Crossing Swords with Senescence

Nothing fucks you harder than time.

Game of Thrones

Photo by Scott Robinson – (https://flickr.com/photos/clearlyambiguous/27211012)

Aging is a self-evident truth. It is so much a part of our life that we never question it but accept it as a fundamental nature of life. I didn’t bother to question it when I started to lose my hair or when my beard turned grey. Strangely at some point I even started enjoying it, after I falsely convinced myself that these are signs of wisdom and knowledge. However the reality finally hit me right on the face. It was the day when I noticed my chest hair turn grey! I could not take it any further. It hits even harder when we notice the rapid decline in our parent’s health and physical strength.

Aging is a process of progressive and irreversible decline in the vitality of the human body. Why do we age and die? Is it possible to stay youthful forever? Can death become an option? I am well aware of the existence of fundamental impossibilities in reality. It is impossible to create or destroy energy-mass (Conservation laws). And it is impossible to create a machine that generates work with 100% efficiency (Laws of thermodynamics). Do aging and death belong to the realm of biological laws of impossibility? But, I also strongly believe in a sweet little rule – There is always something more to do. Impossibilities will always exist and the realm of possibilities will always continue to expand.

To understand human aging we need to break down our body into individual elements. We are fundamentally made of atoms like every thing else in the universe. These atoms of carbon, hydrogen, nitrogen and oxygen join with each other and form molecules of variety of shapes and forms. Trillions of molecules cooperate to form a machine called cell. Trillions of cells cooperate to form the next level of organization, organ. Organ systems cooperate to form the human body. Where does aging operate in this hierarchy of an organism? Is it at the atomic level or at a level above it?

Let’s get our definitions clear before we leap into understanding the truth

Phases of life

There are four phases in life

Birth is an event when the First cell is formed by the fusion of an egg and sperm. This first cell carries all the knowledge that is needed to form a mature organism when adequate material and energy are provided.

Growth is a process during which cells increase in number, organs get bigger and the organism grows up in size to attain maturity.

Aging is a continuous process of progressive decline in the vigor and the ability to flow energy. It gradually takes the body towards death with time.

Death is an event in which the coherent functioning of organ systems fail and the organism loses its ability to flow energy. The body will be spontaneously dismantled to its elements following this event.

Molecular aging

Do atoms or molecules in our body undergo changes over time and contribute to initiation or progression of aging? I am not a physicist, but I am pretty sure that stable atoms in general are immortal for all practical considerations. We are predominately made of stable atoms and they were formed billions of years ago in some far away stars. Over these years they have not changed their shape or form in any obvious ways. So they should not be changing during the life span of an organism. However our body also carries unstable atoms in its structure. The unstable atoms are the ones that decay over time. We have plenty of Carbon – 14 and Potassium- 40 in our structural make up. Imagine what would happen when a Carbon -14 in the DNA of a brain cell spontaneously decays and disrupts the bond and the DNA structure. I would expect a significant domino effect. Apparently over a lifetime, around 50 billion C-14 decays occur within human DNA! I don’t even know how we exist in spite of these molecular explosions within the code-script. At this rate I would expect our body to be studded with cancerous cells on a daily basis. Well, thanks to repair mechanisms that subdue this effect. Also the atoms in our body are constantly recycled. Molecules break down, gets purged out and new molecules are created using fresh set of atoms from the air we breathe and the food we eat. The atom that is part of my body today will probably belong to a worm or a bird next week. Only the organization of the atoms remains more or less constant but the building blocks are continuously recycled. Only the atoms that go into making the DNA of brain cells, proteins in the eye lens and the calcium in our tooth enamel once incorporated stays with us for the lifetime. At death, the physical properties of these atoms would look exactly the same, as it was when they first got stuck with us.

In conclusion, atoms don’t age, they are continuously recycled and unstable atoms in our body constantly try to collapse our integrity.

Cellular aging

Cells form the next layer in the organizational hierarchy of human body. There are trillions of cells in our body and they cooperate to maintain the structure. Previously it was thought that cells don’t age and they are immortal like the atoms. It was believed that the cells divide into daughter cells and that every time they divide it maintains the youthfulness and vitality. Later it was proved that the healthy cells are only capable of a limited number of divisions. It is partly due to the fact that a fraction of DNA does not get copied during each replicative cycle and its content gets progressively smaller. Eventually it reaches a point where it can not replicate any further. Hence in general, cells age with time and then it eventually dies.

