that some forms and ways of exercising are more conducive to health and optimal function than others. For instance, it’s highly unlikely that paleo people ran slowly for long distances. A paleo approach to exercise would include lots of walking and play, lifting heavy things (especially using compound movements rather than isolation movements), and occasional all-out sprinting. Aerobic fitness seems to be achieved much more efficiently and with lower risk of repetitive stress injuries by high-intensity interval training than by jogging for long distances.

Being highly regimented and regular in an exercise program can lead not only to boredom but to a declining level of physiological response. Paleolithic people didn’t exert themselves in exactly the same way every day. They might have to sprint at unpredictable times to catch food or to avoid becoming food. Some days they would have heavier burdens to carry or drag back to camp than on other days. Again, history and modern exercise science agree in recommending that you vary your exercise, mixing it up for variety, and frequently surprising your body with something new.

So that’s Paleo 101 for cryonicists who aren’t eager to dive into the dewar. My goal here has not been to convince you but merely to intrigue you and interest you in investigating further. The evidence for the paleo approach looks strong to me, based not only on the evolutionary rationale but also on the direct evidence.

My personal experience reinforces this. Despite having been following the paleo diet for less than half a year, I’ve gotten significantly leaner (my waist now back to where it was 20 years ago), my triglycerides have come down from an already good level, my HDL/LDL ratio has improved further, my health has been good, and my energy level has been noticeably more stable and my appetite less demanding. I believe that people who are overweight, diabetic, or suffering many other health challenges will benefit even more.

Further reading and resources

You will no doubt have many objections, doubts, and questions that I haven’t the space to answer here. Doesn’t saturated fat cause heart disease? Why do so many mainstream nutritionists (backed by the US government’s Food Guide Pyramid) promote a diet very different from paleo? Very likely, every one of your questions has been thoroughly addressed in one of the following sources.

Loren Cordain, The Paleo Diet.

Nora T. Gedgaudas, Primal Body, Primal Mind.

Mark Sisson, The Primal Blueprint.

Gary Taubes, Why We Get Fat.

Gary Taubes, Good Calories, Bad Calories.

Arthur de Vany, The New Evolution Diet.

Web resources:

http://www.thepaleodiet.com/

http://www.thepaleodiet.com/faqs/

http://www.paleodiet.com/

http://www.proteinpower.com/drmike

http://www.marksdailyapple.com/primal-blueprint-101/

http://www.proteinpower.com/drmike/intermittent-fasting/fast-way-to-better-health/

http://www.marksdailyapple.com/health-benefits-of-intermittent-fasting/#more-19683

http://www.thepaleodiet.com/articles/2010_Organic_Fitness_Physician_and_Sports_Med.pdf

http://www.kurzweilai.net/how-to-achieve-biological-immortality-naturally

Michael Rose’s video (about 38-minute mark on diet): http://telexlr8.blip.tv/file/4225188/

At last, a sure-cold way to sell cryonics with guaranteed success!

A humorous romp through a promising new technique in aesthetic medicine from one cryonicist’s (warped) point of view.

Figure 1: Before cryopreservation (L) and after cryopreservation (R).

As everyone involved in cryonics for more than a fortnight is sadly aware, cryonics doesn’t sell. Indeed, if we were pitching a poke in the eye with a sharp stick, we’d more than likely have more takers than we’ve had trying to ‘market’ cryonics to the public. To see evidence that this is so, you need only wander around a shopping mall on a weekend and observe all the (painfully) stainless steel lacerated and brightly colored needle-pierced flesh sported by the young and trendy and increasing by the old and worn, as well.

Yes, it’s clear; we misread the market, to our lasting detriment.

It’s true that we’ve tried the ‘you’ll be rich when you wake you up line,’ and heaven knows we’ve beaten the ‘you’ll be young and beautiful forever’ line, well, virtually beaten it to death. And while people are certainly interested in great fortune and youth, both of these things share the same unfortunate shortcoming, namely that they are things that people either don’t have but want, or do have and don’t want to lose. As anyone who is really savvy at marketing will tell you, the best way to sell something is to promise (and preferably be able to deliver) that you can get rid of something that people have and really don’t want – something that is ruining the quality of their life, destroying their health, draining their pocketbook and, worst of all, making them really, really ugly.

So, it turns out that for onto 50 years now, we’ve missed the real selling point of cryonics that’s been there all along: IT WILL MAKE YOU THIN! Guaranteed!

Can such a claim be true? Well, surprisingly, the answer would seem to be an almost unqualified, “Yes!”

Recently it’s been discovered that adipocytes, the cells responsible not only for making you fat, but for making you hungry, as well, are particularly susceptible to a phenomenon in cryobiology that has proved a nettlesome (and only recently (partially) overcome) barrier to solid organ cryopreservation: chilling injury. Quite apart from freezing damage due to ice crystals forming, adipocytes are selectively vulnerable to something called ‘chilling injury.’ 1-5 Chilling injury occurs when tissues are cooled to a temperature where the saturated fats that comprise their cell membranes (external and internal) freeze. You see, saturated fat, which is the predominant type of fat in us humans, freezes well above the temperature of water – in fact, it freezes at just below room temperature. That’s why that big gash of fat on the edge of your T-bone steak is stiff and waxy when it is simply refrigerated, and not frozen.

Figure 2: Chilling injury is thought to result from crystallization of cell membrane lipids.

Chilling injury isn’t really well understood. In the days before both cryobiology and indoor heating, humans used to experience a very painful manifestation of it in the form of chilblains – tender swelling and inflammation of the skin due to prolonged cold exposure (without freezing haven taken place). In the realm of organ preservation it is currently thought that chilling injury occurs when cell membranes are exposed to high subzero temperatures (-5oC to -20oC), again, in the absence of freezing.

There is evidence that the lipids (fats) that make up the smooth, lamellar cell membranes undergo crystallization when cells are cooled much below 0 deg C. Since the crystals are hexagonal in shape and have a hole in the middle, this has the effect of creating a pore or hole in the membrane. Cells don’t like that – those holes let all kinds of ions important to cells keeping their proper volume and carrying on their proper metabolic functions leak in and out, as the case may be. This isn’t merely an inconvenience for cells, it’s downright lethal. Without boring you with technical details, it is possible to partially address this state of affairs in organ preservation by adjusting the ‘tonicity’ of the solution bathing the cells: oversimplifying even more, this means by increasing  the concentration of salts to a concentration higher than would normally be present

Figure 3: Contouring of the skin in a pig subjected to brief, subzero cooling of subcutaneous fat.

But, to return to our chilled adipocytes and the promise not only of weight loss, but of a fat-free future; adipocytes are killed, en masse, when their temperature is dropped to between 0 and -7oC. Within a few days of exposure to such temperatures they undergo programmed cell death (apoptosis) and within a couple of months they are phagocytized by the body; and all that ugly and unwanted fat is carted off to be used as fuel by the liver. Now the rub would seem to be that this effect is most pronounced when the temperature of the tissue is cooled to below the freezing point of water and held there – preferably for a period of 10 minutes or longer.

That sounds dire, doesn’t it? What about the skin, the fascia, blood vessels, and the other subcutaneous tissues that will FREEZE (in the very conventional sense of having lots and lots of ice form in them)? Well, the answer, as any long-time experimental cryobiologist will know (even if he won’t tell you) is: pretty much nothing. Way back in the middle of the previous century, a scientist named Audrey Smith and her colleagues at Mill Hill, England found that you could freeze hamsters ‘solid’ – freeze 70+% of the water in their skin and 50% of the water in their bodies – and they would recover from this procedure none the worse for wear. Similarly, those of us who have carelessly handled dry ice for a good part of our lives will tell you that we see parts of our fingertips turn into stiff chalky islands of ice all the time, with the only side effect being a bit of temporary numbness that resolves in a few days to a week – certainly a side effect well worth it to avoid the considerable inconvenience of rummaging around to find a pair of protective gloves.

Figure 4: The Zeltiq Cool Sculpting Cryolipolysis device.

But alas, we scientists (most of us, anyway) are not a very entrepreneurial lot, and so we never thought either of inventing the ZeltiqTM cryolipolysis system, or using ‘the thin-new-you’ as a marketing tool for cryonics.

