How Does Aging Work and How to Fix It (Eventually)

Due to unpopular demand, I have made the lowly anticipated sequel to last week’s article on aging. This article will also be about getting old. However, I will also be discussing the best potential cures for aging science has to offer! 

Previously, I explored how aging is considerably more complex than most people think. Remember how I explained that aging is caused by four or five different unrelated things happening simultaneously? Well, that wasn’t even all of them. In fact, that 9-page long article covered almost none of them. All I really did was provide a number of explanations for why aging happens. I didn’t talk much about how aging happens, which I think is a very interesting topic that not a lot of people talk about. 

Why? I’ve created an accelerated aging device called the Boomerinator™ before having made a way to reverse accelerated aging. A Boomer antidote, if you will. This may have been a bad idea in retrospect. My lab doesn’t have the tightest safety protocols and we’ve already had several incidents with it. 

To rectify this situation, I have produced an untested and highly experimental anti-aging serum. Despite my having access to a nigh limitless supply of T-Class test subjects to test it on, as a mad scientist, I am psychologically compelled to test any serums I produce on myself. I’ll do that after I finish writing this article, then I’ll leave taking the featured photo and publishing the article to my lab assistants. Here’s hoping it works!

• Mutation Accumulation, Reproductive-Cell Cycle, & Inflammaging
• Insane in the Frail Brain
• Mutants, Hormones, & Autophagy
• Crunchy Arteries
• Going White
• The Cure(s)(?)
• Comments

Catching Up 

I’ve heard from other mad bloggers around the water cooler that blog readers rarely retain everything from post to post. In fact, some think they retain almost nothing. I’ll help you remember part 1 throughout, dear addled reader. I’ll also slip in some new information I neglected to mention in the previous article.

Mutation Accumulation

Remember what I said about Antagonistic Pleiotropy (AP)? It’s the idea that evolution doesn’t select against genetic diseases which are beneficial early in life but negative later in life. Evolution only cares about your ability to reproduce, not your ability to survive.

Well, there is another similar hypothesis that I didn’t think worth mentioning at the time but I will throw in now. Mutation Accumulation (MA) works very similarly to AP, the only difference is that MA diseases aren’t ever beneficial. They’re bad when you’re old, but don’t do anything while you’re young. They don’t specifically get selected for but also aren’t selected against so they can still pop up and spread a bit. This can explain things like osteoarthritis, atherosclerosis, and frailty which, while common, never present in a majority of old people. Also Sarcopenia, which has a funny name.

The Reproductive-Cell Cycle Theory 

Remember how I said in the previous article that menopause and possibly andropause are good, actually? That it’s evolutionarily beneficial for grandmas and grandpas to stop having kids so they can help their existing kids raise their grandkids? This adaptation, while beneficial, might still be a bit crudely implemented. Menopause is caused by the loss of ovarian follicular cells (which control menstruation), and andropause by the loss of testicular Leydig cells (which make testosterone) and Sertoli cells (which support testicular function). 

The problem is that all these hormones were never meant to just disappear. They evolved with the expectation that you’d reproduce as long as possible. They aggressively drive quick growth during youth and drive reproductive priority to maximize reproductive capability. Since they’ve always been around for hundreds of millions of years of evolution, many seemingly unrelated signaling and metabolic pathways have evolved to include them in various ways (because why wouldn’t they? That would make too much sense). Without these hormones, these things become dysregulated and stop working properly. This dysregulation isn’t catastrophic in any way. If it was, you’d expect eunuchs and transgenders to have more health complications than they do. But it’s still worth noting.

Inflammaging

Remember how I said that senescence (when a cell loses its telomeres) slows how quickly the body can heal because cells can no longer divide? That is true, but I left out the part where these senescent cells also start secreting a bunch of chemicals known as the senescence-associated secretory phenotypes (SASP). SASPs include inflammatory cytokines, growth factors, and matrix remodeling proteases that cause inflammation and tissue deterioration. So not only do senescent cells slow down how quickly you can heal, but they’re also slowly destroying your other cells. 

Insane in the Frail Brain

You keep the same neurons you were born with for your whole life. Neurons don’t divide, so they can’t really become senescent. However, this also means that damage to them is a lot harder to repair. Various deteriorating factors lead to brain atrophy through the loss of neurons and synapse connections. 

Not all of the cells in your brain are neurons. You also have special cells called glial cells, most notably the microglia and astroglia. Microglia are the brain’s resident immune cells, similar to white blood cells or macrophages. They will attack and eat any pathogens they find in the brain. They also eat any waste buildup they find. Astroglia are star shaped cells that take a purely supportive role in the brain. They feed the neurons, regulate them and other cells, and are involved in the repair of the brain. Glial cells do divide and so can become senescent, when they do they’ll start pumping SASP into your brain. Which is bad.

Oxidative stress also plays a role. I know I’ve previously said that oxidative damage isn’t that important in humans, which is true under ideal situations. But we do know that the brain is particularly vulnerable to oxidative damage. (In fact, the brain is probably the most biochemically fragile organ). It’s not much of a problem if your brain is making a healthy supply of natural antioxidants for itself. But if you lose those antioxidants your brain becomes very vulnerable. This is why mercury poisoning is such a problem for the brain. Mercury really likes to bond to selenium. Selenium is an element that your body uses to make a number of important antioxidants. 