Cells are an active enterprise that continuously process energy and generate work. It has a powerhouse that generates useable form of energy from food. The energy feeds the molecular machines that moves and pumps cargo within the cells. There is a data center that has instructions to accomplish all of these activities. It is as busy as a human city with efficient nanobots doing all the chores. Hence atoms are the structural unit and the Cells are the functional unit of the body. Over time this functional unit accumulates error in reproducing the data, carrying out the instructions from the data, building abnormal molecules that accumulate, nanobots that are dysfunctional and a structure that is fragile – In short they age. But cells have been in existence for over 3 billion years and it had acquired mechanisms to counteract this effect by evolution. Errors in DNA replication can be corrected, abnormal proteins can be removed before they could form molecular machines and most molecules are continuously recycled and refreshed to maintain the youthfulness.

There are immortal cell lines that can multiply continuously and maintain the vigor. Cancer cells or certain types of genetic mutations gives cell the capacity to multiply rapidly and indefinitely. HeLa cell line is the most popular immortal cell line. However, though these cell lines can divide continuously they do not have the order that exist in healthy mortal cells. They accumulate mutations as they divide and the daughter cells may not have much resemblance to the parent cells. So these rogue cells may not age but they change so much that the parent line can be considered dead for all practical purposes.

Conclusion, cells age and die. But it has robust repair mechanisms which also eventually succumbs to time. If they don’t age and die then they mutate, become deviant and incapable of maintaining any higher level of organization like organ system or human body.

Aging organ

An organ is a complex organization of different types of cells working in synchrony to produce a set of functions. Heart is an organ that pumps the blood and lung is an organ that take up oxygen from air and loads it in blood. Though the actual function sounds simple, they are extremely sophisticated structures. For example, the human heart beats about 100,000 times in a day and pumps about 2000 gallons of blood everyday. During the lifetime, it pumps about a few billion times before it stops.

Everyone of us must have personally experienced the changes associated with an aging organ. Aging skin is the most obvious. Lungs attain the maximum capacity at around 25 years of age and then it continues to lose about 25-30 ml of air every year for rest of the life. The vitality of an organ greatly depends upon the health of each and every cell and it’s ability to co operate. These cells are held together in a precise three-dimensional structure by specialized supporting proteins. Unfortunately this delicate and complex network of cells and proteins that support them are prone to wear and tear with time. The cells become less vigor, the structure loses its physical properties and the organization (organ) gradually loses its function.

Aging human body

If you notice carefully as we climb up in this hierarchy we observe an interesting phenomenon. The atoms that are static in form for billions of years associate with each other and builds highly dynamic networks. When the atom is a free folk, it is battered repeatedly by the molecular storm of heat and it wanders aimlessly. Once it is incorporated in the organization of molecules, cells, organ or organism it becomes part of a system performing directed work using energy. These structures are capable of performing variety of functions including highly sophisticated ones like wanting to go to the moon or crave for a cold beer.

Aging and death is only applicable to the higher organizations but not to the building blocks. Atoms are ageless – But molecules break, cells lyse, organs weaken and the organisms age.

Human body is a cooperative network of different organ systems. Each organ loses its vitality at different rate. The heart and blood vessels together called as the cardiovascular system, is the first to age to failure. ‘Natural death’ does not happen to a human body by the aging of the lungs, kidneys, liver or skin. Even when the body is 100 years old, these organs could still function normally albeit with much less vitality. However it is likely that the cardiovascular system would have aged to failure before the centenary celebration.

Not so wise

To avoid aging, the individual parts of our body must be recycled and refreshed continuously otherwise the body will be corroded by the natural elements within a short period of time like other non-living things. The process of replacing the molecules and cells with new ones maintains the youthfulness of the organism. Thus the body must remain dynamic and should keep hitting refresh button to prevent corrosion yet the overall structure and form should remain static and the exact same. This is possible only when the knowledge to build the structure is intact but the material that goes into the construction will be replaced. This is like an obsessive builder who is sitting inside a house and does constant repair. To maintain the integrity of the house, the builder replaces few bricks every day with a new set of bricks. In this way the overall structure is always maintained new. However it only last as long as the builder has the knowledge to build the house. Once he loses his memory or after he dies the house will begin to disintegrate. Similarly with time a key aspect of our life crumble and this process of recycling cannot continue indefinitely. The key aspect is the ‘evolutionary knowledge’ that is present in the ‘First cell’. A knowledge that was accumulated by trial and error over a couple of billion years of evolution – The accurate three-dimensional arrangement of trillions of atoms in the First cell. This knowledge that was present in our First cell is capable of building the human body by taking in the material and energy from the environment. With every successive replication of the cell, errors creep into the knowledge and the daughter cells are not as wise as the mother cell. Before the knowledge could be permanently lost from the body and while the body is still in its prime health, the sperm cell and the egg cell from the human body passes the intact knowledge to the next generation of life, and in this way the knowledge continues to survive in the species while the individual withers away with time.

