Monday, August 24, 2009

The 7 Types of Aging Damage That End up Killing You

The 7 Types of Aging Damage That End up Killing You
The longer you live, the more time you have to explore the world. (Photo by iko)

If aging merely meant the passage of time, there'd be nothing wrong with it.

In fact, it'd be a good thing. The older you got, the more things you would know, the more skills you would've acquired, the more experiences you would've had, and the more people you would've met. All this while retaining the strength and vigour of youth. Doesn't sound too bad.

The problem is that what aging really means is the passage of time accompanied by a set of degenerative biological processes that harm the abilitity of our bodies to function and eventually cause us to die. What good is all that knowledge and all those experiences if you can't remember any of it? What good are all those skills when you're no longer able to use them?

We don't really know why we age. That's an interesting question in its own right, but it's beyond the scope of this post. The point of this post is to take a closer look at the biological processes that accompany the passage of time and together form the seven classes of aging damage.

It is because of this process of biological decay that we grow old. Not old the way vampires are "old" yet still magically look the same, but the way people and animals are old
fragile, weak and sick. To be clear, despite what most people tell themselves, there is nothing good about growing old, because all it really means is a cumulative and irreversible increase in fragility, weakness and sickness.

The good news is that despite decades of studying aging, we have identified only seven types of primary damage to our bodies from aging. The rest are secondary consequences of primary damage. If you prevent the primary damage from occurring, you will prevent the secondary consequences as a result, but not vice versa.

And why is it a good thing that there are seven causes of aging? Because it means that the aging process is not a complete mystery anymore. Or rather, the consequences of the aging process are not a complete mystery to us. Even though we don't have a clear explanation for why these seven types of damage occur in the first place (i.e. why are we not born biologically immortal?) we have a pretty good understanding of how they work.

And if we know all the things that are going wrong with our bodies as we age, we can begin to fix them.

The three approaches to the sinking boat problem

Imagine that the human body is a boat. For many years, the boat sails without a problem. But then, somewhere in the middle of the ocean, there's a problem: a hole has appeared in the bottom, and the boat is going to sink.

Now imagine that on that boat, there are three people: an architect, a mechanic, and a museum keeper. You go to them and ask each one in turn what could be done to fix the situation.

The architect has no experience in repairing boats. He is interested in understanding the nature of boats. He has heaps of drawings of boats and calculations for which kind of materials are suitable for a specific type of boat, but he doesn't actually build the boats. His suggestion is to study the boat carefully to understand the exact reasons that caused the hole to appear. If we understand the causes, he figures, we are better equipped to fix the problem.

You know there's no time for all that because the boat is sinking fast, so you go to the museum keeper. He runs a museum with old boats on display and has some experience on renovating worn down boats for museum use. He's not really interested in making them actually usable at sea; all they need to do is look good. His suggestion is to just let the boat sink, because sink it will, and then come back later to drag it from the bottom of the ocean and put it on display.

That doesn't feel like such a great idea either, so you turn to the mechanic. He has no idea where the hole came from, isn't familiar with the exact type of boat, and is in no hurry to visit the ocean floor. But he does have a plan: have two of you scoop the water back into the sea as fast as possible, while the other two find something to fill the hole with. There's no guarantee that another hole won't appear later on, but at the very least, his plan is going to buy you extra time.

At this point, extra time sounds pretty damn good, so you go with the mechanist's suggestion and grab the nearest bucket to start scooping.

Gerontology, engineering and geriatrics

There are three approaches to the study of aging: gerontology, engineering and geriatrics. In the boat metaphor above, the architect is the gerontologist, the mechanic is the engineer, and the museum keeper is the geriatricist.

Broadly defined, gerontology is the study of aging. It encompasses a wide range of subfields, but for the purposes of this post, biogerontology is the subcategory of interest. Biogerontologists seek to understand the biological processes that cause aging. A fascinating field of study, for sure, but as the boat example illustrates, when you're the one actively falling apart, perhaps a bit too theoretical.

Geriatrics, on the other hand, is a branch of medicine focused on the health care of the elderly. The emphasis is on treatment rather than prevention. One could even say it's about alleviating the symptoms rather than reversing the damage, much less fixing the cause. The problem is that the geriatricist has no interest in helping you unless your boat is already beyond repair.