Centennial Mutants

You know about X-Men? Mutants whose mutations give them superpowers? Well, I hate to burst your bubble comic fans, but in real life mutations usually just do nothing. Or, if you are very lucky you might get a nice cancer, which doesn’t help much against invading aliens, monsters, or mad scientists. But sometimes, ever so rarely, a mutation is actually good. Most people who live past 100 most likely could do so only because they were mutants. Yes, having a healthy lifestyle is also necessary. But we’ve also found that really old people tend to have a few rare genes in common. In order to understand, I’ll have to explain signaling pathways.

Signaling pathways are THE BANE OF MY EXISTENCE. Any biomajor will empathize, they are the worst part of cellular biology. Pathways are the way that cells communicate with themselves and others. See, evolution doesn’t find the best solution. It finds the first solution which miraculously happens to vaguely work in any capacity, and will keep doing it that way for hundreds of millions of years or until the end of time. 

Say that you need to tell a cell to start producing a certain protein. This is usually done with a special protein called a transcription factor that can turn a gene “on” or “off”. The obvious and best solution would be to just release that transcription factor into the cell and have it go to the nucleus (where the DNA is) on its own. This is almost never how it works. Instead, the body sends a hormone that flips a molecular switch on the cell surface that causes a kinase to be released inside the cell which deactivates an enzyme that was destroying a constantly produced transcription factor immediately after production, allowing that transcription factor to deactivate a different gene for a microRNA that was canceling out the mRNA of another transcription factor allowing it to be created and activate the gene for the protein you wanted.

Pathways are almost always some insane convoluted Rube Goldberg machine like this. And they’re usually interconnected and/or have multiple lanes. If you’re in med school or are taking a cell-level bio course you’d be expected to memorize all that for dozens, if not hundreds, of pathways. And just to make everything a little less fun, each step is named some BS like “GP130” or “Oct-3/4”. The best part is that most doctors never end up using them.

Growth Hormones

Researchers have found that the Growth hormone/Insulin-like growth factor 1 signaling pathway is correlated with age. This pathway is involved in growth during childhood and adolescence and has nothing to do with insulin. People born without the pathway become dwarves, so it’s probably a good thing to have. But in adults, who don’t need to be growing anymore, it seems to be a cause of age and reduced life expectancy somehow. We don’t actually know how yet. Scientists just noticed that adults who are genetically predisposed to decreasing this pathway tend to live longer statistically. This makes it a prime example of antagonistic pleiotropy as it’s very beneficial early on but becomes negative after the age one would pass on their genes. 

Autophagy

As you age your cells will start to fill up with literal garbage. Several pathways produce molecular byproducts which don’t get cleared or are produced faster than they are cleared. Or some parts become old and damaged and are just left there, like a forgotten second bathroom that your father had promised to fix for the past five years but still hasn’t. Some bioaccumulative toxins in your food or environment may also collect in your cells. Even if they don’t do anything, over time these molecules will just cause so much clutter that it slows your metabolism. Your signaling and metabolic pathways go slower because there’s just so much shit in the way.

Evolution has provided us with an effective and safe way of solving this problem that all humans possess called “autophagy” which means “self-eat-y”. But it’s, like, turned off? We all have the genes to autophage, but we just don’t?

There is a variant of the FOXO3A gene, again named to torture bio students, which scientists have also correlated with longevity. Luckily, we actually have an idea how it works. The variant gene modifies the sirtuin pathway which then deactivates mTOR (the protein that suppresses autophagy). This allows for a longer and healthier life.

mTOR actually does a lot besides turning off autophagy. It’s involved in DNA transcription, cell survival, protein synthesis, and many others. So this may be another case of antagonistic pleiotropy. Evolution evolved a really useful protein. The fact that it broke autophagy didn’t matter since it isn’t really needed until after you have kids anyways. 

mTOR is also related to the insulin pathway (the actual one, not the insulin-like growth factor 1 pathway). Basically; more calories = more mTOR = less autophagy. This is why scientists in the past have correlated higher calorie diets with aging. We used to think that overfed mitochondria producing more oxidants was bad. Turns out the oxidants weren’t the main issue there.

Crunchy Arteries

Surgeons have long had the displeasure of knowing that people’s arteries tend to get “crunchy” as they age. It wasn’t hard to find out that this was due to calcium phosphate (what bone is made of) forming deposits inside the arteries. But it did take a while to figure out why that was happening. 

It turns out that a beloved protein that helps repair damaged cells and DNA lovingly known as poly(ADP-Ribose), or PAR for short, really likes to bond to calcium. So as people get old calcium leaches out of their bones. PAR in their blood will stick to the calcium and form what is known as “droplets”. These droplets then collect on the artery walls. As you are aware by now, getting old causes a lot of cellular and DNA damage, hence why they’d also have more PAR in their blood. Hence why older people have the crunchiest arteries. [5]

Having crunchy arteries is bad because it reduces the elasticity of the arteries, which is necessary for regulating blood pressure. This reduces your athletic potential.