Cooperation and coherence

In addition to possessing the knowledge to perform functions like producing chemicals (insulin), generating electricity (brain), transferring materials (kidney) or generating brute force (muscle), the cellular machinery also has the knowledge to cooperate and act in coherence with other cells.

Cooperation is a trait in which the individual cells invest in behaviors that are costly to themselves but benefit the organization. The cells have the higher knowledge to understand that fitness of an individual cell depends on the survival of the organism.

Both types of knowledge were acquired over 3 billion years of cellular evolution. The first set of functional knowledge was predominantly acquired during evolution of unicellular life like bacteria or yeast. The evolution of multicellular organisms like animals and trees endowed cells with cooperative knowledge. Every human cell carries accurate and comprehensive details of all the knowledge that was acquired by life over 3 billion years. Our cells are very similar to bacteria or yeast. A small change in some of the molecules decides whether the first cell is going to become a bacteria, chicken or human.

During the life of an organism, nature corrodes this knowledge and we gradually lose our youthfulness.

Cellular senescence is characterized by both loss of function and cooperation. Cells become weak and cancerous. Cancer cells are rogue cells that have lost the understanding of usefulness of organization. This usually happens due to changes in the data center (Genome or epigenome). They go about independently trying to establish a less organized state and eventually both the organism and the cancer will die with the collapse of the superstructure.

Aging is the most significant risk factor for cancer development. It is much more potent than cigarette smoking and alcohol put together in causing cancer. In fact aging is the most important risk factor for almost all type of human diseases including heart attack, stroke, diabetes or hypertension. It is the major cause for natural death of an organism!

Ancient war between Biology and Physics

Disciplined observation and experimentation have enabled us to listen to the language of nature. Now we can understand disease at the molecular level and treat cancer and many other diseases by manipulating the molecular structure of the body. In the last couple of decades, science has unraveled the molecular underpinnings for aging. We are currently at a point where aging can be dealt and treated like disease and not as an inevitable aspect of life! Few decades ago, tuberculosis was not seen as something that could be treated and death due to it was considered inevitable. But now it is a curable disease and so are many of the cancers.

Firstly, aging is not an active process and there is no gene in our body that actively instructs people to wind down with time. Our ‘First cell’ was programmed to last forever. We don’t have any clock inside of us that is ticking away. It is the nature outside of us that is gradually chipping us away. Aging is a physical process in which chaos consumes order with time. We see it everywhere, things naturally tends to disorder. This is purely a natural behavior, popularly described as the second law of thermodynamics. Knowledge is needed to establish order and then continuous work output is needed to maintain it.

The cellular knowledge and the work it performs hold the system against time for a certain period. Eventually it succumbs once the knowledge is irreversibly lost. The advancing human knowledge regarding this order and how to maintain it might further prolong this ancient fight against the tide of time.

Researchers who have been diligently working against aging were able to identify genes and molecules that constantly do the work of repairing the genomic and the epigenomic changes that causes aging. Simple measures such as the stress of fasting and exercise boosts the efficacy of these repair bots and keeps the knowledge and hence the order intact for a longer period. In the future we may be able to tweak this whole system by just adding molecules like the way we thwarted small pox and lot of the infectious diseases!

Yes, aging can be treated and death can be delayed or even conquered. There is always something more to do… we are only limited by how much we know.

References:

1. Lifespan: Why we age and why we don’t have to. David A Sinclair and Mathew D. LaPlante. Atria Books. Sept 2019.

2. Intercellular competition and inevitability of multicellular aging. Paul Nelson and Joanna Masel. PNAS. Dec 2017.

3. Information and knowledge in biology: time for reappraisal. L Kovac. Plant signal Behav. March 2007.

4. Life’s Ratchet: How molecular machines extract order from chaos. Peter M. Hoffmann.

5. Physics makes aging inevitable, not biology. Peter M. Hoffman. http://m.nautil.us/issue/36/aging/physics-makes-aging-inevitable-not-biology.