Yes, that’s right; some very clever folks have found a way to make a huge asset out of a colossal liability – to organ preservationists, anyway. Around 2004 a Minneapolis dermatologist named Brian Zellickson, MD, who specialized in laser and ultrasonic skin rejuvenating procedures, made a not so obvious connection. Both laser and skin ‘face-lifting’ and skin ‘rejuvenation’ procedures rely on the subcutaneous delivery of injuring thermal energy to the tissues of the face, or other treated parts of the body (cellulite of the buttocks and thighs are two other common areas for treatment). These energy sources actually inflict a second degree burn in a patchy and well defined way to the subdermal tissues.

Now this may seem a very counterintuitive thing to do if you are trying to induce ‘rejuvenation’ or ‘lift’ a sagging face. But if you think about it, it makes a great deal of sense. As any burn victim will tell you, one of the most difficult (and painful) parts of recovery is stretching the highly contracted scar tissue that has formed as a result of the burn injury. Indeed, for many patients with serious burns over much of their body, the waxy, rubbery and very constricting scar tissue prevents the return of normal movement, and can lock fingers and even limbs into a very limited range of motion. Many burn victims must do painful stretching exercises on a daily basis to avoid the return of this paralyzing skin (scar) contracture.

And it must be remembered that aged skin – even the skin of the very old – can still do one thing, despite the many abilities it has lost with age, and that thing is to form scar tissue in response to injury. Thus, laser and ultrasonic heating of normal (but aged) skin induces collagen proliferation and large-scale remodeling of the skin. For all the bad things said about scar tissue it is still a remarkable achievement in that it does constitute regenerated tissue. Regenerated tissue which does the minimum that normal skin must do to keep us alive: provide a durable covering that excludes microbial invasion, and prevents loss of body fluids. By injuring the tissue just below the complexly differentiated layer of the dermis (with its hair follicles, sweat glands and highly ordered pigmentation cells) much of the benefit of ‘scarring’ is obtained without the usual downsides.

The injured tissues respond by releasing collagen building cytokines as well as cytokines that result in angiogenesis (new blood vessel formation) and widespread tissue remodeling. And all that newly laid down collagen contracts over time, tightening and lifting the skin – and the face it is embedded in. These techniques may justly be considered much safer versions of the old fashioned chemical face peel, which could be quite effective at erasing wrinkles and achieving facial ‘rejuvenation,’ but was not titrateable and was occasionally highly unpredictable: every once in awhile the result was disastrous burning and accompanying long term scarring and disfiguration of the patient’s face.

St some point Dr. Zellickson seems to have realized that the selective vulnerability of adipocytes to chilling offered the perfect opportunity for a truly non-invasive approach to ‘liposuctioning’ by using the body’s own internal suctioning apparatuses, the phagocytes, to do the job with vastly greater elegance and panache than any surgeon with a trocar and a suction machine could ever hope to do. Thus was invented the Zeltiq Cool SculptTM cryolipolysis machine.6

Figure 5: The cooling head of the Zeltiq devive equipped with ultrasonic imaging equipment and a suction device to induce regional ischemia and hold the tissue against the cooling surface.

The beauty of cryolipolysis is that it is highly titrateable, seems never to result to in excessive injury to, or necrosis of the overlying skin, and yields a smooth and aesthetically pleasing result. Not unjustifiably for this reason it is marketed under the name Cool SculptingTM. The mechanics of the technique are the essence of simplicity. The desired area of superficial tissue to be remodeled is entrained by vacuum in a cooling head equipped with temperature sensors, an ultrasonic imaging device, and a mechanical vibrator. The tissue in the cooling head is sucked against a conductive surface (made evenly conductive by the application of a gel or gel-like dressing to the skin) where heat is extracted from it. The tissue is cooled to a temperature sufficient to induce apoptosis in the adipocytes, while at the same time leaving the overlying skin untouched. The depth of cooling/freezing is monitored by ultrasound imaging and controlled automatically by the Zeltiq device.  At the appropriate point in the cooling process the tissue is subjected to a 5 minute period of mechanical agitation (massage) which helps to exacerbate the chilling injury, perhaps by nucleating the unfrozen fat causing it to freeze.7 When the treatment is over, the device pages an attendant to return to the treatment room and remove it.

The tissue under vacuum is also made ischemic – blood ceases to flow, and this has the dual advantage of speeding the course of the treatment by preventing the blood borne delivery of unwanted heat – and more importantly, by making the cooling more uniform, predictable and reproducible. It also has the effect of superimposing ischemic injury on top of the chilling injury which is something that seems to enhance adipocyte apoptosis. The whole treatment, in terms of actual cooling time, takes about 60 minutes. In the pig work which served as the basis for the human clinical treatments, the duration of treatment was only 10 minutes: but the cooling temperature was also an ‘unnerving’ -7oC. The degree of temporary and fully reversible peripheral nerve damage (that temporary numbness us ‘dry ice handlers’ know so well) was more severe at this temperature, although it resolved in days to a week or two, without exception.

As previously noted, cryolipolysis causes apoptosis of adipocytes and this results in their subsequently being targeted by macrophages that engulf and digest them. This takes time, and immediately after treatment there are no visible changes in the subcutaneous fat. However, three days after treatment, there is microscopic evidence that an inflammatory process initiated by the apoptosis of the adipocytes is underway, as evidenced by an influx of inflammatory cells into the fat of the treated tissues. This inflammatory process matures between seven and fourteen days after treatment; and between fourteen and thirty days post-treatment, phagocytosis of lipids is well underway. Thirty days after treatment the inflammatory process has begun to decline, and by 60 days, the thickness of interlobular septa in the fat tissue has increased. This last effect is very important because it is weakness, or failure of the interlobular fat septae that is responsible for the ugly ‘cottage cheese’ bulging that is cellulite. Three months after the treatment you get the effect you see below on the ‘love handles’ of this fit, and otherwise trim fellow. Thus, it is fair to say that Cool SculptingTM is in no way a misnomer.

Figure 6: Art left is a healthy, fit young male who has persistent accumulation of fat in the form of ‘love handles’ that are resistant to diet and exercise and the same man 3 months after cryolipolysis.

Does cryolipolysis really work? The answer is that it works extremely well for regional remodeling or sculpting of adipose tissue – those pesky love handles, that belly bulge around the navel, that too plump bum, or those cellulite marred thighs. So far it has not been used to try and ablate large masses of fat – although there seems no reason, in principal, why this could not be done using invasive techniques such as pincushioning the fat pannus with chilling probes, as is done with cryoablation in prostate surgery. However, this would be invasive, vastly more expensive, and likely to result in serious side effects.

And that was one of the really interesting things about the research leading up to FDA approval of cryolipolysis: it seems to cause no perturbation in blood lipids, no disturbance of liver function (the organ that has to process all that suddenly available fat) and no global alterations in immune function. It seems to be safe and largely adverse effect free. There is some localized numbness (as is the case in freezing of skin resulting from handling dry ice) but it resolves without incident with a few weeks of the procedure.8

So, all of this makes me wonder, since human tissues tolerate ice formation and respond to it in much the same way as they do to laser or ultrasound ‘rejuvenation’ (depending upon the degree of damage) a logical question is, “would it be possible to use partial freezing of the skin – just enough to provoke the remodeling response – as a method of facial rejuvenation?” It should be safer than a chemical people and it is, like laser and ultrasound therapy, titrateable.

Figure 7: “Gad darn it, this shiny gold stuff keeps getting into the silt I’m tryin to git out of this here river!”

Which returns me to the whole subject of cryonics: fat is very poorly perfused and it seems unlikely that things done to moderate or abolish chilling injury will be nearly so effective for the adipocytes in fat (if it they are effective at all). That means that we might well all come back from our cryogenic naps not only young, via the magic of nanotechnology and stem cell medicine, and rich via the miracle of compound interest (which none other than Albert Einstein once remarked was “the most powerful force in the universe”), but also THIN! For all these years organ cryopreservationists, like Fahy and Wowk, have been panning for the mundane silt of a way around a chilling injury9 all the while discarding the gleaming nuggets of gold that were persistently clogging up their pans.

