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Overweight is a serious risk?????

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Here we go again. The merry go round of nutritional research. According to this research overweight is a serious health threat. This contradicts some of the research recently discussed.


No and No. We've already been around this particular merry-go-round once, if you recall. 


You'll notice from the detailed analysis in that post of the study you reference (PMID: 27423262), the optimal BMI does go up with age. Granted, optimal BMI is only 24 in the elderly, but being thin is as bad for men as being obese: the mortality risk of the 18.5-20 BMI men was almost as high as men with a BMI in the 30-35 range.


Furthermore, you aren't reading or thinking very carefully if you believe this study "contradicts some of the research recently discussed", if by that you mean this discussion of evidence for the obesity paradox that I presented yesterday.


As I pointed out in that analysis, being fatter was associated with an increased prevalence of risk factors like diabetes and high blood pressure - no doubt about it. And those risk factors are associated with increased mortality. But what the data I discussed yesterday was really intended to show was that if you are a metabolically-healthy old person, being obese gives you a lower risk of dying than being thin or even overweight. As I summarized it yesterday (new emphasis):


...being fat in old age is not a disadvantage if you enter old age with a healthy metabolism. In fact a fat and healthy phenotype looks like it might be a distinct advantage relative to being normal weight and healthy in old age.


The distinctions are that:


a) Your study looked at all people, while my analysis (yesterday) focused on metabolically healthy people

b) Your study followed people from middle age, and mine (yesterday) focused on older people


In short, being fat doesn't necessarily increase mortality risk. But if you're fatness is associated with metabolic dysfunction (likely a result of the toxic effects of visceral fat), that's bad news.


Finally, note that both your study and mine observed that being thin stinks when it comes to mortality.



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With due respect I ask if these studies aren't a waste of time and resources? Patience is wearing thinner than my CRed BMI. Stop nutrition science. We get it already: eat a whole foods plant based diet and hit RDAs. Eat food, mostly plants, not too much. Simple enough. Next.

Next is to spend more precious effort focusing on repairing the damages caused by the natural metabolic processes of human bodies. Fix human damage. Not rats. Not mice. Not primates damage or diet: people. Not worms. Not compounds in petrie dishes. Not more met analyses about stupid BMIs.

So You Want to Live Forever? [iNFOGRAPHIC]

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Cool infographic! I've embedded it in your post so everyone can see it easily. 


With due respect I ask if these studies aren't a waste of time and resources? Patience is wearing thinner than my CRed BMI. Stop nutrition science. We get it already: eat a whole foods plant based diet and hit RDAs. Eat food, mostly plants, not too much. Simple enough. Next.


I hear you on the "enough already - eat food, mostly plants, not too much" mantra. Here's you and me Sthira, on the same wavelength:





But it's the "Next" part that gets tricky.


You wrote:

Next is to spend more precious effort focusing on repairing the damages caused by the natural metabolic processes of human bodies.


You say that but even the infographic you post shows this SENS approach of repairing metabolic damage isn't the only game in town, and not everyone agrees the SENS approach makes sense - hence the references to "quackery" at the bottom of the infographic. 


I happen to agree with you, that the SENS approach seems the most promising of the bunch, at least until we get body cloning and that whole head transplant thing worked out, or better yet, mind uploading, also mentioned in your infographic.


But simply saying we're going to clean up the damage is a whole lot easier said than done. Aubrey sometimes draws an appealing analogy between the SENS approach to health and life extension with automotive maintenance and repair. That would be a good analogy, if we had no friggin' idea how cars worked or what fundamentally goes wrong with them. Because that's pretty much where we're at with the human body.


It reminds me of another analogy. After the self-driving car stuff, I worked in R&D at Intel for a few years. I was fortunate to get to visit several Intel Fab facilities around the country, and go inside their clean-room manufacturing facilities wearing one of those bunny suits.


