In a few months I'm turning 30 so maybe the fact that I'm again interested in longevity and aging it's not a coincidence. My chronological age doesn't bother me; if anything, today I'm stronger, faster, leaner, happier, wiser and more knowledgeable than a decade ago. But my biological age does bother me. It's a slow decay barely noticeable when I look in the mirror but it's there. And I know that with time it's going to accelerate.
But why? Why my immune system will decay slowly over time? Why my skin will get wrinkles? Why I will have more and more an increased risk of cancer, diabetes, cardiovascular disease and mental illness? Why I'll eventually lose most of my bone and muscle mass? And most importantly what is causing all that at the the most basic level? That's what I want to share with you. I'm not going to lie to you: this is going to be a long read but it's a actually a short recap on the science of aging. So grab a cup of your favorite hot beverage and let's ask: Why do I age? and Why do you age?
In the past month I've read many books that go over the science of aging so you don't have to. Just kidding. You have to. You definitely do. My advice is to grab at least one of these books and do a deep dive. But only after you've subscribed, read and shared this post, of course. Let's get started.
There are several theories of aging, and there are so many because the aging process is extremely complex and not fully understood. Not by me and not by anyone. You'll see why in a minute. But we do have some good hypothesis about why aging happens. You may have heard about some of the theories:
- Oxidative Stress Theory → proposes that aging is caused by the damage that free radicals cause to cells and tissues when their levels are too high or when they are not properly regulated. This is the main reason why health and supplement brands want to sell you antioxidants. They can donate an electron to the free radical, neutralizing it in the process
What are free radicals?
The cosmos is within us. We are made of star-stuff. We are a way for the universe to know itself. In this spirit, let's consider the role that free radicals play in the grand scheme of things.
Free radicals are highly reactive molecules that contain at least one unpaired electron. This makes them unstable and prone to reacting with other molecules in order to try to stabilize themselves. Free radicals can be formed in a variety of ways, such as through the normal processes of metabolism, or as a result of environmental factors like pollution or radiation.
While free radicals are a natural part of life, they can also be harmful if their levels become too high. This is because they can attack and damage cells and DNA, leading to a host of problems including inflammation, aging, and even cancer.
However, free radicals also have some beneficial effects. They can help to kill off infected or damaged cells, for example, and they also play a role in the body's immune system.
So, in a sense, free radicals are like the cosmic messengers of change, bringing both destruction and renewal as they travel through the universe of our bodies. They may be small, but they are an integral part of the grand cycle of life.
Explanation in the style of Carl Sagan courtesy of ChatGPT.
- Immune Theory → proposes that the aging process is caused, at least in part, by the degradation of the immune system over time
- Telomere Theory → suggests that the aging process is related to the shortening of the telomeres with each cell division. They eventually become too short to protect the chromosome, leading to cellular senescence or death
What are telomeres?
Think of telomeres as the protectors of the genetic information within our cells, much like how the atmosphere protects the Earth from the harshness of space. Just as the Earth's atmosphere shields us from harmful radiation and cosmic debris, telomeres help to protect the ends of our chromosomes from damage or degradation.
But just as the Earth's atmosphere is not impervious to all threats, telomeres also have their limits. Every time a cell divides, the telomeres become slightly shorter, eventually reaching a point where the cell can no longer divide and begins to age or die.
This process plays a role in the aging of our bodies, as well as in the development of certain diseases. It is a reminder of the delicate balance that exists within the universe, and the important role that even the smallest structures can play in the health and well-being of life on Earth.
So the next time you look up at the night sky and contemplate the vastness of the universe, remember the tiny but vital role that telomeres play in the grand scheme of things.
Explanation in the style of Carl Sagan courtesy of ChatGPT.
- Information Theory → also known as Epigenetic Theory suggests that the aging process is caused by the gradual loss of important information from cells and tissues due to damage from different sources
- DNA Damage Theory → proposes that the accumulation of DNA damage over time is the major contributor to the aging process
These theories, and many others, propose different mechanisms by which aging occurs, and they are not mutually exclusive. It is possible, plausible and highly probable that multiple mechanisms are at play in the aging process. What we know for sure is that aging is caused by a limited number of mechanisms and in 2013 a group of researchers categorized them in what we today know as The Hallmarks of Aging.
The Hallmarks of Aging
I have a software engineering background so it's normal that I like frameworks. The Hallmarks of Aging is just that: a framework which identifies nine biological mechanisms that we believe to contribute to the aging process. These are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These mechanisms are not necessarily mutually exclusive, and they can interact with each other in complex ways. Let me briefly explain each of them.