The engineering approach to aging is to fix the damage as it occurs. The purpose is not to fully understand all the reasons that the damage happens in the first place, interesting as it may be; it's enough to know that it's there. Rather, the emphasis is on periodic repair and maintenance, so that even after years of use, the boat still looks, feels and sails like new. And if during those extra years of use maintenance buys us we learn something new about how to make boats more resistant to damage, all the better.

To me, the engineering approach is a matter of priorities. Yes, it would be fascinating to understand the complete workings of the human body, but it's much less fascinating to die trying now than it is to live significantly longer and find out later. Besides, the more years you have left, the more time you have for things like research and thus the more chance of succeeding in mapping out every possible metabolic pathway. Life should be our first priority in everything, because death cuts everything else short.

The seven deadly sins of aging

Without further ado, let's take a look at what the seven types of aging damage are and what we think can be done about them. Again, while identifying the different ways in which aging manifestates itself doesn't really explain why the damage happens, or even why there are exactly seven types of damage, it does provide us with clear goals for an engineering approach to life extension.

This approach of focusing on rejuvenation rather than slowing down aging itself is referred to as SENS, or Strategies for Engineered Negligible Senescence, a term originally coined by Aubrey de Grey in his book The Mitochondrial Free Radical Theory of Aging. Each of the SENS strategies targets one of the seven types of damage, listed below.

1. Cell loss and shrinking tissue

Worn out cells in the body are usually replaced by cell division. However, as we age, some of the cells we lose can no longer be replaced or they are replaced very slowly, which means that cells are being lost faster than they are produced.

In skeletal muscle, cell loss means shrinking tissue and weaker muscles. In the heart muscle, it means a more fragile heart. In the brain, it means a loss of neurons and causes a host of mental problems. Currently, one of the best approaches to cell loss is exercise, but its effects are nevertheless very limited.

The solution: stimulating cell division or introducing new cells (repleniSENS)

2. Mutations in the cell nucleus

Two types of changes in our chromosomes occur as we age: mutations and epimutations. The former are changes to the DNA itself, while the latter are changes to the propensity of the DNA to be decoded into proteins.

In some cases, changes to the DNA can lead to the formation of cancer. Non-cancerous mutations and epimutations do not in most cases contribute to the aging process, and in the rare cases that they do pose a problem, they are taken care of by other strategies (repleniSENS and apoptoSENS), so we don't have to worry about them at this point. Cancer, however, is definitely a problem, as anyone who's looked at mortality statistics in the Western world can testify .

The solution: removing the genes needed for telomerase (OncoSENS)

3. Mutations in the mitochondria

Mitochondria are known as the "power plants" of cells, because they play a key role in energy production. They also control cell growth and the cell cycle. Mitochondria contain their own mitochrondrial DNA (mtDNA), which encodes a small but important part of the proteins in the mitochondrion.

The problem is that the mitochrondrial environment is highly oxidative, and the repair mechanisms are much less sophisticated than those in the cell nucleus, which contains most of the DNA. The result is that mitochondria are very vulnerable to the accumulation of mutations, which is thought to accelerate aging. Therefore, preventing the accumulation of mitochondrial mutations requires a strategy of its own.

The solution: moving the DNA into the cell nucleus for better protection (MitoSENS)

4. Cells that refuse to die

Sometimes cells can acquire a state in which they are no longer able to divide but refuse to die, causing damage to neighboring cells. There are three classes of cells that can go into this harmful state: visceral fat cells, senescent cells and immune system cells. The problems that the accumulation of these cells cause are insulin resistance, tissue degradation, and vulnerability to infection.

Normally, the body is able to get rid of such harmful cells through apoptosis, a signal for the cell to kill itself. When the cells stop responding to these signals, other methods are needed to destroy them. While surgery can be used to remove visceral fat, the main alternatives to destroying senescent and immune system cells are injecting something to force apoptosis or stimulating the immune system to kill the cells.