What you soon discover is that Intel chip foundries look remarkably alike. It is no coincidence. Intel pioneered a manufacturing strategy appropriately named Copy Exactly. They found that because of the fragility and exactly standards required for a working end product (computer chips) and because of how incredibly finicky the manufacturing process was, they had to duplicate exactly what was found to work in one factory to make sure it worked, and worked consistently, in another. Intel engineers became incredibly obsessed with the "copy exactly" mantra - all the way down to the color of a worker's gloves, the length of the power cables on tools, and the type of fluorescent lights in the building. Nothing was allowed to vary. And it worked - at least until they stumbled and missed that whole mobile thing...


The moral? The only way Intel could get tiny artifacts (which, BTW, are the size of organelles in the human cells, or receptors on cell surfaces) to work was to make sure they were all identical, and were produced in the exact same way, under incredibly controlled conditions. And if a mistake was made along the way and a chip didn't function properly, you just threw it out - even if that meant wasting millions of dollars worth of wafers with chips etched into them. There was no way you were ever going to figure out exactly what was wrong, to say nothing of figuring out how to fix it. Sure you'd try to do a little diagnostics, but in the end you'd tweak a tiny part of the assembly line and hope that fixed the problem. 


And this was for an artifact we'd designed ourselves and knew exactly how it worked and how every component was supposed to function together. Oh yeah, and that was for an artifact many orders of magnitude less complex than the human body. And one that is sitting motionless and lifeless under a microscope with clearly visible components which are supposed to be wired together in ways we completely understood.


So when you say:

Fix human damage. Not rats. Not mice. Not primates damage or diet: people. Not worms. Not compounds in petrie dishes. Not more met analyses about stupid BMIs. 


I don't think you realize just how optimistic (I hesitate to say naive) that sounds. Aubrey is a good salesman (except for his appearance) with his analogy between repairing a car and the human body. But in actuality, the chasm between the human body and the most complicated artifact humans have ever designed and manufactured is so wide, it's really a pipe dream to think we're going to get any sort of handle on what damage is and how to repair it in the former anytime soon.


But Aubrey has a retort. We don't need to fix all the damage that occurs in the human body all at once. If we can fix a few of the things that cause the most damage first, that should buy us time to fix the more subtle things - leading to "longevity escape velocity". 


The problem with this story is that if it were easy to fix just a couple things and get a significant health / longevity boost as a result, nature would have already done it. Or more accurately, nature would have cut corners on the other, more competent maintenance and repair functions so that the body wasn't wasting resources keeping some parts of the body in good working order when some other part was quickly and inevitably falling apart and would soon kill the organism.


So that's one problem - most bodily systems fail (nearly) simultaneously as a result of many diverse forms of damage, and there isn't any single (or just a few) points of failure, types of damage or key drivers of aging.


The second problem is inherent in the incremental nature of the SENS approach itself. Anyone whose ever worked on a big computer programming project knows this first hand. Sometimes it's better to just throw the whole system out and start from scratch. When you try to tweak one part of a system, particularly a system without documentation and which neither you or anybody understands, there are inevitable unintended side effects, which are often worse than the problem you set out to fix.


That's why we still use 5.25" floppy disks in our nuclear weapons programs, and why we just finished replacing our 40-year old national air traffic control system. Despite the fact that it represented 'only' 2 million lines of code, the new air traffic control system (called En Route Automation Modernization - ERAM) was about a billion dollars over budget ($2.1B total) and delayed by several years.


Ironically it's already obsolete. In fact, the project to replace ERAM, with the Next Generation Air Transportation System, or NextGen, was launched in 2003, and is now projected to not be completed until 2030 at a cost of $32 billion. All for a system to track a few thousand aircraft slowly traversing the relatively open skies of US airspace without running into each other - an infinitely simpler task than fixing all the things that go wrong millions of times per second on a microscopic scale in the human body, while keeping it running the whole time.