Wrinkles and Gray Hair

Skin wrinkles because of the gene Transforming Growth Factor beta (TGF-β) which causes loss of subcutaneous fat. Subcutaneous fat is a thin layer of fat directly under the skin which provides support to the skin and has a minor role in fighting infections. Having it doesn’t make you fat, everyone has it. Well, not exactly everyone, old people lose it causing their skin to collapse and wrinkle like a raisin. 

Hair turns gray when Interferon regulatory factor 4 (IRF4) causes the loss of hair follicle melanocytes. A melanocyte is a cell that makes and contains a lot of pigment, usually melanin. The number of melanocytes in your body is typically inversely proportional to the amount of privilege you have.

I think these two things didn’t evolve through not antagonistic pleiotropy or mutation accumulation, as I’ve said in the previous article. A social species like humans benefit from being able to judge the relative age of someone just by looking at them. Skin wrinkling and white hair just happened to evolve and work well enough. Of course, that’s not much consolation to people who don’t want to look old for cosmetic reasons. 

The Cure(s)(?)

An experimental treatment of aging frailty, given the horrible acronym “Aging FRailTy via IntravenoUS Delivery” (CRATUS) (where did the C come from??) shows promise^[1]. Basically, it just involves injecting a bunch of stem cells into the patient’s arm. The stemcells then join frail tissues, replacing lost cells and/or releasing hormones that degraded tissues no longer can. They also combat the effects of inflammaging in senescent cells.

Don’t worry, these stem cells don’t come from babies or anything like that. In fact, no one gets their stem cells from abortions these days. Now we grow stem cells in Petri dishes giving us an infinite supply. Yeah, most of those cell lines originally came from abortions, but that’s in the past. Also, we now have the capability to transform a small number of skin cells into a large number of stem cells which can then become any other cell type. This is the far better option for stem cell therapy as there is no chance of tissue rejection since they’re your own cells.

There are still some kinks that need to be worked out. Since these stem cells come from the patient who presumably is old and has short telomeres, it won’t be long until the newly regenerated cells also become senescent. So this treatment won’t be as effective as possible until science finds out how to reliably regenerate the telomeres of these cells before reintroduction. Also, there is concern of cancer. Cells are known to have increased chromosomal instability when grown outside the body, increasing their chances of becoming cancerous. Mesenchymal stem cells also can produce some chemicals which help tumors grow and evade the immune system.

As for combating telomere attrition and senescence directly, as well as problematic pathways, the best eventual solution might use viruses. Some viruses insert their own DNA into the host’s genome in order to reprogram them to make more viruses. Scientists have previously used this to make viruses that insert a new genetically modified gene into a host. Progress has been made in using this tactic to safely modify mice so they produce their own telomerase and other anti-aging factors^[2].

The whole crunchy artery thing can possibly be solved by taking minocycline, which is currently used to treat acne. Minocycline antagonizes PAR ^[4]. Though one might think that antagonizing PAR, a protein that repairs cells and DNA, might cause other issues.

Metformin (also sold as glucophage) looks like it’s one of those miracle drugs that seems too good to be true at first so you just assume it’s snakeoil, like CBD, aspirin, or placebos. To be fair, the research on metformin is still out and it’s not entirely understood how it works, so don’t get too excited. But multiple studies have found evidence that metformin can slow aging in multiple ways, such as inhibiting mTOR, reducing inflammation, is an antioxidant, etc.  It’s even had some use against certain cancers and COVID. Which is weird because metformin was originally a diabetes medication that can also help with weight loss. It also has relatively minor side effects. [6]

So while these treatments show a lot of promise, they won’t be approved for human use for at least a decade or more. Even after we fix the bugs, drug approval always takes an extremely long time unless it’s for a pandemic.

So for now, enjoy slowly getting old and frail as the very code that defines you falls apart and your system breaks down. Try to look forward to retirement. Collagen skin creams and hair dye help, I guess^[3].

Sources:

[1] Zhu, Y., Ge, J., Huang, C., Liu, H., & Jiang, H. (2021). Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics. Theranostics, 11(12), 5675–5685. https://doi.org/10.7150/thno.46436

[2]https://everynewsportal.wordpress.com/2022/05/15/sustain-a-long-and-healthy-life-via-new-intranasal-and-injectable-gene-therapy/

[3]https://labmuffin.com/video-collagen-supplements-work-wrinkles-younger-skin/#more-8462

[4]Müller, Karin. et al. (2019). Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization. Cell Reports. 27(11), P3124-3138.E13. 2019 DOI:https://doi.org/10.1016/j.celrep.2019.05.038 

[5] Wikipedia

[6] Agnieszka Zajda, Kristiina M. Huttunen, Joanna Sikora, Maria Podsiedlik, Magdalena Markowicz-Piasecka, Is metformin a geroprotector? A peek into the current clinical and experimental data, Mechanisms of Ageing and Development, Volume 191, 2020, 111350, ISSN 0047-6374, https://doi.org/10.1016/j.mad.2020.111350. 

https://erepo.uef.fi/bitstream/handle/123456789/23728/16056152831246675634.pdf