We cryonicists should not repeat their error and should realize a good thing when we see it. Now, for the first time, we can credibly claim that if you get cryopreserved you’ll come back not only young and rich, but young and rich and beautiful and thin!

Methinks there must be very few in the Western World today, man woman or child, who can resist a product that has all that to offer – and which, by the way, bestows practical immortality in the bargain.

Ok, Ok, maybe we shouldn’t mention that last part about immortality; it might scare the children.

REFERENCES:

1)     Wiandrowski TP, Marshman G. Subcutaneous fat necrosis of the newborn following hypothermia and complicated by pain and hypercalcaemia. Australas J Dermatol 2001;42:207–10.

2)     Diamantis S, Bastek T, Groben P, Morrell D. Subcutaneous fat necrosis in a newborn following icebag application for treatment of supraventricular tachycardia. J Perinatol 2006;26:518–

3)     Lidagoster MI, Cinelli PB, Levee´ EM, Sian CS. Comparison of autologous fat transfer in fresh, refrigerated, and frozen specimens: an animal model. Ann Plast Surg 2000;44:512–5.

4)      Wolter TP, von Heimburg D, Stoffels I, et al. Cryopreservation of mature human adipocytes: in vitro measurement of viability. Ann Plast Surg 2005;55:408–13.

5)      Manstein D, Laubach H, Watanabe K, Farinelli W, Zurakowski D, Anderson RR. Selective cryolysis: a nivel method of noninvasive fat removal. Lasers Surg Med 2008;40:595–604.

6)     Avram MM, Harry RS. Cryolipolysis for subcutaneous fat layer reduction. Lasers Surg Med. 2009 Dec;41(10):703-8. Review. PubMed PMID: 20014262.

7)     Zelickson B, Egbert BM, Preciado J, Allison J, Springer K, Rhoades RW, Manstein D. Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model. Dermatol Surg. 2009 Oct;35(10):1462-70. Epub 2009 Jul 13. PubMed PMID: 19614940.

8)     Coleman SR, Sachdeva K, Egbert BM, Preciado J, Allison J. Clinical efficacy of noninvasive cryolipolysis and its effects on peripheral nerves. Aesthetic Plast Surg. 2009 ul;33(4):482-8. Epub 2009 Mar 19. PubMed PMID: 19296153.

9)     Fahy GM, Wowk B, Wu J, Phan J, Rasch C, Chang A, Zendejas E. Cryopreservation of organs by vitrification: perspectives and recent advances. Cryobiology. 2004 Apr;48(2):157-78.

Meta-research and medical skepticism

The Atlantic features an important article about “meta-researcher” Athina Tatsioni, who has published a number of influential papers about the quality of biomedical research:

He and his team have shown, again and again, and in many different ways, that much of what biomedical researchers conclude in published studies—conclusions that doctors keep in mind when they prescribe antibiotics or blood-pressure medication, or when they advise us to consume more fiber or less meat, or when they recommend surgery for heart disease or back pain—is misleading, exaggerated, and often flat-out wrong. He charges that as much as 90 percent of the published medical information that doctors rely on is flawed. His work has been widely accepted by the medical community; it has been published in the field’s top journals, where it is heavily cited; and he is a big draw at conferences…

He chose to publish one paper, fittingly, in the online journal PLoS Medicine, which is committed to running any methodologically sound article without regard to how “interesting” the results may be. In the paper, Ioannidis laid out a detailed mathematical proof that, assuming modest levels of researcher bias, typically imperfect research techniques, and the well-known tendency to focus on exciting rather than highly plausible theories, researchers will come up with wrong findings most of the time. Simply put, if you’re attracted to ideas that have a good chance of being wrong, and if you’re motivated to prove them right, and if you have a little wiggle room in how you assemble the evidence, you’ll probably succeed in proving wrong theories right.

This raises a number of important issues from a life extension perspective. For starters, these findings reinforce that it is just not credible for mainstream researchers and medical professionals to sustain these arrogant attitudes towards serious research efforts in life extension and cryonics. Good research is hard to do, and there is little of it.  This applies particularly to research that translates into meaningful medical benefits.  It  may be hard to swallow that a lot of  what constitutes conventional medicine is based on flawed studies and interest-driven research, but there is no escaping this conclusion.

Having a strong interest in the results is a double-edged sword. On the one hand, it makes one more susceptible to bias and cherry-picking. On the other hand, it can produce a determined mindset to tackle ambitious research goals (rejuvenation, vitrification). For example, the breakthroughs in vitrification technology at a company like 21st Century Medicine would have been unthinkable if the principal researchers would not have had an enduring strong personal interest in the technologies they are researching. This phenomenon can  also throw some light on the observation that often committed amateurs have more knowledge than professional researchers. Academic researchers often move from one (grant-funded) fad to another without obtaining a wide and deep understanding of the fields they are investigating. Unfortunately, such fashionable researchers are often featured in the media as “experts.”

Athina Tatsioni’s findings should also have a sobering effect on those who think we are in a period of accelerating medical progress. Even the  more credible medical research often fails to contribute to the expected clinical breakthroughs. To those familiar with the complex biochemistry of life, and the opportunity to introduce (long term) side-effects along with beneficial interventions (including attempts to just “repair” something), this should not be a surprise.

Naturally, Athina Tatsioni does not have a high opinion on research that claims benefits for vitamins and supplements:

For starters, he explains, the odds are that in any large database of many nutritional and health factors, there will be a few apparent connections that are in fact merely flukes, not real health effects—it’s a bit like combing through long, random strings of letters and claiming there’s an important message in any words that happen to turn up. But even if a study managed to highlight a genuine health connection to some nutrient, you’re unlikely to benefit much from taking more of it, because we consume thousands of nutrients that act together as a sort of network, and changing intake of just one of them is bound to cause ripples throughout the network that are far too complex for these studies to detect, and that may be as likely to harm you as help you. Even if changing that one factor does bring on the claimed improvement, there’s still a good chance that it won’t do you much good in the long run, because these studies rarely go on long enough to track the decades-long course of disease and ultimately death.

The take-home message is that skepticism is a useful disposition when looking at all research, medical practice, and triumphant claims about accelerating technological progress. One advantage of those who have made cryonics arrangements have is that they have time and, in theory (!), should be less prone to wishful thinking and jumping on the latest bandwagon. As Michael Anissimov writes, “When I talk to older transhumanists that are into cryonics, I see people who are psychologically calmer than those who endlessly obsess over their food, questionable supplements, and other minutiae that will mean jack squat if they get into a simple car accident.” It also reinforces the approach of arguing in favor of cryonics using skeptical arguments (about our arbitrary and evolving concepts of death)  instead of making bold claims about existing and future science.

Further reading: John P. A. Ioannidis – Why Most Published Research Findings Are False.

Ben Best on nuclear DNA damage and aging

The June 2009 issue of Rejuvenation Research features an article by Cryonics Insitute President Ben Best about the involvement of nuclear DNA damage in the aging process:

Abstract

This paper presents evidence that damage to nuclear DNA (nDNA) is a direct cause of aging in addition to the effects of nDNA damage on cancer, apoptosis, and cellular senescence. Many studies show significant nDNA damage with age, associated with declining nDNA repair, and this evidence for the decline of nDNA repair with age is also reviewed. Mammalian lifespans correlate with the effectiveness of nDNA repair. The most severe forms of accelerated aging disease in humans are due to nDNA repair defects, and many of these diseases do not exhibit increased cancer incidence. High rates of cellular senescence and apoptosis due to high rates of nDNA damage are apparently the main cause of the elderly phenotype in these diseases. Transgenic mice with high rates of cellular senescence and apoptosis exhibit an elderly phenotype, whereas some strains with low rates of cellular senescence and apoptosis show extended lifespan. Age-associated increases of nDNA damage in the brain may be problematic for rejuvenation because neurons may be difficult to replace and artificial nDNA repair could be difficult.

HT Longevity Meme

CPR and the breath of death?