Just one tiny example of this problem of unexpected side effects and the complexity of fixing things in biological systems was evident at the recent SENS Rejuvenation Biotechnology conference. Judith Campisi gave a great talk (direct link - she starts at 1:27:45 in this video). She studies senescent cells and what to do about them. She points to evidence that senescent cells all over the body secrete things that do damage to neighboring cells and cause aging. At 1:39:45, she outlines two strategies for preventing this - either prevent them from secreting the junk (e.g. by suppressing that multi-function printer/copier/fax mTOR), or kill them off / clear them out entirely. The drugs that prevent their secretions have many side effects (e.g. rapamycin clobbers the immune system), so she favors killing off senescent cells.


But then she discovered (1:45:39) that senescent cells were critical for wound healing. If you clear out an animals senescent cells (or when subjected to CR for that matter), their wounds don't heal. There is "always an evolutionary tradeoff we're going to have to deal with" (1:46:10). She actually ends on a rather pessimistic note with this slide at the very end showing the world record lifespan extension in different species, and then asks the audience to extrapolate to humans, saying "maybe evolution is telling us something...":





Later in the session (at 2:26:45) Aubrey poses a question to Campisi. If senescent cells are important for wound healing, do we really want to eliminate them entirely? He says "who knows how many more things are we going to find that they are good for." He suggests a different approach to "get the best of both worlds" - keep senescent cells around to do the good things they need to do, and just clean up the bad things they do one step down the line. 


Campisi disagreed. She knows much better than most the multiple negative effects of senescent cell secretions, and isn't optimistic that cleaning up all that damage is  going to be feasible. She thinks it a much better idea to get rid of most senescent cells for most of an organism's life, and just let senescent cells be induced locally at the time and place of a wound (e.g. right before surgery), or perhaps even better, inject or apply the beneficial growth factor that the missing senescent cells would normally secrete to assist with wound healing.


 In short, tweaking with (to say nothing of taking a hammer to) critical cellular components or metabolic pathways is fraught with peril and the potential for very bad side effects and unintended consequences if done too heavy-handedly. 


The same "double-edged sword" danger arises in virtually every anti-aging intervention, whether SENS-like or not. For example:

The body is much too much like computer "spaghetti code" to think that either fixing it or cleaning up all the damage is going to be straightforward. We can't responsibly just jump straight to treating people without risking doing more harm than good. So it is going to take decades if not centuries to figure out what's going on and how to clean up the all the various forms of damage without causing more trouble.


In the meantime, all of us want to live as long & healthy lives as possible. Studies that elucidate the cause of the "obesity paradox", for example, might help in this regard. Is it that some types of fat are better or worse for health than others (e.g. visceral vs. subcutaneous, white vs. beige/brown)? Is it that being fat in old age is protective against frailty? Does exercise prevent the dysfunctional metabolic state normally associated with visceral fat? Would subcutaneous liposuction / lipectomy help? (probably not) etc.


Are such studies going to make us immortal? Obviously not. 


We're in the unenviable position of being perhaps the first generation to rationally imagine the defeat of aging within our lifetime, but at the same time we remain unlikely to actually experience the defeat of aging before we die. 


This sucks, no doubt.


But impatience or frustration with the situation isn't going to change it. The effort required is daunting and sequentially linked (i.e. an initial therapy will inevitably have side effects requiring researchers to discover them and develop another therapy to correct them, which itself has side effects etc...). Even a buttload of funding isn't going to make much difference in the rate of progress, despite Aubrey's expressed optimism.


Make peace with the continued inevitability of death, and then you'll be pleasantly surprised if SENS makes rapid progress or successful cryopreservation buys us more time to benefit from slow progress.



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Gather ye rose-buds while ye may,

Old Time is still a-flying;

And this same flower that smiles today

Tomorrow will be dying.


The glorious lamp of heaven, the sun,

The higher he’s a-getting,

The sooner will his race be run,

And nearer he’s to setting.


That age is best which is the first,

When youth and blood are warmer;

But being spent, the worse, and worst

Times still succeed the former.


Then be not coy, but use your time,

And while ye may, go marry;

For having lost but once your prime,

You may forever tarry.

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