The Hallmarks of Aging

Intuitively, for each one of us, aging is “when you grow old and ultimately die”. However, aging is an incredibly difficult phenomenon to define precisely, and no general consensus has yet been reached by the scientific community as to what exactly it means. Today, the best framework we have to describe and understand aging is a set of 14 biological mechanisms, called “The Hallmarks of Aging”. Addressing each one of these mechanisms is the best action plan we have today to slow down aging.

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Before 2013, there was a permanent fight between scientists, in a “there can be only 1 of us” conflict, each one of them trying to prove that his theory of aging was the right one, at the detriment of the neighbour’s. However, as some theories were able to explain some observations related to aging, none was able to reasonably explain all of them. Eventually, scientists came with this “Hallmarks of Aging” framework, which encompasses the complexity of the phenomenon, and determine everyone to collaborate in good faith again to move the science of aging forward.

This article is going to be a little bit longer, first because as discussed earlier, aging is a complex phenomenon, which even if simplified to the extreme, still needs some focus and time, and secondly because this post is going to put in place the general knowledge and structure of what’s coming in the news weeks or so, as we’ll do deep dives in each one of the topics below, to illustrate the research that’s being made to address each specific hallmark of aging, and the mind-blowing breakthroughs we expect to come in the next years coming from these specific directions.

1. Telomere Attrition

Telomeres are the small bits of DNA at the end of your Chromosomes. Every time one of your cells divide, and your chromosomes within those cells are copied, these bits of non-coding DNA will shorten. After a couple of dozen of divisions, the telomeres are shortened to exhaustion, and any further cell division will end up cropping small bits of your useful DNA information.

2. Genome Instability

There are 2 main reasons why your DNA information is partially lost as you age. The first one is that when your cells divide, the copying of your DNA is indeed incredibly accurate, but not perfect. The second reasons is that throughout your life, your whole body will suffer a certain level of stress, due to internal and external factors: oxydative stress (from so called ROS – Reactive Oxydative Stress), what you eat, sun radiation, even cosmic radiation. Multiple mutations to your DNA generate dysfunctions in your body, as the cells don’t fully fulfil their roles as they should anymore.

3. Proteostasis Perturbation

Your body is a wonderful piece of chemical machinery, with literally thousands of incredibly complex processes at the cellular level, which govern how the whole system works. At the core of these processes are the proteins, which are the basic bricks of human life. How these proteins are produced, maintained in the right balance and the adequate concentrations, is paramount to the vitality and health of your body. As we age, the dynamics and concentrations of these various proteins in our body starts to dysfunction, leading to frailty, diseases and ultimately death.

4. Stem Cell Exhaustion/Degeneration

Stem cells are undifferentiated cells, similar to the ones foetuses are created from. As kids and healthy adults, we all have stem cells spread all across our bodies, which are used by our body to regenerate (as part of systemic physiological processes, as well as in case of accident). However, the proportion and quality of stem cells decreases as we age, resulting in our body being unable to properly regenerate damaged tissue anymore.

5. Epigenetic Deprogramming

It’s common knowledge nowadays, that our DNA dictates how our body works. However, DNA is just half of the story (in fact, some scientists say it’s only around 20% of the story, but more on this later). The rest of the story is that as cells differentiate from stem cells to specialized cells (such as neurons, skin cells, etc.), large portions of our DNA get silenced by a mechanism called “methylation”, and only the pertinent portions of the DNA related to the specialization of each cell are being expressed. This makes total sense, as you don’t want neuron-related portions of DNA being expressed in skin cells, for example. Well, the bad news is that as we age, this “methylation” mechanism gets chaotic. Thus, you end up having cells in certain tissues behaving as cells in other tissues. No surprise that this partial loss of cell identity ends up in a big mess 🙂

6. Altered Energy Sensing

When you’re young and in good health, your cells have a remarquable capacity to adapt to a wide range of energy and resources related situations. It senses how much oxygen you have in your blood, what the demand in terms of energy production is, how urgent and critical it is, how much glucose and insuline is in your blood, etc … As you age, the performance of the whole “energy sensing” system decreases, with cells taking the wrong decisions as to how much energy to produce and what to do with it, which leads to dysfunctional mechanisms (as for example insuline resistance, related to Diabetes).

