Wednesday, April 4, 2018

The Vampire Approach to Longevity - Young Blood Revives Muscle, Brain & More | Plus: 6+ Less 'Horrific' Alternatives

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You will probably remember from the SuppVersity Facebook news (@SuppVersity | March 15, 2018) that scientists believe that they've found the molecule that's responsible for the rejuvenating effects of "young blood". In their study, which expanded on rodent data indicating that the injection of "young blood", i.e. blood from young mice, into the circulation of old(er) mice has multi-dimensional rejuvenating effects, the researchers grew human muscle cells (C2C12 myoblasts) in a petri dish and stimulated them w/ media conditioned with 5% plasma from healthy male participants that were either younger (n = 6, 18–35) or older (n = 6, >57 years).

What Kalampouka et al. (2018) observed was that the muscle cells reacted differently to a stimulus in form of a scratch (intended to simulate muscular injury and recovery) depending on whether the cultured in media conditioned plasma from younger (18-35 years) or older individuals (>57 years).
This is quite the long article, so you better get your coffee ready ;-)

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Traditionally, experiments like that have been done to establish the effect of individual signaling proteins and/or other endocrine factors on certain biological processes. In the study at hand, the goal was yet not so much to isolate, extract, analyze, recreate, patent and cell one of the growth factors/inhibitors. Rather than that, Kalamouka et al. the put a deliberate focus on the "environmental change" of which they believe that it was the true underpinning of the effects of ageing on muscle function.

While this is an 'innovative' conception that contrasts the (still prevalent) assumption that aging was a process that's completely innate to the tissue, it is by no means new. Eventually, the scientists simply replicated a specific aspect of the rejuvenating magic of what scientists call "parabiosis". The compound word its inventors derived from the Greek words "para" (beside) and "bios" (life) is used to denote states of shared blood supply as they would naturally occur in regular twins or animals that share the same placenta in the womb or conjoined twins, as well as in the laboratory, when scientists knit rats together in a way that allows the blood from one rat to pass through the body of the other (see Figure 1). As Megan Scudellari highlights in her 2015 article
"[...] parabiosis presents a rare opportunity to test what circulating factors in the blood of one animal do when they enter another animal" (Scudellari 2015). 
If we are honest, though, this technology is by no means revolutionary new. In fact, it has been known and used back in the early 21st century already and significant breakthroughs in endocrinology, tumor biology and immunology (Bunster 1933; Coleman 1973; Walker 1973, etc.) depended on it. Against that background, it is quite surprising that for reasons that "are not entirely clear, the technique fell out of favor after the 1970s" (Scudellari 2015) and reappeared on the radar of contemporary researchers only recently. As I pointed out in yesterday's episode of Super Human Radio with Carl Lanore, it is possible that the concept of (ab-)using plasma transfusions (PT) or conjoining animals is perceived to be rather the topic of a science-fiction, dystopian or horror novel than scientific practice.
PRP may be done locally and with a concentrated form of your own (not a younger person's) blood plasma, but the purported mechanism is identical.
Plasma transfusion vs. stem cells - What's the difference? The answer to this question is probably best explained with an example you are more familiar with: Platelet Rich Plasma (PRP) and stem cell treatments as they have been offered in orthepedic practices all around the world for years, now. Both are (local) rejuvenation techniques which are meant to help your ligaments repair and regenerate faster. Even the underlying mechanisms are similar. What? Yeah. The mesenchymal stem cells (MSCs) that are extracted from someone's own fat tissue have the ability to differentiate into multiple lineage pathways, but what kind of cell they'll become depends on the cellular environment and chemical signaling.

The latter, i.e. the signaling part, is fulfilled by cytokines and (growth factors/signaling) proteins in the platelets. It is the specific cocktail of signaling molecules that stimulates stem cells and activates the cellular repair process in the surrounding tissue.

"Ok, I get it, PRP helps with tissue repair and is used for skin rejuvenation, hair growth etc. but that's PRP not the plasma of a 20-year-old fellow human being, wtf!?"

