Ending Aging

Chapter 1 - The Eureka Moment

A list of what damage is done that causes aging:

• Glycation
• Extracellular Aggregates
• Intracellular Aggregates
• Cellular Senescence
• Depletion of Stem Cell Pool
• Mitochondrial Mutations
• Mutations in DNA -> Cancer

All of those are fundamentally solvable. Hence aging is fundamentally solvable. But somehow nobody thinks of it that way... he put forth a pathway to solve the problems of aging within SENS - strategies for engineered negligible senescence - p. 4

To design therapies, all you have to understand is aging damage itself: the molecular and cellular lesions that impair the structure and function of the body's tissues. - p. 5

Chapter Summary:

7 things that constitute the problem of aging. All of them are solvable. Aging is a solvable problem.

Chapter 2 - Wake Up - Aging Kills!

In the sense that matters most, aging is just like smoking: It's really bad for you. - p. 10

When one is faced with a fate that is as ghastly as aging and about which one can do absolutely nothing, it makes perfect psychological sense to put it out of one's mind. - p. 11

There is a 10000$ price to show that it doesn't make any sense to even try following SENS. So far nobody has been able to show that, which means that it has a point to be tried and implemented, so that aging might end. - p. 12

Aging is, in principle, just as amenable to Modulation and eventual elimination as specific diseases are. - p. 13

The point of the book is to convince the reader that efforts like SENS can work and that everybody's funding and work is necessary to make them happen in our lifetimes within the next 2-3 decades. He thinks it is a perfectly reasonable goal, to eradicate aging as a human problem within a short enough time frame so that the people now alive working on the problem could reap the fruits of their investment. - p. 12-16

When humanity as a whole is behind the effort of ending aging and willing to pay for it with taxation, then there'll be ample funds available. - p. 15

Chapter Summary:

People are stuck in an aging is "ok" trance. That has to change. Because aging can be prevented. But it needs the combined efforts of a lot of people, their time, creativity and their money.

Chapter 3 - Demistifying Aging

Gerontologists used retoric to fence off their funding, by saying that aging and age related diseases are not the same thing. Because of it, aging is not characterised as a disease, even if curing it would have huge benefit, people who could finance research don't get the point. Short term financing interest hindered long term financing. - p. 16-18

The more we age, the more our self-repair functions decline, so the less able our body is to stop us aging, so we age faster and faster. - p. 19

All age related diseases are universal, the only thing is that one usually is dead after having developed the first one and therefore doesn't get old enough to develop the others. - p. 21

Aging of the body, just like aging of a car or a house, is merely a maintenance problem. - p. 21

Biology makes a tradeoff between longevity and early maturity. Basically building up bodies that reach maturity early means their structure will be worse for the long run.

Famines change the balance of that tradeoff towards longevity. During a famine early and fast reproduction is nonsensical. So the bodies built are targeted more for longevity instead.

Repair is better than prevention in the case of aging. Also the slowdown of aging due to fasting has less of an effect in humans than in nematodes. The maximum possible life extension that can be had by caloric restriction is still too low. Even if it's 20-30 years.

Chapter Summary:

The current methods are not enough. Caloric restriction is good, but only for a few decades, it's not solving the fundamental problem. We need more understanding for that.

Chapter 4 - Engineering Rejuvenation

People take maintenance of their body not serious enough until too late in life. Prevention is usually better than cure.

Preventing again is soon enough but too complex, curing the diseases of aging is simple enough but too late.

Free radicals produced in mitochondria are responsible for most of aging related damage. Mitochondria get leakier as people get older.

Free radicals also act as signaling molecules, in a way the body needs them to work normally. So restricting free radical creation, or taking them out with powerful antioxidants has serious side effects. Sheltering the mitochondrial DNA in the nucleus to stop it from accumulating damage might be a way out.

Similarly, all the other damages of aging have solutions, currently still in infancy but good enough to give hope.

Engineers were making workable use of electricity, superconducting magnets, and even nuclear energy long before they had a coherent theoretical explanation for the forces they were manipulating.

In other words, aging can be viewed as an engineering problem to solve, without fully understanding it, but by bootstrapping and using the parts we do understand.

Our bodies are designed to survive for a biological "warranty period": they are given enough robustness and self-repair capability to function at peak performance for as long as they can reasonably be expected to stay alive in the wild, but no longer.