And the Lord God formed man of the dust of the ground, and breathed into his nostrils the breath of life; and man became a living soul. Genesis 2:7

For breath is life, and if you breathe well you will live long on earth.  – Sanskrit Proverb

breath1

In the Beginning…

Since the beginning of modern resuscitation over 40 years ago the sequence of interventions, and to a great extent their importance, has been determined by the ABCs of cardiopulmonary resuscitation (CPR): Airway, Breathing and Circulation. [1] Without breath there is no life and the most obviously and easily detected sign that life is fleeing is the absence of breath. What’s more, in many in whom breathing has newly ceased, simply opening the airway, or giving a single rescue breath will restore spontaneous respiration. We are told that breath is life and there is great truth in this saying.

Negative Pressure Ventilation

The physiology of the vertebrate chest is a truly amazing thing and it can take very bright men years to master its implications. One of the hardest concepts for me to grasp was that under normal conditions the pressure inside the pleural space (the space around the lungs) and the mediastinal spaces (the space that surrounds the heart and the great vessels of the chest) is always negative relative to both the atmospheric pressure and the pressure in the rest of the body (more on this later). [2] In other words, there is always a slight vacuum in those parts of the chest. Mostly this is a result of the fact that we breathe using our diaphragms and the muscles of our chest wall to create a low grade vacuum inside the chest into which air rushes via the trachea to fill our lungs.  When we relax those muscles, the natural elasticity, or recoil of the chest wall and diaphragm acts to squeeze the air out [I], and the cycle is then repeated. We thus breathe by means of negative pressure ventilation.

Naturally enough, when medicine began to try to restore breathing when it had ceased, most of the attempts that were made were attempts to simulate the natural process whereby air is moved in and out of the lungs; principally by negative intrathoracic pressure. [3]

breath2

Above: an illustration of the Silvester method of artificial respiration circa 1880. (Silvester HR., A new method of resuscitating still-born children, and of restoring the persons apparently drowned or dead. BMJ 1858;2:576-9.)

Understandably, trying to mimic the complex action of the diaphragm and accessory muscle of the chest wall in normal negative pressure ventilation were difficult, cumbersome and often ineffective.  By 1959 rescue breathing using the mouth-to-mouth technique had become the mandated medical standard. [4]

There is no question that mouth-to-mouth resuscitation is vastly more effective than the medically endorsed methods that preceded it. What’s more, the class of ventilation to which mouth-to-mouth belongs, intermittent positive pressure ventilation (IPPV), has become essentially the only modality for assisting or replacing breathing in humans.  IPPV long ago displaced negative pressure ventilation (NPV) in the form of the iron lung and the cuirass shortly after polio was vanquished in the 1950s.

Below: Polio patients suffering from respiratory paralysis in iron lungs during an epidemic in the early 1950s.

breathpol

Below: A contemporary cuirass ventilator; this new breed of machines uses a biphasic approach that employs negative pressure on inspiration and positive pressure assisted exhalation. The Hayek biphasic cuirass ventilator is capable of  delivering higher tidal volumes (negative inspiratory tidal volume and positive expiratory tidal volume),  greatly increased frequency of ‘breaths’ from 6 to 1200CPM, and allows control of the inhalation to exhalation ratio without depending upon the passive recoil of the patient’s chest. Courtesy of United Hayek Medical: http://www.unitedhayek.com/products/mrtx

breath3

While IPPV has many advantages over NPV, it is un-physiologic in one way that turns out to be of crucial importance in the setting of CPR. IPPV dramatically reduces the return flow of blood from the body to heart. The physics and physiology of this are complex, and even the shortest and most lucid tutorials run to many pages of text; often studded with equations and difficult to interpret graphs and charts. Among the many reasons IPPV’s effects are so complex in the human with a beating heart is that the body can respond to changes in venous blood flow, ventricular volume, and so on by dynamically adapting; heart rate can be increased, vascular tone can be altered, and even the amount of fluid retained by the body can be altered. [5]

The Danger of Positive Pressure Ventilation in CPR

For the patient in cardiac arrest none of these adaptive changes is possible. That makes discussion of the problems posed by IPPV much simpler, while at the same time making the adverse consequences more serious and potentially life threatening.

To understand why IPPV is so dangerous in the setting of CPR it is necessary to understand the concept of preload. Most simply, preload can be defined as “the load to which a muscle is subjected before shortening.” If this doesn’t leap out at as a point of great significance it is because this definition needs to be understood in connection with a physiological principle named after the two great physiologists who discovered it, the Frank-Starling Law of the Heart [II]. The Frank-Starling law of the heart (also known as Starling’s law or the Frank-Starling mechanism) states that the greater the volume of blood entering the heart during diastole (the period between cardiac contractions or the end-diastolic volume), the greater the volume of blood ejected during systolic contraction (stroke volume). This may seem pretty obvious: what you put into the heart before it contracts determines what you’ll get out of it after contraction is complete. But, as it turns out, this relationship is rather more complex than simple double entry bookkeeping would suggest.

breath4

Above: Frank-Starling Cardiac Function Curve. Courtesy of Wikimedia Commons.

In the diagram above the Y-axis shows the cardiac output and the X-axis shows right atrial pressure. While the above diagram shows only one line, a classic Frank-Starling plot often shows three separate lines, each roughly the same shape, one atop of each other, to illustrate that shifts on the same line indicate a change in preload, while shifts from one line to another indicate a change in afterload or contractility. This allows the cardiac output to be synchronized with the venous return and with the cardiac output; without depending upon external regulation to make changes. For our purposes this diagram does the job in that it shows that the relationship between venous return from the body to the right heart has a powerful effect not only on how much the blood the heart pumps, but also on the efficiency with which it pumps that blood.

As the heart is increasingly loaded with blood it becomes better and better at pumping it out to the body (up to a point) by contracting more forcefully and emptying the cardiac chambers more completely with each heartbeat. However, as the graph also shows, there is a threshold of filling or stretching of the ventricles beyond which further filling, or preload, causes no further improvement in cardiac output and (not shown) ultimately causes a decrease in pumping efficiency with a corresponding decrease in cardiac output.

Special attention needs to be paid to the Y-axis on the graph because the huge change in cardiac output shown on X-axis happens due to a change in right atrial pressure of just 3 mm Hg, or 4.1 cm H20. [6]

breath5

To put this change in right atrial pressure in context it is only necessary to look at the graphic above to realize that a change in pressure of 3-4 mm Hg is the maximum that occurs over the course of the whole respiratory cycle. Even more importantly, as is also illustrated above, is the seeming impossibility that the pressure inside the pleural mediastinal spaces, the latter of which which contains the heart and the great vessels, is always negative throughout the entire respiratory cycle. Put another way, the areas inside the chest that conduct blood away from and back to the heart always operate under a low vacuum: ~ -6.8 cm H2O during the height of inspiration, and ~ -2.0 cm H2O at the end of exhalation. [7] This continuous negative intrathoracic pressure serves to aid venous (and lymphatic) return from the body to the heart and thus to facilitate preload and optimize cardiac output.

By contrast, a quick glance at the graphic below, which is an actual pleural pressure tracing from a patient undergoing mechanical IPPV, shows that the thoracic viscera, including the vena cavae and right heart, are subjected to positive pressures throughout the respiratory cycle which, at their peak, are typically 30 to 40 times higher than those experienced during normal (negative) pressure breathing! In fact, the situation is even worse than it seems at first glance because not only does the intrathoracic pressure never go to zero (let alone to a negative value), it is deliberately kept positive, in this case by about 8 cm H2O. This is done because in the absence of lung expansion under the influence of the intrathoracic vacuum, the alveoli, the small air sacs of the lungs, begin to collapse and stick to each other. Collapsed alveoli are very difficult to re-open and restore ventilation to. Thus, it is necessary to keep them inflated at the end of exhalation by maintaining some positive pressure in the airways. Since this pressure is applied and maintained at the end of a breath (and between breaths) it is called positive end expiratory pressure, or PEEP, for short. [8]

breath6

Intrapleural pressure tracing of a patient with acute respiratory distress syndrome unergoing intermittent positive pressure mechanical ventilation wih a PEEP of 8 cm H2O

The graphic below shows the effect of only 3 cm of H2O PEEP on blood flow from the head and upper body through the superior vena cava (SVC). Just 3 cm H2O of PEEP reduces superior vena cava (SVC) blood flow by 25%! [9]  A patient with a spontaneously beating heart can (and does) usually compensate for this reduction in return blood flow from the body in many ways, none of which are available to the patient in cardiac arrest.