7. Altered Intercellular Communication

Cells communicate with each other, and it has even been recently discovered, as incredible as it may sound, that in extreme situations, “better off” cells will create nano-bridges/nano-tubes to connect with other stressed cells, to send them parts (such as mitochondria) and nutrients, to prevent them from dying. As we age, this communication is more and more disturbed. Not only cells don’t help each other anymore, but stress signals emitted by certain cells end up contaminating the cells around them, in a snowball effect.

8. Cellular Senescence

Cells are meant to fulfil a certain function, and reproduce as part of the natural regeneration tissue flow. However, when the DNA baggage of a certain cell is damaged or the overall disorder in that cell goes beyond a certain threshold, this leads either to cell death (called apoptosis), either to cell senescence, which may also be remembered as “zombie mode”: the cell is not dead, but is not working properly anymore, is not dividing anymore. Therefore, not only does it use resources at the detriment of other healthy cells, but it also sends negative signals to its proximity, contaminating other cells and turning them into zombie cells as well.

9. Mitochondrial Dysfunction

Mitochondria are the energy production factories of our cells. In short, they eat up glucose, and turn it into another product called ATP, which is used as energy currency in the cell. As we age, there are fewer mitochondria, and their quality is also lower, and without proper levels of energy, the maintenance processes of our cells are heavily impacted.

10. Compromised Autophagy

When cells don’t have enough energy, it may actually be a good thing (more on this in future posts). In those situations, cells turn into a particular mode where they’ll recycle and clean up accumulated toxines and unused reserves. This is positive, as these unused waste is at risk to clutter the cells, and increase the disorder in their processes. Well, as we age, autophagy does not work properly anymore, so the damaded parts of the cell don’t get recycled anymore.

11. Microbiome Disturbance

The Microbiome is the whole bacteria and other micro-organism ecosystem, which lives in symbiosis with your body, and is located in your gut. The nature of these micro-organisms, and how they interact with your gut, is closely related to your health: digestive diseases come from microbiome problems, even neuro-degenerative diseases seem to be related to it. Recent studies seem to suggest that as we age, the microbiome changes also, leading to our food being less well decomposed into basic nutrients for our body.

12. Inflammation (also called inflamm-aging – no pun intended)

Inflammation is the way our body reacts to agression. It is a healthy and essential part of how our body protects itself from pathogens. When it’s “business as usual”, you get a wound, a disease, and then that part of your body will swell, 2 hormones proper to inflammation are produced – bradykinin and histamine – and everything is set up for recovery. However, as we age, the inflammation may become permanent (chronic), leading to exhaustion of your immune system. In addition to this, your immune system gets disoriented, and starts attacking healthy cells, further affecting the overall functions of the affected tissues.

13. Altered Mechanical Properties

Our cells do not just plainly “stick” together by themselves. They’re placed in “collagen complexes”, that come in many shape and sizes, which form the basic “scallfolding” structures for our bodies. For example, the degradation of our collagen structure accounts for our skin being less and less flexible as we age, and wrinkles appearing on our faces. Collagen is produced by a specific category of cells called fibroblasts. Well, chaotic collagen creation and preservation generates not only aesthetic discomfort, but also functional damage, in our bones, our muscles, heart, etc.

14. Splicing Dysregulation

Splicing is the process by which the DNA gets transcripted into mRNA. In order to understand it, let’s get back to basics (remember your high school biology classes). Your DNA lies within the nucleus of your cells. When your cell needs to create a protein, the first step is to unfold the DNA from the chromosomes, and to copy the portion of relevant DNA in the form of mRNA, which is then sent outside the nucleus of the cell, to manage the creation of that protein. The process by which DNA is turned into mRNA is called the transcription. However, the mRNA is not an exact replica of the relevant DNA. Before it is sent outside the nucleus of the cell, it suffers a process called “splicing”, which consists of cutting portions of the copied DNA, and linking them back together. Well, this process of “splicing” works less well in old cells.

Tadaaaaaa, this is it! Now you have the big picture of what’s going on in your body as you age, and also what the scientific community is working on as I write this, in their laboratories!