Chapter Summary:

Aging is an engineering problem we can solve. The pro-aging trance can be dispelled entirely and the real work started. All the categories of damages relevant to the problem are known and solutions for each are in the works with not too many things standing in the way. This gives rise to the terminology of SENS. Strategies for Engineering Negligible Senescence.

Chapter 5 - Meltdown of the Cellular Power Plants

Free radicals and antioxidants and their roles and interactions in aging are complex.

Free radicals in biology are, oxygen based molecules that are missing one of the electrons in their normal complement.

Electrons come in pairs within their orbitals, if one misses - the chemical becomes unstable and reactive, trying to steal, or give away the uncomplemented electron. This leads to a chain reaction though, because now another molecule lacks / has an electron too much, so it becomes a free radical in turn. This chain of free radicals tears through biological protein machinery and DNA unless it is stopped by an antioxidant.

Antioxidants are molecules which are still stable and not reactive even with an unpaired electron.

Mitochondria generate the majority of free radicals in human bodies. They concert chemical energy from difficult to use forms like glucose into a form that is much easier to use "energy currency of the cell"ATP - adenosine triphosphate.

Mitochondria pump protons across the mitochondrial inner membrane, using something called the electron transport chain. The ETC is a sort of proton pump that uses electrons stripped from glucose and transfers them onto oxygen eventually. It builds up the reservoir of protons and thereby an electrostatic Potential gradient that can be used to do work. Complex V then is something much like a turbine, a protein that uses the flow of protons to convert the energy of the electrostatic gradient into a more usable form, rotation - i.e. kinetic energy that is then catalyzing the reaction of ADP and phosphate into ATP. The whole chain of events is called oxidative phosphorylation. OXPHOS for short. Oxygen is the last resting place for the electrons from the glucose, each oxygen gets 4 electrons in total under normal circumstances, but sometimes an oxygen breaks out of the chain when it's not read, yet, having not enough (or too many) electrons attached to it. Those oxygen molecules are the free radicals produced by the mitochondria. They are called superoxides.

Superoxides and other free radicals do damage right on the spot, so they damage mitochondrial proteins and mitochondrial DNA. Mitochondria are the only organelles that still have their DNA with them. Which gets damaged by the free radical leakage from the ETC.

Mitochondrial oxidative damage is linked to aging. But how? Over time damage to the proteins of the ETC and the inner mitochondrial membrane accumulate, leading to more free-radical leakage, leading to yet more damage, making the whole process of ATP generation, slower, less efficient and more unreliable over time. Also the increased leakage starts causing other problems in the cell eventually. Accelerating mutations in the DNA for example... This explanation is wrong!

Book Recommendation: The Joy of Sex by Alex Comfort

The nice runaway explanation doesn't work because mitochondrial components get replaced constantly and destroyed and recycled in the lysosome when faulty. Healthy mitochondria then replicate to fill the gap left by the ones tagged for destruction for being faulty.

Whether you're five years old or fifty, any given mitochondrion in your cells contains membranes and proteins that are on average only a few weeks old.

The damage to the DNA however can still accumulate. Higher rate of mutation over time leads to more copying errors in mitochondrial DNA and this way also to more and more faulty OXPHOS machinery when people get older. But it gets freakier. Mutations in mitochondria are always in the same location. And when a cell has a single mutated mitochondria, it usually has all of its mitochondria mutated. Different cells have different mutations, so the mutations differ between cells, but not within?! Furthermore most of those mutations were deletions of large sections of DNA, effectively shutting down the creation of mitochondrial proteins.

Mutant mitochondria produce essentially no free radicals, and the change in each mitochondrion can be attributed to a single, catastrophic event.

Only 1 percent of old people's cells have defective mitochondria.

Mystery 1: Clonal Expansion - i.e. shutting down free radical production completely yields a survival advantage for mitochondria which means that those defect, slowly take over their cells. The survival advantage is that they aren't tagged for destruction because of stray free radicals.

Lysosomes directly target the recycling of proteins and cellular components. And they have to be targeting things specifically, since some compounds might be actively harmful to the cell at large and need to be taken care of immediately. Basically lysosomes can target and destroy mitochondria that have free radical damage in their ETC or inner mitochondrial membrane.

Mitochondria with leaky membranes waste resources from food, trying to maintain a proton reservoir that can't be maintained because of the leaky membrane.