breath7

The effect of a 3cm H2O water change in PEEP on the flow of venous blood returning to the right heart from the upper body via the superior vena cava. [9]

During conventional closed chest CPR, or in the case of the cryonics patient cardiopulmonary support (CPS), the patient experiences truly massive increases in intrathoracic pressure that last longer and reach extremes never seen in IPPV. The largest and most deleterious source of this pressure results from the physical compression of the thoracic contents during the down-stroke of chest compressions. This raises the intrathoracic pressure to between 80 and 110 cm H2O for roughly 50% of the CPR duty cycle – in other words, the pressure inside the chest is about the same as the normal averaged (mean) blood pressure in a healthy adult for half of the time the patient is undergoing CPR/S! Added to this pressure is the additional pressure of IPPV and the PEEP (usually 5 cm H2O) required to keep the small airways open. The effects of these profoundly un-physiologic pressures on the return of venous blood to the heart and consequently on cardiac output during CPR are devastating. [10]

Overcoming Increased Intrathoracic Pressure and Preserving Cardiac Output

Following the development of active compression decompression CPR (ACD-CPR) by Cohen, et al., in 1992  [11] the critical importance of maintaining negative intrathoracic pressure during the decompression phase of the CPR duty cycle has become increasingly understood. [12, 13, 14]  There is a rapidly growing body of both animal and clinical CPR research documenting improved survival and decreased neurological morbidity when the intrathoracic pressure is kept negative during the decompression (release of chest compression) phase of CPR by the use of inspiratory impedance threshold devices, such as the ResQPod, and ACD-CPR. [15, 17, 18]  An instructive video demonstration of how the ResQPod works can be seen at: http://www.advancedcirculatory.com/

breath8

ResQPod impedance threshold device. Courtesy of Advanced Circulatory systems, Inc. http://www.advancedcirculatory.com/

Similarly, there is accumulating evidence that the increased intrathoracic pressure that results from excessive IPPV during CPR dramatically reduces cardiac output (CO) and causes increased morbidity and mortality. [19, 20, 21].

In 2004, Yannopoulos, et al., reported the development of a device which allows for the continuous application of negative intrathoracic pressure by applying controlled suction to the airway. [22] This device combines an ITD with a vacuum source and a negative pressure regulating valve to maintain an intrathoracic vacuum of between 5 to10 mm Hg (6.8 to 13.6 cm H2O), while allowing IPPV to proceed normally. This device, called the intrathoracic pressure regulator (ITPR) allows IPPV to be delivered as needed during ACD-CPR, while maintaining negative intrathoracic pressure when PPV is not being administered. The device effectively restores the intrathoracic space to its natural state as a low negative pressure (vacuum) chamber; increasing venous return from the body and consequently increasing preload and cardiac output. The ITPR also markedly increases coronary perfusion pressure (CPP) [III] while at the same time decreasing intracranial pressure (ICP). In CPR ICP is typically elevated from the basal value of 12-16 mm Hg to 22-30 mm Hg (as the result of pressure transmission by blood in non-valved veins and by transmission of intrathoracic pressure via the cerebrospinal fluid) further compromising already inadequate cerebral perfusion. [23] Reduction of ICP during CPR has been shown to improve both survival and neurological outcome in an animal model of CPR. [24]

Prototype ITPR (Advanced Circulatory Systems, Inc.) in position in a typical bag-vale resuscitator – ET tube set-up.

breath9

The ITPR has been shown to dramatically improve gas exchange, hemodynamics, cardiac output, vital organ perfusion, and short-term survival during ventricular fibrillation (VF) cardiac arrest in a porcine model of sudden cardiac arrest and CPR. [25] The ITPR is able to not only overcome the high intrathoracic pressures associated with CPR (45 to 55 mmHg or ~61 to 75 cmH20 [26]) but to both create and sustain negative intrathoracic pressure (determined indirectly by measuring the ET tube pressure) continuously during prolonged periods of ITPR-CPR, even in the presence of induced hypovolemia. [27]  In hemorrhaged (hypovolemic) pigs, Yannopoulos, et al., were able to sustain CPP at >15 mm Hg (the accepted threshold for successful defibrillation in human sudden cardiac arrest) and the isovolemic VF animals in the study maintained CPP at >25 mm Hg throughout the full 15 minutes of ITPR-CPR. In both groups, the ETCO2 was consistently maintained above 25 mm Hg, and the 1-hour survival was 100%, as contrasted with 10% in control animals receiving AHA standard CPR (P = 0.0001).

By comparison, after 3 minutes of conventional CPR the control animals had a mean coronary perfusion pressure of less than 15 mm Hg and all had developed pseudo-respiratory alkalosis indicative of the ventilation/perfusion mismatch of standard CPR. [28] Blood gases in VF animals were strikingly preserved during ITPR-CPR; paO2, which was 96±2 mm Hg at baseline, was 214±12.37 mm Hg after 10 min and 198±6.75 mm Hg after 15 min of ITPR-CPR. These findings would seem to suggest that ITPR-CPR may be reducing or eliminating the pulmonary edema that accompanies CPR and the high intrathoracic (and thus pulmonary arterial and venous pressures) generated during CPR.  ITPR is similarly effective at improving both hemodynamics and survival in a swine model of severe hypovolemic hypotension. [29]

The Breath of Death?

However, even with the use of the ITPR, each ventilation transiently raises intrathoracic pressure and decreases CO. In the setting of CPR/S it might be said that each breath is potentially a ‘breath of death’ in terms of its impact on perfusion.

In 2007 the author began experimenting with ways to eliminate tidal ventilation during CPR/S using simple mechanical systems to simulate the lungs and thorax. Based on this preliminary work it appears that it will be possible to eliminate tidal ventilations completely while at the same time maintaining a negative intrathoracic pressure during the non-compression portion of the CPR/S duty cycle. This is possible by the simple expedient of connecting the patient’s airway to a regulated vacuum source while at the same time delivering the desired minute volume of ventilating gas to the carina of the trachea. This scheme is illustrated in the schematic below.

breath10

Above: Experimental implementation of continuous negative pressure ventilation in CPR/S. A conventional endotracheal tube is modified by passing a fenestrated suction catheter down the lumen to the level of the carina through a side opening in the tube through which ventilating gas is continuously delivered at the desired minute ventilation volume. Negative intrathoracic pressure and removal of waste gas is achieved by applying continuous, regulated suction to the 15 mm adapter on the end of the ET tube. Movement of gas to and from the distal airways is achieved by the action of the ACD chest compressor-de-compressor operating at 100 cycles/min on the ventral thorax.

Continuous Non-Tidal Negative Pressure Ventilation

A (negative) airway pressure regulator is attached to the 15 mm connector of a modified endotracheal tube. Continuous negative airway pressure is generated by connecting the airway pressure regulator to a vacuum/suction source. Ventilating gas of the desired composition (i.e., oxygen concentration, therapeutic additives, etc.) is continuously delivered to the patient’s lungs by a ventilation gas delivery catheter that can be advanced or withdrawn through the lumen of the ET tube. The ideal position for the ventilation gas delivery catheter is at the point where the trachea bifurcates into the main-stem bronchi; the carina. Movement of the ventilating gas to the distal airways is achieved by the dynamically varying force on the chest resulting from cardiac compressions, with or without  active decompressions. The desired minute volume is determined by the flow rate of ventilating gas delivered to the carina.

In cases where pulmonary edema is preventing adequate gas exchange and it is deemed necessary to apply positive intrathoracic pressure (at the expense of cardiac output) it is easy to do this by adjusting the pressure on the airway pressure regulator to the desired positive pressure setting; as would be done with the application of positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) as is done for the treatment of pulmonary edema by a different means with the Boussignac tube. [30, 31]

breath11

The illustration above shows a possible configuration of a dual-lumen endotracheal tube that would accomplish continuous non-tidal negative pressure ventilation in conjunction with an attached airway pressure control valve.

breath12

Prototype Active Comnpression-Decompression square-wave HLR constructed to the author’s specifications by Michigan Instruments, Inc., of Grand Rapids, MI. The device incorporates a continuous ventilation gas flow meter (red arrow) which allows for delivery of air blended oxygen at the desired oxygen concentration and minute volume.