The solution: forcing cell suicide or using the immune system to kill target cells (ApoptoSENS)

5. Tissue stiffening from crosslinks

The body is much better at keeping the insides of cells clean than it is maintaining proper functioning outside the cells. Inside the cells, proteins are regularly destroyed and rebuilt to keep things running smoothly, but outside, some proteins are recycled very slowly or never. With time, these long-lived proteins can run into problems.

Chemical reactions can sometimes cause two proteins to form a chemical bond known as a crosslink, which hinders their ability to slide across or along each other. Advanced glycation endproducts (AGEs) are probably the most famous example of crosslinks. When too many crosslinks occur, tissues lose their elasticity and problems arise. In artery walls, for example, tissue stiffening causes an increase in blood pressure. Breaking these crosslinks is needed to maintain a youthful state.

The solution: using specific enzymes or proteins to break crosslinks (GlycoSENS)

6. Junk outside the cells

This is another form of junk outside the cells that accumulates with aging, but it differs from crosslinks in that it has no useful function whatsoever. This junk should be cleared out of the body, but as in the case of death-resistant cells, the body is not able to digest or remove the material.

An example of junk outside the cells are the amyloid plaques in the brains of Alzheimer's patients. This web-like material accumulates in everyone's brains with age, but problems become visible only after a certain threshold has been reached. In supercentenarians, extracellular junk is one of the biggest killers.

The solution: stimulating the immune system to clear out the junk (AmyloSENS)

7. Junk inside the cells

As mentioned earlier, the body is fairly good at breaking break down proteins and other molecules in the cell which are no longer useful. However, sometimes these molecules have gone through chemical changes that makes the cell unable to digest them any longer. They then end up in the lysosome, which is the most powerful place to degrade molecules. If the lysosome is unable to get rid of them, they end up as intracellular junk and stay there practically forever.

In dividing cells this is not too big of a problem, because each division dilutes the junk, and the threshold where problems occur is not reached. But in non-dividing cells, the accumulation of this junk eventually causes the cells to stop functioning correctly. The result is problems such as atherosclerosis, blindness, liver spots, and a host of neurogenerative diseases.

The solution: making the lysosome more powerful to degrade the junk (LysoSENS)


There you have it, the seven types of aging damage that need to be fixed in order for true rejuvenation engineering to happen. And how do we know the list ends here? Isn't it possible there are other causes we just don't know of yet? Theoretically, yes, but it seems highly unlikely. Here's an explanation taken from the SENS Foundation website:

We can be confident that this list is complete, first and foremost because of the fact that scientists have not discovered any new kinds of aging damage in nearly a generation, despite the facts that research into aging has been slowly accelerating and that we have had ever-increasingly powerful tools with which to investigate the aging body.

Challenging as fixing this damage may be, the fact that we know what we need to do should still leave you with a fairly optimistic view of things. As I've said before, solving these problems is really a question of "when", not "if". And the sooner it is, the better – for all of us.

Even if you're not studying or working in the field, there are a couple of very practical ways to help make these rejuvenation therapies come true in your lifetime. The SENS website has a pretty good list of things with something for everyone, but I'll mention two important ones here.

Money is always needed, so one good option is to donate to the Methuselah Foundation or to the SENS Foundation to support research (and if you're sceptical of donations actually doing anything, here's some good news: a recent target of $16,000 was succesfully reached and exceeded earlier this month for research on using lasers to remove intracellular junk).

Another important thing is to talk to people and spread the word: many people don't have any idea that life extension is not just science fiction anymore. Significantly longer and healthier lifespans are the future, and just how far away this future is depends entirely on us.

For more information on preventing aging, see these posts:

How to Live Forever: My 5 Steps to Immortality
Slowing Down Aging with Intermittent Protein Restriction
Who Wants to Live Forever? Results from a Global Survey
Anti-Aging in the Media: New York Times on Caloric Restriction and Resveratrol

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2 kommenttia:

gwarm April 27, 2011 at 5:41 PM  

What do you make of this Neu5Gc?

I have been eating red meat for the carnosine glycation inhibition, but what about this?

JLL April 28, 2011 at 12:33 PM  


Not sure what to make of it at this point -- but I wouldn't read too much into the rodent studies. Avoiding red meat to avoid obesity just makes no sense. As for other diseases like cancer... well, I'd like to see some hard data on that first.


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