Ironically, large deletions in the mitochondrial DNA would actually allow them to escape from the very mechanism that cells use to ensure that damaged mitochondria get slated for destruction.

Question: Could one design a new protein tag, that targets mitochondria with deleted sequences in their DNA for lysosomal pickup?

Key question: How do cells with dysfunctional mitochondria produce energy for survival?

Glycolysis - glucose into pyruvates and ATP + electrons which are used in OXPHOS. Glycolysis produced electrons are put onto NAD+ converting it to NADH, which can then be taken to the ETC in the mitochondria. The pyruvate is also delivered to the mitochondria, where it gets turned i to acetyl CoA. Again releasing electrons, that get put onto NAD+ turning it into NADH. Acetyl CoA is then used as input for the tricarboxylic acid cycle (TCA) - i.e. Krebs or citric acid cycle. Even more electrons get created during those reactions, which again are fed into NAD+.

NAD+ is depleted in cells with dysfunctional mitochondria. Because NADH has nowhere to go and deliver the electrons. Excess NADH might even have toxic effects on cells.

TCA is highly active in dysfunctional mitochondria, and there is no rise in lactic acid (which would happen if more glycolisis would happen because the pyruvate would be broken down into it)

Rho zero cells have mitochondria without mitochondrial DNA.

Cells with defect mitochondria can export excess electrons outside of the cell using the Plasma Membrane Redox System (PMRS). Turning NADH back into NAD+ closing the bottleneck. These excess exported electrons then cause damage outside of the cell which produces them.

The way that damage happens is due to the electrons being transferred onto oxygen, creating free radicals - superoxides - at the faulty cell boundary. However those superoxides are to unstable to do damage to the whole body since they would only attack the very close surroundings. There's another chemical they could attack however which is stable enough to travel but still unstable enough to do damage. Serum cholesterol. Specifically LDL.

Cells need cholesterol for the manufacture of their membranes, and LDL is the body's cholesterol delivery service.

When cholesterol has oxidative damage, this would deliver oxidative stress directly into the cells where LDL is going. Spreading the oxidative stress from the cells with faulty mitochondria directly into lots of other cells in the body.

Chapter Summary:

Mitochondria produce free radicals. Those damage mitochondrial DNA and proteins in the mitochondria. Mitochondria with broken proteins or membranes get destroyed by lysosomes. Sometimes a mitochondrion acquires a deleterious mutation which makes it stop producing functional ETC chain proteins entirely. These mitochondria don't produce free radicals anymore, therefore they are not picked up by the lysosomes anymore. Hence they slowly spread through a cell, which let's "intact" mitochondria replicate to replace those destroyed by the lysosome. Slowly cells start to fill up with these broken mitochondria. The TCA cycle, supplying electrons in the form of NADH to the ETC doesn't stop though. The cell can get rid of those extra electrons and convert the NADH back into NAD+ via the PMRS. This effectively puts the electrons outside of the cells membrane, where they can react to form free radicals - superoxides - on the cell membrane surface. Those superoxides can then attack LDL molecules, reducing them and effectively turn them into trojan horses of oxidative stress. The thus poisoned LDL molecules travel around the bloodstream, delivering their free radical cholesterol package to different cells, thereby spreading the oxidative damage generated by a single faulty cell to the whole body. Over time the ratio of healthy - faulty cells increases and so does the oxidative stress, leading to the role of damaged mitochondrial DNA in aging.

Chapter 6 - Getting Off the Grid

Aging is a deadly pandemic disease.

Ideas against stopping the buildup of damage in mitochondrial DNA: give them catalase! An enzyme which breaks down hydrogen peroxide (thereby limiting the amount of damage free radicals can do) - it works in mice, maximum life expectancy in treated mice went up 20%. But: clinical studies can't be done, since there is no short term benefit that's measurable and the long time nature of the prevention scares away venture capital from even trying. Those in power to do it, have incentives not to.

Also 20% is not good enough, science can already do better. We should aim for indefinite. Furthermore hydrogen peroxide plays a role in cellular signalling as well, hence it might have unintended side-effects to have catalase at places where it usually isn't. Specifically hydrogen peroxide plays a role in apoptosis, telling mitochondria to purposefully destroy their membranes and thereby destroy the cell as well.

Second solution, use allotopic expression for the 13 key mitochondrial genes. In simple words, place those genes somewhere else - in the cell nucleus. This way those genes would evade damage and mitochondria could keep working normally.

