Layman’s overview of the pathways to aging, pt.2

A while ago, I posted an article presenting the broad lines of 5 of the 9 pathways of aging, as classified by this influential Cell paper. Today, I want to finish up that series and perhaps, in the future, go over other pathways not presented by Cell but aknowledged by SENS or other systems.

Before I begin, though, we have to ask ourselves why is it important to talk about aging and know about aging. My answer to that is for the same reason we need to understand cancer or multiple sclerosis: because it undermines quality of life and we want to find out how to stop it. Quite like a disease, though it happens to more than 50% of people. (Interestingly, with increasing air pollution and junk food consumption, cancer and diabetes are well on their way to happen to the majority. Will they no longer be diseases? Will aging be considered a disease? Will the governments turn a blind eye to this inconsistency and keeping denying funding for longevity research on a basis which no longer stands? There, I’m getting worked up again. One of those days, I’ll need to write about why it’s important that aging be recognized as a disease.).

Ok, today though, we’re exploring what aging does. Without further ado, here are 4 additional hallmarks of aging as classified by Cell.

Loss of proteostasis or lysosomal dysfunction

The lysosomes are organelles, or subunits of the cell, responsible for clearing out the waste in our cells. Unfortunately, sometimes the lysosome is not able to break down those waste proteins, because of the lack of an enzyme necessary to do so. Think back to when you probably learned in high school biology that being able to build proteins is incredibly important: this is one of the reasons why.

Without the right enzymes for the lysosomes, those waste proteins just stay inside of it, leading it to malfunction. This eventually results in the death of the cell.

A worrying fate, considering cells cannot be made the replace the dead ones indefinitely: stem cells age too (we talked about stem cell exhaustion in part 1). So what causes this lack of protein in the lysome, and can we fix it?

One of the reasons understanding aging is complex is that the pathways feed on each other, however, there appear to be a few main pathways from which the others flow. Genomic instability is one of these pathways, also explained in part 1. In short, that’s when DNA gets irreparably damaged (at least irreparably through natural means). Perhaps you recall that DNA encodews the information necessary to make proteins. Hence, no information, no protein, and no lysosome doing its job. The fascinating thing, however, is that genomic instability is not the ONLY way lysosome dysfunction could happen. For that, I have to once again send you back to part 1 to learn about the epigenome, if you are not already familiar.

Mitochondrial dysfunction

Mitochondrial dysfunction, which looks a lot like lysosomal dysfunction, but with a different organelle. It happens when the mitochondria cannot do its job anymore, which is producing energy in the form of ATP, because it lacks a necessary protein to do so.

This can happen when the mitochondrial DNA gets damaged. Each mitochondria has its own DNA, which is different from the nuclear DNA and even from one mitochondria to another! Still, it encodes 13 proteins that are necessary for energy production.

The mitochondria is like a power plant for our cells, and like all power plants, it generates waste. In the mitochondria’s case, this waste is created in the form of free radicals. Since they are generated so close to the mitochondria, they are thought to be especially prone to damaging the mitochondrial DNA. It should be said that this is one hypothesis as to why mitochondrial dysfunction happens, and I went into some other ones in my article on allotopic gene expression, a very niche but fascinating avenue for solving this particular mitochondrial dysfunction problem.

No matter how the damage happens, it is clear that it does happen. So if the mitochondria’s DNA gets damaged in such a way that the instructions for the production of energy aren’t available anymore, then it’s unfortunately the end for that particular mitochondria.

Thankfully, cells have many mitochondrias, but the least of them are working, the least energy that cell can use. At some point, the cell doesn’t receive enough energy anymore, and it either dies or enters senescence, which was explored in part 1.

Deregulated nutrient sensing

As we age, many systems in our bodies become damaged. The nutrient sensing systems are no exception.

A nutrient sensing system could be defined as a pathway that indicates to cells whether a particular component that we can eat is plentiful or scarce in the organism. These components can be the amino acids that make up proteins, for example.

There are 4 main nutrient sensing systems of interest when it comes to longevity. I’m going to give you a brief overview of each of them.