If the above reflects your thoughts accurately, you're obviously right. The plasma transfusions (PT) let alone para-symbiotic treatments (I hope nobody ever tries that on human beings) are not identical with either PRP or stem cell therapy, but the underlying processes are identical. You get what supplement vendors would label "the full spectrum of rejuvenating signaling molecules" albeit (and that's not as marketable) not from your own blood, but rather from the blood of human specimen with fewer years of wear and tear on their scalp/hairline, their facial skin, their tendons, and and all the other body parts/organs (see illustration) where PRP is currently being used for "medical" purposes in beauty clinics - ah, and as gross as it may seem to be injected with someone else's plasma logic alone (and the papers discussed in this article) suggest that - disregarding potential side effects that are beyond the scope of this article - you're better off with the growth factor + signaling molecule mix from a younger + healthier individual than you'd be with the reinjection of a more concentrated version of the cocktail you already have in your blood.
A more likely explanation for the transient disinterest in this line of research is the success scientists have had with the isolationist approach to drug development. If you have identified an individual substance as a drug candidate for the treatment of a given disease that's obviously of much greater interest for the pharmaceutical industry that's sponsoring your research than the creepy and impractical concept of collecting human plasma from young donors to rejuvenate clients via [comparably] complex and expensive plasma transfusions (PT).

Where the isolationist approach to drug development fails, plasma transfusions may succeed

Since what I've previously labeled as "the isiolationist approach to drug development" has been hitting walls for years now, scientists have started turning back to the good old Frankenstein + Dracula methods to find a cure for life-threatening diseases such as cancer and Alzheimer's and the fountain of youth. As part of modern cancer-, (anti-)aging and auto-immune research parabiotic experiments have thus gotten more scientific and, due to their nature and promising initial results, public attention. Within the past decade, only, pertinent studies observed...
Figure 1: Schematic depicting the parabiotic pairings in Villeda 2014; a treatment that's obviously far more invasive than a blood transfusion.
  • the regeneration of the myelin sheath that's defective in MS patients in mice (Ruck 2012), 
  • the successful treatment of murine auto-immune cholangitis (inflamed bile ducts | Yang 2016),
  • the reversal of age-related cognitive impairments in mice (Villeda 2014),
  • the vascular and neurogenic rejuvenation of the aging mouse brain (Katsimpardi 2014),
  • kidney-specific anti-aging effects of young blood in mice (Huang 2017), and ...
  • substantial insights into the aging immune system in heterochronic (see Figure 1, right) rodent-models (Davies 2015).
Be warned, though, in some, but not all of the studies, the things the scientists did to their hairy subjects were far worse than what you'll see in your average vampire flick or even the "medical treatments" in the TV show "The 100" where the inhabitants of an old bunker depend on the blood of the young, radiation adapted protagonists and their peers.
Figure 2: Katsimpardi et al. (2014) saw a significant restoration of the blood vessel volume (left) and cerebral blood flow (right) in the SVZ region of the old (O) mice, when they were in parabiosis with young (Y) mice (i.e. young+old mice that share one circulatory system); since baseline data from the young mice is missing, it is not possible to answer the question from the podcast, i.e. whether the young mice in a heterochronic parabiotic pair will age faster.
Both, Katsimpardi et al (2014 | Figure 2) and Yang et al., for example, didn't just inject the sick mice with the blood of healthy peers, just as it was common practice in the early days of this research, they literally knit the mice together (see Figure 1) so that they would share a common circulatory system.

You don't want to be together with someone else? Don't worry.

Calm down, scientists believe and have actually shown that similar benefits as they occur when you actually join the two organisms may be achieved by the transfusion of blood plasma or specific bloodborne factors from young humans to older ones. In that, it is only logical that rejuvenation of the human brain and body being one of the applications that receive the most attention (Musiek 2014), the previously hinted at profane benefits of PRP therapies such as a younger skin, regrowing scalp hair etc. are yet probably as marketable "side effects" of the treatment ;-)
Ambrosia LLC has been running a pilot study. Data acquisition has ended only in Jan 2018, though. So don't expect published data before the end of 2018 (very optimistic estimate).
Will the Thiels and Trumps of this world live forever, while the rest of us perish? Shortly after the publication of the previously cited study by Katsimpardi et al., people began to voice concern about ethical issues. In her "in-depth" article in "Nature", Jocelyn Kaiser writes that - over all the excitement over the latest research results - people tend to overlook that "there's a big caveat" - a financial caveat worth $8,000-$10,000 per treatment. The latter is what the company, Ambrosia, currently to charges participants for a one-time treatment with 1l or 2l of "young blood", respectively... needless to say that logic (and the fact that all this originated from parabiosis studies, in which the blood is constantly rejuvenated) dictate that you would have to repeat this procedure in pretty short intervals. Even the generous assumption that you'd have to undergo the two-day treatment (I know vampires are faster ;-) only every-other-week puts a $208,000-$260,000 price-tag on a treatment that is as of yet "experimentally".