- Genomic instability → our DNA is constantly exposed to environmental stressors, damage from toxins or radiation and errors during replication or repair. The cell usually repairs most of the damage but not always. So over time DNA accumulates genetic mutations and changes in its sequence. Most of the times this will cause loss of cellular function and cell death but as we age this greatly increases the chances of cancer, neurodegenerative disorders, and cardiovascular disease
- Telomere attrition → the replication mechanisms of our DNA can't copy all the way the end. Nature is smart and has placed protective caps (telomeres) at the ends of our chromosomes that shorten with each cell division. When telomeres become too short, cells can no longer divide. This leads to a decline in immune and tissue function which highly increases our risk of cardiovascular disease, diabetes, and cancer
- Epigenetic changes → most cells in our body, as different as they are, have the same DNA. But instead of using it all some genes are active (or expressed) and others are dormant. As we age, the activation and deactivation (epigenome) of specific genes become increasingly unstable. This eventually leads to loss of cellular function and an increased risk of cancer, neurodegenerative disorders, and cardiovascular disease
- Loss of proteostasis → all mechanisms that keep us alive depend on proteins; without them, life would not be possible. They are our body's molecular machines: elaborate, highly complex and absurdly diverse. Proteostasis is the balance of their synthesis, folding, and degradation within a cell. As we age, proteins get damaged and stop folding and working the way they're supposed to. So most cellular mechanisms that life depends on, also stop working they're supposed to
- Deregulated nutrient sensing → our cells have the ability to sense and respond to nutrients that are available in their surrounding. As we age, this ability gets well... deregulated. This is caused by changes in hormone levels, altered gene expression and the accumulation of damaged proteins. This eventually leads to diabetes, obesity, cardiovascular disease, poor functioning of the immune system and the decline of tissue and organ function
- Mitochondrial dysfunction → the mitochondria are the powerhouses of our cells, responsible for generating energy. The thing is... they act more or less independently and they have their own DNA. So as we age, the same genomic instability and loss of proteostasis will occur within the mitochondria too: damaged and mutated DNA and accumulation of damaged proteins and other waste products within it. All this eventually leads to a decrease in energy production, to an increase in oxidative stress and can even produce harmful byproducts, leading to a decline in cell function
- Altered intercellular communication → as we age, the communication between cells can become impaired. This can include changes in the signaling pathways that cells use to communicate with each other, as well as changes in the structure and function of the cells themselves
Why do cells need to communicate with each other?
The universe is a vast and complex place, filled with countless forms of life and an infinite variety of phenomena. At the most fundamental level, all living things are made up of cells, which are the basic units of life. These cells are the building blocks of life, and they perform a wide range of functions that are essential for the survival and reproduction of organisms.
One of the most important functions of cells is communication. They communicate with each using chemical signals and electrical signals. This communication is essential for the coordination and regulation of the many processes that occur within an organism.
For example, cells in the human body communicate with each other in order to maintain homeostasis, which is the balance of internal conditions that is necessary for the survival and function of the body. Cells in the immune system communicate with each other in order to fight off infections and protect the body from harmful pathogens. And cells in the brain communicate with each other in order to process and transmit information, allowing us to think, feel, and interact with the world around us.
The universe is a vast and complex place, filled with a diversity of life forms that are all connected through the intricate web of cellular communication. It is this communication that allows cells to work together to maintain the balance and harmony that is necessary for life to thrive.
Explanation in the style of Carl Sagan courtesy of ChatGPT.
- Senescent cells → with time, some of our cells stop dividing and enter a state of zombiness. Not entirely dead but not quite alive either. The immune system usually gets rid of most of them but not all. The ones that stick around release inflammation-promoting molecules and alter the microenvironment of surrounding cells. They can accumulate in various tissues and organs as we age, and their presence has been linked to cancer, cardiovascular disease, and neurodegenerative disorders
- Decline in stem cell function → stem cells are the cells in the body that have the ability to self-renew and differentiate into different cell types. As stem cells divide and replicate over time, they accumulate damage: DNA mutations, oxidative stress, and inflammation. This leads to a decline in their ability to function properly and to a reduction in the production of new stem cells. This reduces the ability of tissues and organs to regenerate and repair themselves which further increases the risk of cancer, cardiovascular disease and neurodegenerative disorders
There is some debate in the scientific community regarding the exact number and nature of the hallmarks of aging. Since the original publication of this list, several additional hallmarks have been proposed, including immune system decline, chronic inflammation, compromised autophagy, and changes in the microbiome. There is also ongoing debate about the relative importance of each of these hallmarks in the aging process, and how they may interact with one another.
