User:BumblingBuffoon

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Greytide.

Life goals? I promised myself that I would at some point get out of my trash heap and go through college and university, looking into biology disciplines (probably genetics, and cellular biology) to find a way to prolong my life. As it turns out a lot of very rich people also don't like the idea of dying, who could know why? And have been dumping money into life-extension research for a long time now 1.

Most people have to specialize in their life and pick something that defines them, I am an artist, they'll say, an engineer, a doctor, and they have to spend ever increasing amounts of time to become those things. Time is everything, if we had more time, we could do everything. So it just seemed to me to be the biggest priority. The reality of the situation is that I will soon be thirty, and that's making me anxious, procrastination is terrible. Nothing fills me with more anxiety than running out of time, how about you?

Its likely that DNA damage over time which then gets copied between cellular mitosis over time plays some role in the ageing process, perhaps even a central role. [1] However, its not clear which came first, does organelle damage cause DNA damage which then leads to dysfunction? Or does DNA breakage lead to cellular dysfunction which then leads to more DNA damage? What is true is that DNA and epigenetic inheritance seems to be important for the historical impacts of the environment against our bodies over time. Which means that gene therapies that aim to restore function may be a way towards controlling our age, perhaps remaining young for as long as we are capable of replacing our dysfunctional cells.

But our DNA isn't the only DNA that exists inside of us that is crucial to our survival, we picked up something (stole it by eating it) a long, long time ago in our journey on the planet, the mitochondria. And damage to that organelle's DNA will also result in dysfunction. [2]

Some bullshit about that

Telomeres are the holy grail right? Except when they haven't actually worked. If you have ever been interested in life extension for realzies, telomeres is one of the first things you'll see. The idea is that the hayflick limit (the amount of divisions a cell can undergo) is determined by how much telomeres that your cell's DNA has. Every division shortens the caps on the end of DNA, just a lil bit, and when they run out, the DNA becomes unstable leading to death or other painful mutations (and then death). What if we could hypothetically extend the telomere caps then? Well, as it turns out that isn't a new theory for the natural world, in fact, cancer does this quite swimmingly. There is telomerase, this enzyme essentially maintains telomere length, alright let's experiment on some rats (as we do) it can delay ageing, but it only delays ageing. I have never seen a report in nematode worms, fruit fly or mice that telomere extension by itself has ever been enough to indefinitely prolong life. The indefinite part is important, as it means something else must contribute to eventual senescence (death), thus no model that hopes to explain senescence solely using telomeres can hope to be correct.

Supplements

There was once a Chinese emperor who hoped to obtain immortality, and he was eventually sold mercury by a quack. Today's quacks like nutritional supplements, because they're cheap and easy to produce and thus easy to turn a profit on reselling. They do nothing.

Blood replacement

Young blood is the best according to these vampires, bonus points if they're a capitalist corporate CEO exploiting the blood of a proletariat underclass. More on parabiosis here.

Epigenetics

As a Christmas present I decided to include news about epigenetic research to show that the quest for the Holy Grail is still very much alive. [3] It is a newer model to determine biological age versus chronological age, based on DNA methylation, and some trials are proposed to reverse some of this ageing in future trials. It's good to see that the world is still interested in living forever.

Systematic organ failure and cascades

A bad liver leads to a cascading effect where it not filtrating toxins causes damage in another area of the body which then fails and causes the liver to suffer more as a result of the changes, a feedback loop of failures that progresses gradually over time. This is how I imagine many illnesses to occur. Scar tissue is an example of a change in the body that is permanent and results in an immediate closing of the wound but at the cost of not creating functional tissue. Some tissues are capable of regenerating more than others are, and in the human fetus, injuries are capable of healing without any scar formation at all. [4] Suggesting that given the correct cellular pathways are active that scars can heal (maybe, I'm not sure about the mechanisms, but cellular signalling pathways are essentially 'everything' that determines what cells do in their circumstances as far as I know). The reason that scar formation is important to address is that fibrosis is a known killer, which need be addressed in organs.

Sometimes it only takes a specific thing to kill someone, like a fat buildup in an artery that causes an aneurysm in the brain, this is usually due to cholesterol, as bodies age, the body loses its capacity to properly clear this cholesterol, but how does it lose its ability to clear cholesterol? Well the liver is the primary driver of LDL destruction and fibrosis of the liver impacts its ability to unclog the arteries, although it may not be the only reason that it occurs. For example, damage to the endothelial cells in artery walls can contribute to plaque buildup. Which brings us to how endothelial cells repair themselves, simplified, this process is helped by something called Klotho that is made by the KL gene, which interestingly seems to increase longevity of mice when it is over expressed. As we age, klotho protein expression goes down, which as a result leads to this cascading effect in some cases. [5] Why do these genes turn off? The answer is epigenetic signals, as we age our DNA and its methylation change, the first changes by DNA damage that can occur for example by radioactive decay sources and it can repair improperly. Basically, the rock gets thrown through our metaphorical window and we can't replace it. Epigenetic changes can be reversed however. DNA damage would require a genetic therapy introducing a transgene, that's assuming the cell isn't simply destroyed before that happens (hello cancer).