In 1996 a prototype heart–lung resuscitator capable of delivering non-tidal continuous negative pressure ventilation in conjunction with ACD-square wave-CPR was fabricated by Michigan instruments of Grand Rapids, MI (shown above). Unfortunately, this device was never evaluated in a canine or porcine model of CPR in cardiac arrest. Bench testing with a sophisticated test lung did demonstrate that the unit could deliver adequate minute ventilation while maintaining operator specified negative (or positive) intrathoracic pressure throughout the decompression phase of the CPR/S duty cycle.

If animal research confirms that this mode of ventilation (which is an extension of the ITPR) is both safe and effective it should be possible to apply it to cryonics patients without the years-long wait for regulatory approval. In the case of CPR in the clinical environment, non-tidal continuous negative pressure ventilation using this scheme will likely remain one of the many intriguing and potentially useful ideas in CPR that await another time and place, or perhaps more accurately, a different universe in order to find application.

The End of the Thumper Era?

With clinical advent of ACD-CPR, and the experimental debut of the ITPR and negative intrathoracic pressure CPR delivered via the trachea, it would seem that the days of the Michigan Instruments, Inc. (MII) Thumper CPR devices, which have been the dominant technology used in cryonics transport operations, are over. Despite the very low cost of used Thumper HLRs ($150 to $500 US) the capability of doubling or trebling cardiac output (and sometimes quadrupling cerebral blood flow during CPR) would seem to mandate the expense of either custom fabricated MII equipment, or purchase of a  LUCAS or LUCAS 2 device ($20,000 US).

However, the reality is that the ITPR offers the older generations of conventional CPR machines a new lease on life. The raison d’être for ‘suction cup’ CPR is to create negative intrathoracic pressure by forcefully pulling up on the ventral chest wall between compressions. This method of creating negative intrathoracic pressure was developed as a consequence of the case of a successful resuscitation from cardiac arrest having been carried out by a layman using a lavatory toilet plunger; not as a result of systematic academic or medical laboratory investigation. [32]

It is the principle that is important, and in this case the principle is negative intrathoracic pressure; something that can be applied by surrounding the thorax with a vacuum in a cuirass, or by using a suction cup to decompress the chest wall. Importantly, it can also be accomplished by the ITPR and without the use of complex pneumatic or electromechanical machinery to move a suction cup to and fro. [IV] The ITPR and continuous negative pressure ventilation suggest a number of novel ways that may allow for the continued use of costly first and second generation mechanical CPR equipment – perhaps with even greater efficacy than is possible with the latest generation HLRs. But, alas, that is a subject for another article.

REFERENCES

1) Eisenberg MS., Cardiac Arrest. The science and practice of resuscitation medicine. In: Paradis NA, Halperin HR, Nowak RM, editors. The quest to reverse sudden death: a history of cardiopulmonary resuscitation. Baltimore: Williams and Wilkins; 1996.

2) West, JB., Pulmonary Physiology and Pathophysiology, Lippincott Williams & Wilkins, Philadelphia, 2000.

3) Baskett, FF., The Holger Nielsen Method of Artificial Respiration Resuscitation (2007) 74, 403-405.

4) Acierno LJ, Worrell LT., Peter Safar: father of modern cardiopulmonary resuscitation. Clin Cardiol. 2007 Jan;30(1):52-4.

5) Luecke , T, Pelosi, P., Clinical review: Positive end-expiratory pressure and cardiac output. Critical Care 2005, 9:607-621 (DOI 10.1186/cc3877).

6) JE, A.D., Carlson CJ, et al., Continuous positive-pressure ventilation decreases right and left ventricular end diastolic volumes in the dog. Circ Res, 1980. 46: p. 125-132.

7) West, JB., Pulmonary Physiology and Pathophysiology, Lippincott Williams & Wilkins, Philadelphia, 2000.

8) Acosta, E, Varon, S. The Use of Positive End-Expiratory Pressure in Mechanical Ventilation. Critical Care Clinics, Volume 23, Issue 2, Pages 251-261.

9) de Waal, KA, Evans, N. Osborn, DA, Kluckow , K, Cardiorespiratory effects of changes in end expiratory pressure in ventilated newborns. Arch Dis Child Fetal Neonatal Ed 2007;92:F444–F448. doi: 10.1136/adc.2006.103929.

10) Jellinek, H., Krenn, H, Oczenski, W, et al., Influence of positive airway pressure on the pressure gradient for venous return in humans. J Appl Physiol, 2000. 88: p. 926-932.

11)  Cohen, T., Tucker, KJ, Redberg, RF, Lurie, KG, Chin, MC, Dutton, JP, Scheinman, MM., Active compression-decompression resuscitation: a novel method of cardiopulmonary resuscitation. Am Heart J, 1992. 124: p. 1145-50.

12) Jellinek, H., Krenn, H, Oczenski, W, et al., Influence of positive airway pressure on the pressure gradient for venous return in humans. J Appl Physiol, 2000. 88: p. 926-932.

13) Aufderheide, T., Sigurdsson, G, Pirrallo, RG, et al. , Hyperventilation-induced hypotension during cardiopulmonary resuscitation. Circulation, 2004. 109: p. 1960-1965.

14) Cheifetz, I., Craig, DM, Quick, G, et al., Increasing tidal volumes and pulmonary overdistention adversely affect pulmonary vascular mechanics and cardiac output in a pediatric swine model. Crit Care Med, 1998. 26: p. 710-716.

15) Cabrini, L., Beccaria, P, Landoni, G, Biondi-Zoccai, GG, Sheiban, I, Cristofolini, M, Fochi, O, Maj, G, Zangrillo, A., Impact of impedance threshold devices on cardiopulmonary resuscitation: a systematic review and meta-analysis of randomized controlled studies. Crit Care Med, 2008. 36: p. 1625-32.

16) Plaisance, P., Lurie, K, Payen, D., Inspiratory impedance during active compression decompression cardiopulmonary resuscitation: a randomized evaluation in patients in cardiac arrest. . Circulation, 2000. 10: p. 989-994.

17) Wolcke, B., Mauer, DK, Schoefmann, MF, Teichmann, H, Provo, TA, Lindner. KH, Dick WF, Aeppli D, Lurie KG., Comparison of standard cardiopulmonary resuscitation versus the combination of active compression-decompression cardiopulmonary resuscitation and an inspiratory threshold device for out-of-hospital cardiac arrest. Circulation, 2003. 108: p. 2201-2205.

18)  Lurie, K., Voelckel, W, Plaisance, P, et al., Use of an inspiratory impedance threshold valve during cardiopulmonary resuscitation: A progress report. Resuscitation, 2000. 44: p. 219-30.

19) O’Neil, J., Deakin, CD., Do we hyperventilate cardiac arrest patients? Resuscitation, 2007. 73: p. 82-85.

20) Chandra, N.C., et al., Observations of hemodynamics during human cardiopulmonary resuscitation. Crit Care Med, 1990. 18: p. 929-34.

21) Aufderheide, T., Lurie, KG., Death by hyperventilation: A common and life-threatening problem during cardiopulmonary resuscitation. Crit Care Med, 2004. 32(No. 9 (Suppl.)): p. S345–S351.

22) Yannopoulos, D., Nadkarni, VM, McKnite, SH, Rao, A, Kruger, K, Metzger, J, Benditt, D, Lurie,KJ., Intrathoracic pressure regulator during continuous-chest-compression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest. Circulation, 2005. 112: p. 803-81.

23) Guerci, A., Shi, AY, Levin, H, Tsitlik, J, Weisfeldt, ML, Chandra, N., Transmission of Intrathoracic Pressure to the Intracranial Space during Cardiopulmonary Resuscitation in Dogs. Circ Res, 1985. 56: p. 20-30.