One key question here: how do the proteins get to the mitochondria? Is there something different in protein synthesis when the DNA is in mitochondria compared to when it isn't? - the answer comes a bit later in the chapter

Mitochondriopathies are a disease that could be used as a bypass for regulation to work on the prevention of aging under disguise.

Evolution has already moved all but 13 from an intial set of over 1000 genes into the nucleus anyways. We just complete the job and move the last 13.

Question: How does this affect mitochondrial inheritance and normal germline inheritance?

Reference: Later in Chapter there is something called code disparity, namely sequences in the mitochondria are coded for differently than sequences from the nucleus. There is yet another concern - the hydrophobic nature of the proteins involved. They can't be transported long distances in the aqueous solution of the cell, which they have to be if they are expressed allotopically. Then they also have to be shuttled through the inner and outer membrane into the inside of the mitochondria. There exist protein channels for this task - the TIM/TOM complexes. (Translocases of the Inner/Outer Mitochondrial Membrane)

Solving the hydrophobicity problem can be done by stealing the design from other organisms. Or by looking at the designs and copying over the principles from other organisms. Both have already been done successfully in human cells an are therefore extremely promising.

Another solution could be inteins, amino acid sequences inserted into a protein that are snipped out at a later point in time. This would stop the proteins from curling up due to their hydrophobic nature. Later the inteins would be cut and the whole thing assembled again. There are a bunch of headaches with this method, mostly about that protein halves get altered by enzymes or they snap together in the wrong way or not at all or at the wrong time.

Chapter Summary

Fixing the problem of mitochondrial DNA damage is definitely possible and there are a bunch of solutions out there, probably the best - according to the Aubrey Grey - is allotopic expression. In other words moving the genes that get damaged to a safe site, the cell's nucleus. There are a bunch of problems about how to get the molecules into the mitochondria, namely that the proteins are highly hydrophobic and change their shape drastically when put into the watery cellular medium, which means they don't fit through the protein import mechanisms of mitochondria anymore. However these problems have already been addressed by different studies with a lot of success, so allotopic expression is still an awesome way to go.

Chapter 7 - Upgrading the Biological Incinerators

Just like our own households, cells generate garbage as an inevitable result of their normal functioning.

Waste can build up incredibly quickly in cities if there is a problem with waste management. The same is true of human cells. Only here, age related problems with waste management are not temporary but keep increasing and aggravating.

Aging cells undergo a progressive degeneration of their waste management infrastructure.

Lysosomes are the "recycling centers" of the cell. They use hydrolysis to break down specific molecules, basically cutting them open at weak sites in their structure. To do that they need specific enzymes called hydrolases and the proper acidity because those enzymes work only in a specific pH range. This acidity is maintained by proton pumps (vacuolar ATPases) across the membrane.

Over time lysosomes accumulate a substance named lipofuscin. It's basically all the gunk that can't be broken down and recycled properly. Some of it comes from molecules twisted and bound together through glycation. Sugars kind of glueing protein places into place, so that their active sites that can be targeted by hydrolases are inaccessible on the inside.

Lipofuscin takes up to 10% of long living cells like heart muscle cells.

Accumulating lipofuscin makes lysosomes disfunctional. Leading to a buildup of toxic waste materials that can't be recycled properly anymore. It also leads to cells accumulating broken mitochondria which increase oxidative stress. None of this is a problem in quickly multiplying cells because there the lipofuscin can't build up since it's effectively halved every time the cell multiplies. But in longer living cells (heart and brain mostly) it becomes a problem.

Arteriosclerosis is strongly tied to liposomal dysfunction. However arteriosclerosis is more complicated then "clogged up veins" like many people imagine it to work.

Cholesterol plays a role. But cholesterol is still important to the body since it is used to build cell membranes. LDL acts as the carrier particle for cholesterol, delivering it from the liver and gut to the places where it's needed.

LDL can be oxidized or reacted with bloodsugar (glycated) in which case it sticks to each other and becomes immobile. The more cholesterol there is the more toxic cholesterol there is because there are more chances of contact between cholesterol and blood sugar/free radicals. This toxic cholesterol can't be properly digested by the lysosomes of the macrophages which try to keep the bloodstream clear of it. So the macrophages fill up with bad cholesterol until they finally burst or die turning into foam cells. When these start to accumulate and stick together they eventually form atherosclerotic plaques which then rupture open and get taken by the blood to the small blood vessels of the heart and the brain where they essentially clog up the system and kill you with a stroke or heart attack.