With the promise of having found the fountain of youth "Ambrosia" has convinced 600 clients to participate in a "study". Since data the collection for the study has ended only recently, we don't know much about these people, but their medium age supposedly gravitates towards 60 years and their sex is almost exclusively male. Some alleged early results that transpired - probably via investors or other players on the finance market - say that the scientists who are running the start-up observed a significant decreases (ca. -20%) of the levels of carcino-embryonic antigens and amyloids - both supposedly causally involved in the growth of cancer and progression of Alzheimer’s disease, respectively. Even if this figure is accurate, though, it cannot tell us whether the plasma transfusions (PT) will actually allow the wealthy clients of Ambrosia to "buy" a significant number of extra-years on earth... or, as the Stanford neuroscientist Tony Wyss-Coray says in an interview: "There's just no clinical evidence [that the treatment will be beneficial] and you're basically abusing people's trust and the public excitement around this".
I guess that's also why it wasn't very difficult for the scientists who founded the start-up "Ambrosia" to find 800 participants for what they label as a pilot trial. Unfortunately, the results of the trial [clinicaltrials.gov (NCT02803554)] are not yet available, which is understandable because Ambrosia LLC has been collecting data until recently (i.e. January 15, 2018). That data analysis, peer-review, and publication will take some time should be obvious and is not a sign of scientific malpractice (rather the opposite). Eventually, we will thus simply have to wait patiently ... I guess at least until early next year for more information.

Despite any pilot studies: No long-term study = no real-world results

Whatever the results of the pilot study may be, there's one thing you should be aware of: the description of trial NCT02803554  suggests that the scientists assessed the 1-months response to a single treatment with 1.5l of "young plasma". Why's that interesting? Well, while it may be true that a single treatment will trigger measurable improvements within 1 month, it is not realistic to assume that those will last "forever". In other words, it is highly unlikely that you can buy 10, 5 or even as little as 1 healthy extra-year on earth for just 8,000-$10,000, which is the current costs of a single blood plasma transfusion (costs according to the Ambrosia website | effective March 2018).
Figure 3: Protein factors and other molecules that circulate in the blood of a young mouse exert rejuvenating effects on the brain of an old mouse after intravenous delivery (Wyss-Coray 2016). It is those protein factors, not the transfusion of "young blood" that is used to identify them, most researchers are ultimately interested in.
Don't get me wrong, I don't want to imply that the costs of a medical procedure determine its efficacy (the US healthcare system provides sad evidence that money cannot buy health - especially not if it's wasted on useless and expensive, but profitable new drugs and an inefficient health-infrastructure | see Figure 3), but let's face it: The origin of the whole concept of "rejuvenation by transfusion", the previously described parabiosis trials, clearly suggests that a continuous exchange of your "old" with a donor's "young" blood will be necessary to provide long-lasting practically significant effects - if you can get away with intervals, e.g. monthly injections, will thus be one of the most important questions researchers and "young blood vendors" will have to answer.
Figure 5: If science teachers us anything, longevity or I should say maximizing your genetic potential for longevity is all about managing. Managing your body comp, your (healthy) diet, your physical acivity, your sleep, your stress levels and your intake and (ab-)use of alcohol and cigarettes. But hey, don't stress about it that's bad for your health! ;-)
Until these (hopefully then placebo-controlled) long-term trials become available (if they are even done) it will probably take decades and the "vampire approach to longevity" is neither the only nor the most promising technique in the coffins of longevity researchers. Chances are that, by the time those trials are available, other hopefully less expensive anti-aging treatments may be available... and if not, there's still the tried and proven, yet unpopular "healthy lifestyle" of which we may not know exactly what its optimal incarnation is (and it may well be that this varies from one person to the other) but which seems to include:
  • staying normal-weight (better maintaining a healthy body composition)
  • lots of exercise- and non-exercise physical activity, 
  • a whole-foods based low (simple-)sugar diet with a balanced fat intake, 
  • conscious monitoring of both sleep quantity and quality, 
  • effective stress management 
  • refraining from cigarettes completely and limiting your alcohol intake to ≤ 1 glass of wine/d
I know it's disappointing to hear that, but as "boring" as it sounds these are the things that will not just increase your chance to make the most of your genetically determined aging potential, but - even more importantly - to allow you to get there being in good physical and cognitive condition.
Figure 6: A proposed hierarchical model for the effects of calorie restriction on health and longevity (based on animal studies | Most 2017)
Things to keep in mind when reviewing the "starve yourself to a longer life"-literature: While there's no doubt that caloric restriction has an effect on longevity, this effect is (a) probably smaller in humans than in roundworms or rodents, that it has (b) always been observed in animals (on humans) on ad-libitum + crappy diets (Heilbronn 2003), that (c) the former only one out of many potentially life-saving (in the literal sense) lifestyle factor that have not been taken into account in the pertinent research, and that (d) it rarely takes into account that significant reductions in energy intake will (and that's proven) comes with side-effects such as reduced fertility (Greer 2009).
In this context, it is also worth mentioning that it is as of yet unknown whether and to which extent chronic reductions in energy intake, as they have (a) been observed in people with exceptional longevity whose diets are often below what you'd expect them to eat based on their body weight and activity levels (Rajpathak 2011) and (b) been confirmed in animal models ranging from roundworms to rodents, actually work in human beings - and, more importantly, to which extent they are able to prolong your life (% or total number of years) without compromising our quality of life is completely unknown as of yet (Heilbronn 2003, Most 2017).
Figure 7: Differential effects of long-term caloric restriction in rodents, non-human primates and (expected effects) in non-obese humans.; (1) total energy expenditure relative to lean mass (Heilbronn 2003).
In spite of the fact that the basic effects of "starving" will be the same in humans (see Figure 7), we cannot expect that "starving yourself" is going to prolong the human lifespan by the same impressive ~42-50% Greer et al. (2009) calculated based on dietary deprivation studies in roundworms or the still desirable ~30% reported by Bartke et al. (2001) for regular mice. Both are - almost certainly - out of reach.  As far as a specific number is concerned, though, I will follow the example of the researchers on whose work I base my assumption and refrain from doubtful guessing... the same goes for the benefits of intermittent energy restriction/fasting, by the way: yes, it looks as if it should provide similar benefits, but there's too little data to recommend any of its various incarnations (16/24 hours, every-other-day, 2/5 days, 2/4 weeks fasting, etc.) as scientifically proven anti-aging tools - as one component of a healthy lifestyle, on the other hand, all the different regimen have been shown to have tangible benefits.
Figure 8: Dave Carpenter nailed it with this cartoon about how most of us feel about leading a 'healthy lifestyle' when he drew this one (Cartoonstock)
So what? Stick to what's definitely working: Commit to a 'healthy lifestyle'. I've already pointed out at the end of the main part of this article that the term 'healthy lifestyle', which is used inflationary and in the absence of a globally accepted standard, has five components you will find in all of its various incarnations: (1) normal body comp., (2) physical activity, (3) diet, (4) sleep, (5) stress management, and (6) the conscious and limited use of drinks and tobacco. Unfortunately, adhering to one, let alone all of the corresponding dos and don'ts is - in the most literary sense - "inhuman". We are great fat storers (1), we are lazy, and programmed to conserve energy (2), feast on energy-dense foods to maximize our energy intake (3), living in a 24/7 work and entertainment world (4), don't understand how stress management works (5), and enjoy (+often depend on) the immediate gratification alcohol, cigarettes & co can provide.