There has also been some controversy about the usefulness of the framework itself and some scientists think it's time to use at least an update version. I personally think that until we don't have a better option, the critique itself is not adding much to the table. Everyone knows the limitations of the framework at this point.
However, most scientists agree that these hallmarks play important roles in the aging process and in the development of age-related diseases. We need to invest in more research to fully understand the mechanisms underlying these hallmarks and how they can be targeted to slow down or even reverse aging.
The army within
Until I turned 10 or so, my tonsils get infected every winter. I remember my father injecting me with antibiotics every 6 hours. It was horrible. My immune system was shit. I had bad luck and maybe even bad genes. Because the immune system typically becomes less efficient as we age. That can lead to an increased susceptibility to infections and a decreased ability to fight off diseases. This decline in immune function is known as immunosenescence and some think it is a hallmark of aging.
There are several factors that contribute to immunosenescence:
- Decreased production of certain immune cells → as we age, our bodies produce fewer T cells, B cells, and other immune cells, which can reduce our ability to mount an effective immune response
- Changes in immune cell function → the function of immune cells can also change as we age, leading to a decreased ability to fight off infections and diseases
- Inflammation → chronic inflammation, which is common in older individuals, can impair immune function
- Environment → exposure to environmental toxins and other harmful substances over a lifetime
- Lifestyle → poor diet, lack of exercise, and other unhealthy lifestyle habits can also negatively impact immune function
- Genetics → some individuals may just be more prone to immunosenescence because of their genes
Despite everything, the immune system is still able to provide some protection against infections and diseases even in older age. But as happens with the process of aging, the immune system is complex, and the exact causes of immunosenescence are not fully understood. Yet.
I contain multitudes
The microbiome is the amazing ecosystem that lives inside each and every one of us: bacteria, viruses and fungi. Specially in the gut, and their relative abundances can vary depending on diet, lifestyle and the use of antibiotics.
In recent years we've learned that the microbiome is much more important than we thought. It helps to regulate the immune system, protects against infections and aids in the digestion and metabolism of nutrients. It's also involved in the production of certain vitamins and other compounds that are important for health.
We now have evidence that the composition of the microbiome changes as we age. For example, some studies have found that the diversity of the microbiome decreases with age, which may be associated with an increased risk of inflammation and metabolic disorders.
There is also evidence that the microbiome may influence the aging process through its effects on the immune system. I've already explained how dysregulation of the immune system can impact aging.
It also may influence aging through its effects on metabolism. The gut microbiome plays a role in the digestion and metabolism of nutrients, and changes in the microbiome may affect metabolism and energy balance.
The microbiome is so complex that, like aging, we don't fully understand it so we need to keep investing in research to understand how it impacts the aging process.
Inflammation is not necessarily a hallmark of aging, but it is a common driver of many age-related diseases. It is a common immune response that occurs when the body's tissues are injured or infected. You are pretty used to inflammation: swelling, redness, heat and pain. It is essential for the body to repair and protect itself. But there is a type of chronic inflammation, or low-grade inflammation that persists for long periods of time, and it has been linked to the aging process and the development of various age-related diseases. We even have a term for that: "inflammaging".
What many people may not realize is that the roots of this insidious process may begin much earlier than we think. While it is more commonly associated with older adults, evidence suggests that various factors – including genetics, diet, lifestyle, and environmental exposures – can all play a role in the development of chronic inflammation at any age. For example, individuals who are exposed to chronic stress, have poor diets, or have certain genetic risk factors may be more prone to developing inflammation earlier in life, increasing their risk of developing age-related conditions like cardiovascular disease, diabetes, and certain types of cancer later on.
Now you and me both have a pretty good understanding about the biology of aging. The science underneath. I do advise you to go deeper. It's a fascinating world so pick up any of the books I mentioned at the beginning of this post and read it. Ageless by Andrew Steel is the one I would pick up first. Alternatively if you're more into YouTube videos than books, check out this playlist by the American Aging Association.
In a future post I'll explore what are the current advancements in rejuvenation therapies and who is working and investing on them.
Meanwhile, check out my practical longevity framework. I've put together a set of tools that I use for practical and applicable longevity in my day to day. It focuses on physical exercise, nutrition, sleep, cognitive health and supplements.
If you'd like to join me in this journey, just subscribe and share it just with one person.