All neurodegenerative diseases are connected to dysfunctional lysosomes.

Cellular junk gets engulfed in a cell membrane structure called an autophagosome or autophagic vacuole. This then attaches to a lysosome which provides the enzymes necessary for digestion of the contents of the vacuole.

In Alzheimer patients the lysosome isn't strong enough to destroy the content of the AV which means that the membrane slowly gets damaged by the toxic content until the whole vacuole gets flagged for destruction at which point it gets engulfed in yet another vacuole and so on like a system of Russian dolls.

People are obsessed with the exact details of how these garbage plaques contribute to the malfunction of cells and the onset of neurodegenerative diseases but they are stuck in a rut, where the search for the exact mechanism effectively prevents them from finding out how to actually cure the disease. It takes them away from an engineering mindset.

Age related macular degeneration - AMD.

Vision, like all of life's processes, is ultimately mediated by a carefully controlled, complex chemical chain reaction, and our conscious perceptions correspond in a one-to-one fashion with the particular electrochemical phenomena that this cascade triggers in our brains.

Rods and cones can detect light by changing a vitamin A derivative between two forms - 11-cis-retinal and all-trans-retinal.

The activation happens by absorbing energy from light and activation means that the molecule is moree reactive. Reactive molecules can spill over and this is what happens in eyes as well, leading to the formation of a compound named A2E. A2E is not digested by the lysosome, slowly filling up the cells with junk. Up to one fifth of an affected cell can be A2E.

Lipofuscin (the general catch all term for stuff that is undegradabale by the cells clean up mechanisms) is fluorescent and therefore cemeteries should glow in the dark because they are filled up with lipofuscin from all the corpses. But they don't! Hence something in the soil breaks down lipofuscin and we can use that against aging.

Given enough time, evolution will find a way to create microbes with the capacity to digest anything we throw at them that is both carbon-based and rich enough in energy to be a worthwhile fuel source.

Bioremediation - the process of using / breeding bacteria to break down pollutants in the environment.

The idea of using graveyard soil bacteria to break down lipofuscin works. Some actually do have the enzymes for it, which can be isolated and then gene therapied into living humans to fix the lipofuscin related problems of aging.

DNA microarrays and gene chips show which genes are expressed. Using those one can determine the exact genes responsible for breaking down lipofuscin.

Even if we know the genes, getting the enzymes into the right cells is tricky. Especially if they should pass the blood brain barrier. And then getting them not only into the cells but into the lysosomes where they are needed is even harder. One approach - chaperone mediated autophagy would involve tagging the necessary enzymes for breakdown which would then fuse them into the lysosome. The last challenge is to protect the enzymes from doing work outside of the lysosomes, which could lead to serious side effects.

Chapter 8 - Cutting Free of the Cellular Spider Webs

Intercellular junk accumulates as people age and causes diseases such as Alzheimer's. Solutions might involve the immune system to clean it up.

Proteins in the body can become misfolded into so called amyloids, that are literally choking the cell, eventually depriving it of nutrient and oxygen access. The misfolds open up reactive sites so that multiple proteins can stick to each other forming hard to break protein webs in and around cells. Usually these reactive sites are folded into the center of a protein structure so that they can't bond with things surrounding it, however, genetic diseases lead to problems in this folding at some point, either the machinery for splicing the genes and proteins is broken, or the gene for the protein itself is broken, or the mediating chaperone agents are broken. But even if none of these genetic conditions apply, there are simply some proteins that happen to be mishaped due to the influence of free radicals or sugars or even just random thermal vibration.

Amyloid precursor protein (APP) is like the name suggests the precursor of the amyloid responsible for Alzheimer's. However it is a necessary ingredient for normal brain function. APP is processed in the cell by alpha-secretase, an endo-protease (i.e. an internal enzyme that cuts proteins)

The problem arises when beta-secretase cuts up APP. Normally beta-secretase should cut other proteins. But sometimes it cuts up APP into something that has the wrong shape. When that protein is sent to gamma-secretase for assembly, it forms beta amyloid. The protein structure because of that changes from an alpha-helix to a beta-sheet. The beta-sheet form is reactive "molecular sticky". The individual monomer fragments then stick to each other forming oligomers that eventually get to big, fall out of solution and form the Alzheimer causing plaques.