At some point epigenetic changes are implicated in our ageing process, and its not clear what to do about it. Knowing why they happen would be nice. Its easy to just say "environment" but it is so non-specific as to be unhelpful.

Why does skin look old?

Lets follow the trail starting with a simple question, why does skin become 'old', well it thins. Why does skin thin? Because the body produces less collagen as we age. Why do we produce less collagen as we age? One study seems to implicate cellular fibroblast ageing and lower "mechanical stimulation". [6] First, what is a cellular fibroblast? Well, its a type of cell. [7] What exactly is "changing" in the ageing fibroblast cell that is producing less collagen? The answer is that the cell's morphology is being changed, meaning its shape. Mechanical tension causes the expression of more collagen. [8] As we age, the connection between the integrin and the collagen in the ECM (the stuff outside of cells is the extracellular matrix, comprised of things like collagen for example), collapses. This collapse causes the cell to downregulate collagen production, which in turn results in a negative feedback loop where other fibroblasts collapse, its a runaway effect. Sunlight accelerates this process, hence people being in the sun for longer tend to have more aged skin over time. The pathways responsible for this are DNA independent, our skin 'ages' in this way not because of a DNA change, but due to cell signals responding to changes in its local environment which leads to the cascading effects. So what can be done to stop or even reverse the damage? Well one way is to use a CO2 laser to basically destroy the superficial skin layer which will cause the entire thing to be replaced by the body, including a functional collagen ECM which will result in skin which looks younger and may even be more functional. Such CO2 laser therapies currently exist. [9] So one mechanism by which we age can be demonstrated to basically have nothing to do with DNA damage over time, which would provide evidence for theories that regard changes to ECM and cell signalling dependent on environmental conditions in other parts of the body as well.

How do you change DNA?

Once upon a time, DNA was thought to be something that was not changeable, until it was, today, genetic therapy is mainstream and abundant (not in humans) but has been demonstrated in multiple animals, citation not needed. The usual hurdles to genetic therapy is the delivery method of transgenes, whether alternatives would suffice (mRNA vaccination posing one example), the relative risk involved in the procedure, and cost. Tailored genetic therapies offer people a very interesting means of removing genes which for example, may be more prone to developing life threatening diseases, like cancer. [10] The medical risk that's involved in genetic therapies has to do with accuracy and the potential for the infection itself to also cause complications, but for the genetic component to be understand, an understanding of how a single nucleotide polymorphism can have disastrous potential effects can be understood by using the example of an SNP related disease, such as my favourite example, sickle cell disease. [11] Many people know of CRISPR by this point, and whilst it is usually safe, it has been known to have unwanted effects. [12] That isn't to say that these problems can't be sorted out, or we can't reach a level that's acceptable, the FDA for example has approved the use of a CRISPR based cell therapy called Casgevy for the aforementioned SNP in SCD. [13] This is unlike that more famous case of He Jiankui who created the quote "HIV immune" twin girls in 2018, who is by the way, now out of prison and back in the lab working on gene therapies, you can see a partial interview here. [14] People who were wondering what became of the children, it turns out that they are apparently living and are fine.

Political byproducts of chasing a dream

Supremacy. But of what? It has been said in history that intelligence can be assigned to genetic factors, personality traits, mental abilities supposedly linked with genes have always been hard to substantiate. Intelligence in particular has always been notoriously hard to define concretely, does it mean the speed at which we process information mentally? Does it have to do with the rate at which we can read, comprehend, and recall things? How much of intelligence is developed environmentally? Learning is about acquiring observational knowledge about the world, and it cannot be given through genetics but rather by education. Our values are not conferred by birth but by our teachings, (ignoring the theoretical model of creating DNA that could then produce the neuronal structures of knowledge itself, which is a science fiction concept at this point). Theoretically, you can construct an adult person by simply programming a cell to turn into them over time, but why do that? You already have such people that respond to their environments.

In any case, physical traits are much more straightforward, more robust immune responses, more strength, more physical adaptability and engineered tools that the body can use, better sight, better hearing, incredible senses of smell, or other 'fun things' that can be conferred. Even if we only focus on making people extremely robust against radiation and diseases, this if only conferred to a richer population leads to an absolute unfairness in the world where people are exposed to equal environmental pressures. The odds are stacked, and they are granted by entrenched generations of stolen wealth, which then feeds back into itself as other people die and they survive. Systems of inequality become emergent in this environment, not simply based on sociology anymore, but inequality that is physically ingrained into the person. You would die in this scenario and I would live. That's an advantage. The only means by which we make this fair is to redistribute this success and wealth amongst people, and give access programs to everyone, especially people who need them.

Where the money goes in terms of genetic therapies inevitably follows the medical needs of those who have it, and by coincidence they may indeed help people who suffer who were less well off at the start of this life, but what of people who do not have representation that would cause capital to invest its resources in areas that they require? These needs must be addressed, but I don't think that we should force people who can escape disease from doing so simply because it isn't fair. Wealth inequality already exists. There's a saying that all that glitters isn't gold, but gold does attract the minds of people. Its how capitalism literally incentives progress and innovation. University students looking for money will end up appealing to the needs of the market, unless some government program exists that they could gain grants from instead.