24) Srinivasana, V., Nadkarnia, VA, Yannopoulosb, D, Marinoa, BS, Sigurdssonc, G,  McKnitec, SH, Zookc, M, Bendittc, DG, Lurie, KG., Spontaneous gasping decreases intracranial pressure and improves cerebral perfusion in a pig model of ventricular fibrillation. Resuscitation, 2006. 69: p. 329-334

25) Yannopoulos, D., Nadkarni, VM, McKnite, SH, Rao, A, Kruger, K, Metzger, J, Benditt, D, Lurie,KJ., Intrathoracic pressure regulator during continuous-chest-compression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest. Circulation, 2005. 112: p. 803-81.

26) Chandra, N.C., et al., Observations of hemodynamics during human cardiopulmonary resuscitation. Crit Care Med, 1990. 18: p. 929-34.

27) Lurie, K., Zielinski, T, Voelckel, W, et al., Augmentation of ventricular preload during treatment of cardiovascular collapse and cardiac arrest. Crit Care Med 2002. 30: p. (Suppl):S162-5.

28) Weil, M., Rackow, EC, Trevino, R, Grundler, W, Falk, JL, Griffel, MI., Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med, 1986. 315: p. 153-156.

29) Sigurdsson, G., Yannopoulos, D, McKnite, S, et al., Lowering of intrathoracic pressure improves blood pressure and survival rates in a porcine model of hemorrhagic shock. Resuscitation, 2006. 68: p. 399-404.

30) Srinivasana, V., Nadkarnia, VA, Yannopoulosb, D, Marinoa, BS, Sigurdssonc, G,  McKnitec, SH, Zookc, M, Bendittc, DG, Lurie, KG., Spontaneous gasping decreases intracranial pressure and improves cerebral perfusion in a pig model of ventricular fibrillation. Resuscitation, 2006. 69: p. 329-334.

31) Weil, M., Rackow, EC, Trevino, R, Grundler, W, Falk, JL, Griffel, MI., Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med, 1986. 315: p. 153-156.

32) Leman P, Greene S, Whelan K, Legassick T., Simple lightweight disposable continuous positive airways pressure mask to effectively treat acute pulmonary oedema: Randomized controlled trial. Emergency Medicine Australasia, 2005. 17 p. 224 – 230.

33) Templier F, Dolveck F, Baer M, Chauvin M, Fletcher D., ‘Boussignac’ continuous positive airway pressure system: practical use in a prehospital medical care unit. Eur J Emerg Med, 2003. 10 P.87-93.

34) Malzer R, Zeiner A, Binder M, Domanovits H, Knappitsch G, Sterz F., Laggner AN. Hemodynamic effects of active compression-decompession after prolonged CPR Resuscitation, Volume 31, Issue 3, Pages 243-253


[I] While most exhalations are passive and do not require muscular  assistance, we do sigh, cough and sometimes forcibly assist air out of our lungs and these instances of assisted exhalation are important to health.

[II] The German Otto Frank and Briton Ernest Starling.

[III] In the setting of resuscitation from cardiac arrest as opposed to CPS in cryonics Transports, the  coronary perfusion pressure during CPR  is the single most important predictor of successful defibrillation and thus of successful  resuscitation.

[IV] It is important to note that this applies only in situations where the chest still possesses its basic structural integrity. In cases of rib fracture or ‘flail chest’ where the thorax has lost its rigidity, only ACD-CPR or the application of an integrated chest compressor and cuirass device would be effective in generating blood flow.

Buried alive?

According to this news item the Alcor Life Extension Foundation is taking legal action against the brother and sister of an Alcor member who “denied the foundation’s request for his body and didn’t notify them of their brother’s death until months after he was buried.” Although some may question the wisdom of pursuing this case in light of the current condition of this Alcor member, Alcor is honoring its contract with the member. As Reason points out in this excellent post about the issue:

I can only imagine that the lawsuit is being undertaken as a point of principle and for the purposes of education: don’t break contracts with Alcor or this will happen….Switching around a family member’s post-mortem arrangements is little different from bullying and controlling folk who are too old and frail to defend themselves. In the case of acting to prevent cryopreservation that was organized and chosen by the deceased, it becomes something like fractional murder: removing that person’s shot at whatever the unknown probability of future revival happens to be.

Spouses and relatives of an Alcor member should not feel confident that if they hide the death of an Alcor member long enough to make cryopreservation no longer meaningful or practical that the cryonics organization will just give up and refrain from pursuing the case. There have been too many cases where hostile, greedy, or indifferent relatives have frustrated the wishes of a person who wants to be cryopreserved. Cryonics organizations should not even give the semblance that this is something they let people get away with. Alcor is to be commended for fighting back and honoring this member’s wishes, even in the most miserable of circumstances.

This episode should be another important wake-up call for potential and existing members of cryonics organizations. There are various  ways situations such as these can be minimized and we should start thinking about them. Most of all, cryonics members should execute living wills that rule out scenarios where greedy relatives will benefit from the patient not being cryopreserved. Furthermore, cryonics members should execute a Durable Power of Attorney for Health Care to ensure that the person who is authorized to make medical decisions on the cryonics member’s behalf has a strong commitment to honoring this person’s wish to be cryopreserved. This often will require giving this authority not to the person who is closest to you but to the person who  is most knowledgeable and respectful of  your cryonics arrangements (such as a long time friend with cryonics arrangements). Last, but not least, cryonics organizations should further expand their methods of determining high risk cases and improve communication with existing members. Although it is not possible, nor reasonable, to expect from cryonics organizations that they can avoid scenarios such as these in every single case, there is an urgent need to beef up membership tracking and response capabilities.

Cryonics organizations are in a delicate situation. We expect them to fight for each of their members without putting existing patients at risk. One solution that has been pursued in the past, and may have to be revived again, is to separate the service delivery aspect of cryonics from long term patient care. If such changes would allow more aggressive action on behalf of existing members with no, or decreased, risk for existing patients, such changes should be pursued.

The red blood cell as a model for cryoprotectant toxicity

Various approaches are available to investigate cryoprotectant toxicity, ranging from theoretical work in organic chemistry to  cryopreservation of complete animals. Because resuscitation of complex organisms after cryopreservation is not feasible at the moment, such investigations need to be confined to viability assays of individual cells and tissues or ultrastructural  studies.

One simple model that allows for “high throughput” investigations of cryoprotectant toxicity are red blood cells (erythrocytes). Although the toxic effects of various cryoprotective agents may differ between red blood cells, other cells, and organized tissues, positive results in a red blood cell model can be considered the first experimental hurdle that needs to be cleared before the agent is considered for testing in other models.  Because red blood cells are widely available for research, this model eliminates the need for animal experiments for initial studies. It also allows researchers to investigate human cells. Other advantages include the reduced complexity of the model  (packed red blood cells can be obtained as an off-the-shelf product) and lower costs.

Red bloods cells can be subjected to a number of different tests after exposing them to  a cryoprotective agent. The most basic test is gross observation of the red blood cells in a cryoprotectant solution. When high concentrations of a cryoprotectant are used (such as in vitrification), a stepwise approach is necessary to avoid  osmotic  injury. If a cryoprotectant solution is extremely toxic rapid hemolysis will follow, which often can be observed by a noticeable change of the color of the solution,  red cell debris sinking to the bottom of the test tube, or negligible difference between the pellet (if there is one at all) and the supernatant after centrifugation. But if the researcher is interested in agents that are not extremely toxic, or wants to compare variants of  similar agents with each other, quantitative methods and detailed observations are required using respectively spectrophotometry and light microscopy.

In 1996, Bakaltcheva et al. used the red blood cell model for an elegant and thoughtful study  of cryoprotective toxicity. The authors did not only use spectrophotometry to measure hemolysis  but also used microscopy to study the morphology of the red blood cell after exposure to various agents at different temperatures. The results of these different measurements were in turn correlated with each other in order to determine if there are general properties  affecting cryoprotectant toxicity. The authors propose that reduced toxicity can be achieved by keeping the dialectric constant of the medium and membrane close to that of an aqueous solution without solutes.  These findings can also explain why cryoprotective mixtures  of various agents (such as DMSO and formamide) can reduce toxicity.  A general rule of thumb for formulating vitrification agents with reduced toxicity seems to be to maintain most properties of water but eliminating the posibility of ice formation. It should not be a surprise that such an approach has guided the choice of solvents in areas such as cryoenzymology.

