To the scientific mind, death is but the next great adventure

29 April 2017
Posted by Alexandra Ashcroft.

Death unites humanity. No matter your walk of life, you will die. It is perhaps the only fact that is truly universally acknowledged. It might shock you then that death does not unite species.

Immortal creatures

Examples of immortality litter the animal and plant kingdoms. There is no single unifying factor: size, environment, and lifecycle seem to have had no impact on the evolution of immortality. Turritopsis nutricula, a tiny species of jellyfish, and distantly related freshwater Hydra are “biologically immortal”. This means that they can theoretically live forever but in reality will probably die from predation. Planarian flatworms are considered “immortal under the edge of a knife”. You can cut them into nearly 300 fragments and still each piece will regenerate an entirely new organism.

If you consider Planarians immortal, then trees such as Old Tjikko, a Norwegian Spruce, may fit your definition too. Old Tjikko’s bark is young, but its roots are over 9500 years old. Old Tjikko has had many trunks and after each one has died, a new genetically identical, or “clonal”, stem has arisen from the root system. Old Tjikko only has one trunk at a time, but clonal tree colonies do exist elsewhere. A colony of Aspen in Utah has more than 40,000 trunks. Genetic testing has confirmed each trunk is an identical clone. Appropriately named  “Pando”, Latin for “I spread”, its root system is thought to be a staggering 80,000 years old.

Mechanisms for immortality clearly exist. Why then, on a planet of nearly 9 million species, have so few evolved? Any evolutionary biologist will tell you that environments change and species adapt to changing environments across generations. Immortal individuals cannot do this and so are extra vulnerable to changing environments. But this still doesn’t answer why we die, not by a long shot.

Is cellular senescence the reason why humans die?

“Why do we die” is akin to asking “where does consciousness come from” or “is life a computer simulation”. They are gargantuan, daunting questions that seem more suited to philosophy than science. However if you break them down into smaller questions and answer those, we can incrementally creep towards true understanding. We will answer these questions as you eat an elephant, one bite at a time. Most scientists now believe that death and aging are inexorably linked and that cellular aging underpins organismal aging. This is not a bad hypothesis - species like Hydra show no observable cellular aging, also called “cellular senescence”.

Counterintuitively the definition of cellular senescence is of cells that can no longer divide to make two new cells, rather than cells that no longer work. This is an important distinction. Individual cells inevitably fail and die, but as long as they can replace themselves with fresh functioning cells, the organ, and indeed organism, will remain intact. Cellular senescence prevents this turnover and we end up with organs that are extremely vulnerable to aging. The human brain is a great example of this.

Cells that have undergone senescene cannot be replaced after they break down

You may have heard that we cannot make new neurons in adulthood, this is because neurons have undergone cellular senescence. But these brain cells still work, you merely reading this article is evidence of that fact. However they won’t work indefinitely; they’ll function until they get too damaged to and, unfortunately, there are innumerable ways to injure a cell. Consider what would happen if a cell gets so damaged that can it no longer function properly and also lacks the ability to replace itself with a fresh cell. On a small scale we’d be missing a few neurons. But if this cellular damage was widespread throughout the whole brain - we’d end up with a dead or dying organ. This is essentially what is happening in neurodegenerative diseases such as Alzheimer’s.

Fortunately for us, of the 37 trillion or so cells in our body, only a relatively small amount have undergone senescence. The majority of our cells can divide and replace themselves, albeit at different rates. The knowledge that some organs can replace themselves has given rise to the myth that you get a whole new body every 7 years. This obviously just isn’t true: afterall you are stuck with the same neurons for your entire lifetime.

Aged cells undergo senescence

Unfortunately the organs that renew themselves cannot do so indefinitely. Eventually cells lose the ability to replace themselves. Scientists say these cells have reached the “Hayflick limit”. Human cells reach the Hayflick limit because of “telomeres”. Every one of our cells contain 46 chromosomes - 23 from mum and 23 from dad. Collectively they contain the unique DNA sequence that makes you, well, you. It’s really important that each cell maintains intact chromosomes. Unfortunately cell division is inherently inefficient. Each time a cell replaces itself, its chromosomes get shorter; a little bit is shaved off their ends. We have evolved to cap our chromosomes with telomeres, sections of meaningless “junk” DNA. If a cell loses a bit of a telomere, it doesn’t affect the integrity of the genetic code that defines you.

Eventually cells go through so many rounds of division that they use up all the telomeres and start losing the important parts of the chromosomes: your genes. When this happens the cell undergoes senescence. "Werner syndrome", a rare and horrific accelerated aging disease, demonstrates just how important telomeres and senescence are. Sufferers lose their telomeres at a much faster rate, end up having premature cellular senescence, wrinkle and grey prematurely and have a life expectancy of about 47.

Cellular aging and cell death are side effects of cancer prevention mechanisms

By stopping the division of cells with no, or at least extremely short, telomeres, cellular senescence protects against problems that arise when chromosomes start to lose their genes. The most famous of these being cancer, “the emperor of all maladies”. Cancer is, fundamentally, just uncontrollable cell division. Unfortunately telomeric protection against cancer comes at a cost.

By preventing cellular division, senescence makes our cells vulnerable to “oxidative damage”. Oxidative damage is caused by “free radicals” that whiz throughout our DNA like bullets, damaging everything in sight. Sadly this is a fundamental part of life, as natural as breathing. Every time our cells convert food into energy, they release free radicals. The free radicals essentially break a cell’s genes and when too many genes get damaged our cells die or turn cancerous. When a senesced cell gets too damaged to function, it activates a genetic kill switch and dies.

Unfortunately the process of telomere shortening, senescence, cell damage and then death is not foolproof. Free radicals damage DNA randomly and sometimes they damage the genetic kill switch, resulting in cells that cannot die. Some free radicals damage the DNA of a cell before it has entered senescence and actually damage the genes that turn on senescence in the first place. These cells are extremely dangerous as they can divide indefintely. If free radical bullets hit these cells again and destroy the genetic kill switch you get immortal and cancerous cells.

It seems, at a cellular level at least, we are in a constant battle against cancer. At one end of the spectrum we have living and at the other, uncontrolled cell growth and division, or cancer. Cell death, of which organismal death may just be a by-product, acts as a break to stop us reaching the cancerous side of the seesaw.

Immortal cells are needed to create humans

The idea that evolution has selected for aging and death to keep us balanced in a sweet spot between cancer and living feels almost kafkaesque. Why are we needing to fight against cancer at all? Cancer arises as a side effect of our ability to replace our cells - so why are we doing it? Why not just have one set of cells that last our lifetimes, like in the brain? The answer lies in your very conception.

When your father’s sperm fertilised your mother’s egg you were just a single cell. A single cell however with the remarkable capacity to divide a million times over to generate an entirely new organism. Although progressively lost throughout successive cellular generations, all of our cells retain this regenerative capacity to some degree. Without checks and balances to limit the regenerative ability encoded in our cell’s DNA, we get cancer. In excess however these mechanisms, such as cellular senescence, cause aging and death.

These theories are but the tip of the iceberg and give rise to more questions than they answer. Why do our brain cells last lifetimes before being too damaged to function, but our gut cells last mere days? Can we use what we know about senescence to fight cancer? Can we limit free radical damage to fight aging? Whatever the answers, it’s clear demystifying death is going to keep scientists going for a long time... It truly is the next great scientific frontier.

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