The first one is a bit of a two-in-one, the insulin pathway and the insulin-like growth factor 1 pathway (IGF-1 for short). Together, they are known as insulin and IGF-1 signalling, or ISS.

ISS signals our cell that food in itself, so calories, are plentiful, and thus our cells should go forth and multiply. And when they do, they are very active, wearing them down faster than if they were more inactive.

It has been shown that decreasing the activity (downregulating) of ISS could increase longevity in multiple studies models. Paradoxically, the activity of the ISS also decreases with normal aging. How to explain this apparent contradiction?

We think the ISS decreases to prevent our cells from growing and multiplying too much during aging, as many of them are damaged. Growth and multiplication could lead to many adverse health effects, cancer being one of them.

In short, due to late life ISS downregulation, our cells become less active than when we were younger.

The second pathway is the mammalian target of rapamycin, also known as mTOR. mTOR signals to cells the abundance of amino acids.

Just like ISS, it causes them to proliferate, but unlike ISS, the activity of mTOR is increased as we age.

We have tried to inhibit mTOR and while it does have some beneficial effects on aging, it also has some downsides such as reduced wound healing, insulin resistance and cataracts. More studies are needed to understand this pathway better so we can potentially target mTOR in a way that would bring more benefits and fewer side-effects.

The third pathway is that of AMPK, which signals the opposite of what ISS and mTOR do: scarcity of food. Interestingly, AMPK upregulation shuts off one of mTOR’s multiprotein complexes. It has also been associated with longevity.

Finally, the fourth pathway is the one of sirtuins, which you might have heard of because of that “sirtfood diet” waaaay back when Adele found success with it (though it is a doubtful diet). Sirtuins aren’t skinny genes, they are epigenetic modulators.

They can be upregulated through calories restriction, though the net benefits on longevity are not as clear cut (some studies, often shoved under the rug, having even found it to decrease longevity in mammals, if they werent the type to gorge on 6000 calories a day). Regardless, activating sirtuins in and of itself should provide a benefit, as they work to keep the epigenome as it should be in the different types of cells. We have already discussed the importance of epigenetics identity, in part 1, and it should be understood that upregulating sirtuins is associated with greater longevity.

Altered cellular communication

Altered cellular communication mostly has to do with inflammation, which, if you remember, is partly triggered by senescent cells. Inflammation alters pathways with which cells communicate with one another.

This is the case, for example, for the immunosurveillance of potentially cancerous cells. It doesn’t happen as much in older people, which is one of the reasons they get cancer at an astonishingly higher rate (though it is by no means the only reason).

Another example of a pathway that gets broken through altered cellular communication is the NF-kB pathway, which is ironically a pro-inflammatory pathway in itself. As we age, that particular pathway is upregulated, which in turn creates more inflammation which further damages other pathways.

Yes, even the pathways of anti-inflammatory messenger RNAs! Infeed, aging is a feedback loop.

It’s no surprise, then, that studies have proven that targeting the altered communication pathways that have been damaged through inflammation increases organismal lifespan.

Conclusion

Now, I did say that altered cellular communication was the final pathway in the Cell journal’s classification, but not all classifications are exactly the same, and the SENS research foundation addresses one further hallmark of aging, which I might write about in the future. (It’s called extracellular matrix stiffening.)

In the meantime, I hope this overview helped you make sense of what happens during aging. May it not happen to you. At least, I vote against that. You can also vote against that with your dollars by donating a little here and there to foundation working to tackle it such as the Buck Institute for Research on Aging, or the LEV foundation by Aubrey De Grey. (that makes me think, I should compile a list of effective longevity foundations sometime soon).

In the meantime, be well, be healthy, I’ll see you in the next one.

Sources

The bulk of the article is from this paper by Cell. It’s a great and very detailed paper which I encourage you to read if that’s something you’re interested in. https://www.cell.com/cell/pdf/S0092-8674(22)01377-0.pdf

Calories restriction shortening mice lifespan: https://pubmed.ncbi.nlm.nih.gov/19878144/