The healthy skeptic

Consumers are constantly bombarded with advice about health. Lower your cholesterol, avoid carbs, take dietary supplements, avoid Teflon, get a full body scan, etc. Such advice does not fall on deaf ears. Who does not want to remain healthy, look good, and extend life? Two other factors contribute to our eagerness to consume and follow health advice. First, the accelerating growth of knowledge in fields such as biology and biochemistry. Second, a reasonable assumption that if some chemicals and behaviors can harm us,  there must be chemicals and changes in behavior that can confer great benefits.

The role science plays in contemporary thinking about health is a double edged sword. On the one hand, it can be used to debunk grandiose claims about health by subjecting these claims to rigorous scientific investigation. On the other hand, the authority of  scientists can can be abused to support products or lifestyle changes for which there is little evidence. For many people and journalists, the phrase that “research proves” something is often enough to act on health recommendations, regardless of the nature and quality of the evidence. But it does make a lot of difference whether “research proves” means a small number of experiments in a test tube or a multi-country randomized human trial.

And that is where Robert J. Davis’ book The Healthy Skeptic: Cutting through the Hype about Your Health comes into play. What makes Davis’ book stand out over other books debunking contemporary health claims is that he gives the reader a set of solid guidelines to evaluate scientific statements about health in general. Another major strength is that the author does not single out one group of health hustlers but argues quite persuasively that misinformation about health is not confined to pharmaceutical companies or sellers of dietary supplements, but is rampant among government, non-profit organizations, and consumer activists as well. For example, as  the author writes about consumer activists:

Simply because they’re looking out for our welfare doesn’t necessarily mean that the public interest groups always tell us the truth. Rather than helping us, they can sometimes cause harm by frightening us unnecessarily and diverting our attention from risks that are far more important. As healthy skeptics, we need to apply the same scrutiny to their advice as we give to that from the industry-funded groups or anyone else.

The most “timeless” aspect of the book is the chapter where the author discusses the use and abuse of science in health. Before drawing our wallet or changing our diet, we can ask ourselves the following eight questions:

1. What kind of study is it (laboratory research, short-term human studies, randomized clinical trials etc.)
2. How big is the effect?
3. Could the findings be a fluke?
4. Who was studied?
5. Is there a good explanation?
6. Who paid for the research?
7. Was it peer reviewed?
8.  How does it square with other studies?

As should be clear from those questions, behind the phrase “research proves” are many shades of grey. As the author points out, the question of how a study squares with other studies is perhaps the most crucial question. There is so much (poor) research being published that almost any claim about health can be supported by scientific studies. Sellers of dietary supplements often exploit this by presenting only studies that “support” their recommendations. If health advice does not come with qualifications and/or opposing research conclusions are not mentioned at all, one should be very wary.

Perhaps the most important chapters for life extentionists are those on dietary supplements and “anti-aging doctors.” Davis gives a number of useful recommendations to evaluate claims about supplements:

– Verify “clinically proven” claims
– Don’t assume that “natural” means safe
– Be skeptical of claims that a souped-up or specifically targeted vitamin or mineral supplement is better than an ordinary one
– Don’t be swayed by weasel words (such as “maintains heart health” or “provides immune support”)
– Be wary of organizations or individuals who provide information about supplements and also sell them

When all is said and done, the book does not recommend any radical interventions to improve health or prolong life and sticks to the usual recommendations (don’t smoke, exercise, moderation in eating and drinking, etc.) This is not because of cynicism, but because the more radical claims are just not backed up by contemporary science.

Life extensionists and futurists may believe that they are mostly immune to wishful thinking and the marketing of snake oil but  they may be less immune to more subtle psychological (deadly) traps such as the belief that “this time, things are different,” or the naive assumption that all problems can be solved, given enough time and knowledge. Although progress in science can benefit from scientists that are committed to achieve  important goals like increasing the maximum life span or even defeating death altogether, in reality it is often hard to tell the difference between being motivated by such desires and simply assuming that they will be satisfied, and thus crossing the line into meliorist dogmatic belief.

An interview with the author can be found on the Amazon page for the book.

Robert Freitas discusses the future of nanomedicine

Nanotechnology idea-man Robert Freitas, Jr. has published an article in the January 2009 issue of Life Extension Magazine providing a tutorial in nanomedicine and documenting its progression toward real-world application.

In “Nanotechnology and Radically Extended Life Span,” Freitas describes several theoretical medical nanorobots, such as the microbiovore, which would “act like an artificial mechanical white cell, seeking out and digesting unwanted pathogens including bacteria, viruses, or fungi in the bloodstream.” In addition to fighting infection, medical nanorobots could invigorate old or diseased cells by replacing chromosomes with fresh new ones, correcting the cellular damage and mutations that lead to aging.

Freitas and colleagues have performed many analyses and simulations of the types of technologies and tools that will be necessary to create these nanoscale medical robots, filing two patents for the mechanosynthesis of nanorobots. Together with Ralph Merkle, Freitas founded the Nanofactory Collaboration to “coordinate a combined experimental and theoretical R&D program to design and build the first working diamandoid nanofactory.” This effort has involved many collaborations with researchers from nine different organizations and four countries, and has resulted in a dozen academic articles.

Now Freitas is eager to test his theories with the help of scanning probe microscopist Philip Moriarty, who is attempting to build several of Freitas’ mechanosynthesis tooltips. Presumably, the creation of working tooltips will lead directly to their intended purpose: the creation of nanorobots. Freitas hopes to manufacture medical nanorobots that can contribute to radical life extension therapies by the 2020s.

Of course, most cryonicists are of the opinion that nanotechnological interventions will be necessary for the reversal of aging and disease in cryopreserved patients. As we move closer to reversible cryopreservation with improved stabilization protocol and cryoprotectant solutions, perhaps the maturation of nanomedicine and cryonics will coincide.

In the past Alcor has supported Freitas’ work at the expense of supporting research that could improve the quality of its cryopreservation procedures for existing members. It is therefore encouraging to learn that the Life Extension Foundation has contributed money to support Freitas’ work on nanomedicine.

Gender differences in stroke treatment and prevention

Over the years, experimental science has developed a standard protocol for the testing of medical hypotheses using animal models which calls for the use of males only. Why? Because no laboratory scientist wants to deal with those pesky female hormones. Female hormone fluctuations are viewed as just another variable to be controlled (generally by excluding females altogether) — all the better for making interpretation of results simple and straightforward.

But, as common sense might dictate, it turns out that results from male-only animal models often give a less-than-accurate view of the whole picture when this research is translated and applied to treatment of disease in humans. Why? Because, as most people without a doctorate in physiology can tell you, physiological gender differences exist. Is it any surprise, then, that disease treatment and prevention should also be prescribed with these physiological differences in mind?

And so the buzz for the past few years in the medical community is the astonishing fact that stroke treatment and prevention are not the same in men and women. In labs that have recently begun to investigate these differences, drugs that were found to protect male brains against stroke in animal models did nothing to protect female brains. The major message behind all this press: doctors cannot continue to apply one-size-fits-all prescriptions for stroke prevention and treatment.

The real fact is that it is even more complicated than a “simple” physiological difference. Traditionally, cardiovascular disease has been viewed as a “man’s disease” (men have about a 19 percent greater chance of stroke than women). Accordingly, studies have found that women are less likely to receive prescriptions for blood pressure medications or be advised to take aspirin, both of which have been shown to reduce stroke risk. Strangely, women are less often treated after having a stroke, even though they appear to respond better to acute stroke treatment (such as tissue plasminogen activator) than men. So while men do indeed have more strokes, women are still more likely to die from stroke.

Women are also at increased risk if they take birth control pills, use hormone replacement therapy, have a thick waist and high triglycerides, or are migraine sufferers. And, contrary to anecdotal evidence, women appear to be less likely to go to the hospital at the first sign of stroke symptoms.

Oregon Health and Science University is at the forefront of research into gender differences in medicine, having developed the first research institute of its kind, the OHSU Research Center for Gender-Based Medicine. Given that Oregon recently ranked 46th out of 50 states for incidence of stroke deaths among women (as reported by Making the Grade on Women’s Health: A National and State-by-State Report Card, 2007), there is obviously a need for gender-based medical research to save the lives of women at increased risk of cardiovascular and other disease.