Part of the problem certainly is that we feel overwhelmed when we hear the long list of things we have to or must not do to qualify as someone who's leading a 'healthy lifestyle'. Plus: We are so used to feeling the way we feel that we don't even recognize that we're suffering from brain fog and would, just as the participants in Small et al.'s 2006 study (35-69 year-old average Joes), see significant improvements in our cognitive function and brain metabolism from as little as 14 days of committing to a lifestyle program that combined mental and physical exercise, stress reduction, and a healthy diet.
Figure 9: Meta-analyses show that you can reduce your all-cause mortality risk by whopping 66% if you adhere to more than 5 of the lifestyle factors (obesity, alcohol consumption, smoking, diet, and physical activity | Loef & Wallach 2012)
If you can say "I got all the five previously listed aspects of a healthy lifestyle dialed in" while being honest to your yourself, props to you. You are doing much better than 97% of the American population, of which a 2005 study by Reeves et al. (data used was from 2000) shows that they miss out on one or more aspects and thus fail to collect the 66% reduction in all-cause mortality risk, two German scientists calculated in what is one of the few large-scale meta-analyses of data that's not limited to specific mortality outcomes (Loef & Walach 2012 | see Figure 7 for details).

There are nevertheless two caveats people tend to ignore. Firstly, we're talking about a 66% reduction compared to the worst of the worst, those who are doing practically everything wrong. And, secondly, your genes are almost 2x more important (Khera 2016) for your life-expectancy than your diet, the amount of exercise, the hours you spend on meditation etc. So, it's hopeless? By no means: As I said on SHR (download the podcast if you haven't done so, yet) what you do for your health before you'll be 6 feet underground determines whether you can fully exploit your genetic healthy-aging potential |  Comment on Facebook!
References:
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