Beta amyloid accumulates over time, and reaches critical, disease causing levels in people when they get old.

The underlying biochemistry is just part of the kind of organisms we are, living in the kind of universe we do.

Everybody will get Alzheimer's if they live long enough.

There are other amyloid related diseases, that we also get when old. The concept is the same as in Alzheimer's it's only plaques formed differently (by other proteins) in other areas than the brain.

Current approaches only treat symptoms of Alzheimer's, not the underlying cause and progression by buildup of beta amyloid. Some people tried inhibiting enzyme activity of the enzymes used in the generation of beta amyloid, such as gamma-secretase. However those enzymes are really important for other processes, so the side effects of treatments like this are harsh.

Some approaches target the formation of the plaques, by breaking them up when they get too large. However it is likely that the thing causing Alzheimer's are not actually the plaques but the oligomers of beta amyloid that are still in solution. They interfere with neuron firing.

Amyloid Plaques could still act as buffers for beta amyloid though, essentially keeping up the beta amyloid concentration in the brain fluid, in which case getting rid of them is still a good thing.

We do not need to understand in detail how aging damage accumulates, or by what mechanism it wreaks its havoc, in order to undo that damage

Microglial cells — the immune cells of the brain — slowly est up and digest away beta amyloid deposits from nerve cells.

One could therefore vaccinate against beta amyloid, using the bodies immunes system to destroy it. However with the first vaccines that did that there were big side effects since the immune response was to strong that it lead to a swelling of the brain and even the deaths of participants in the trials. New generations of the vaccines are being trialed right now that shouldn't have this problem anymore.

Adding antibodies targeting the "beta-sheet" conformation of the amyloids helps the immune system clear them up. One such antibody is 11-1F4 and it's promising because it works across different amyloid Plaques. Hence we could probably use it for helping against most age-related amyloid damage.

This still has to be tested in humans.

Amyloidosis can be fixed with vaccines that make the immune system take care of the amyloids.

Chapter 9 - Breaking the Shackles of Age

The same process that browns a turkey in the oven happens in our own organs. Tightening and binding up proteins in shapes they shouldn't be. Caramelization happens constantly.

Sugar is chemically reactive and that is a problem. AGEs are the result. Advanced Glycation End products. Proteins being warped out of shape by sugars. Crusty old age is the same chemistry as crusty turkey.

Maillard Reactions. Sugar opening up and glycating a protein. This is called a Schiff base and it's unstable. Sometimes it collapses into an Amadori product. HbA1c is such an Amadori product which tracks blood sugar. Amadori products can be further stabilized into AGEs. And they can crosslink with other proteins making the whole thing not work anymore.

This process is what contributes to making diabetes dangerous. Diabetics suffer all sorts of consequences because of AGE proteins.

But AGE accumulation is also bad for normal people. It's related to aging. Having a drug against these glycated compounds would be useful. Simply lowering blood sugar is not enough because blood sugar is necessary for normal function. Also triglycerides can also cause Maillard Reactions. So it's not only about sugars.

Ketosis increases methylglyoxal which in turn helps produce AGEs. Reality is complicated, lowering blood sugar by not eating any carbohydrates still produces AGEs. Ketosis is not really all that good because of this?

Glyco Oxidation is the issue. Free radicals oxidizing sugars wreaking havoc on proteins. However antioxidants in humans don't help. Because metabolism is complicated as fuck. Removing one source of cross links (oxidation via glucose) leads the metabolic products to find other ways to cross link.

Many of these processes are essentially random.

AGE is part of the foam cells process of Atherosclerosis. It's because macrophages attack the fat deposits with myeloperoxidase and that in turn helps form cross links of proteins.

Thought: This is an interesting bridge to the ideas of Outlive by Peter Attia.

Even if you could lower myeloperoxidase you wouldn't want to because it compromised the immune systems function. Again, metabolism is a complicated system we barely understand.

Another idea is to reduce oxoaldehyde burden. Some are like 40.000 times more reactive to tissue proteins than sugar. And they are not like sugar necessary. They are fundamentally toxic. But treating them with medication like Aminoguanidine still didn't work. Because the drug itself has weird side effects and doesn't properly work. Repressing metabolic effects without second and third order thinking is bound to fail.

Thought: This reminds me a lot of the writing of Nicholas Nassim Taleb in books like Antifragile.

The learning: don't mess with metabolism, just remove the dangerous end products.