Dr. Amir Bashan from Bar Ilan University investigates how a process that begins randomly, unplanned and differs between different people and even between different cells in the same person, eventually leads to the same predetermined results?
From the moment the embryo is created, it develops and grows into an adult according to a precise genetic plan. Is aging simply the continuation of the same plan? Most researchers are convinced not. Although the symptoms of aging, such as wrinkles, white hair and a general decline in the body's function, are common to all humans, they are actually the results of a process of erosion and random wear and tear of the cells, the accumulation of a lot of unplanned damage such as random genetic mutations or damage to the DNA structure.
And here is a paradox. How does a process that begins randomly, unplanned and varies between different people and even between different cells in the same person, eventually leads to the same predetermined results?
There are several theories that try to answer this gap - and they will have great significance regarding our ability to influence the aging process and possibly even extend life expectancy. The conventional approach claims that most cells are actually unaffected by the random weathering process because they are only slightly damaged. Aging is the result of a small number of cells in each tissue whose degree of damage has been great enough to cause serious failures. For example, a cell that is significantly damaged can activate a "self-destruct" mechanism or enter a kind of coma - and stop functioning. This can cause a decrease in the function of the entire tissue.
In contrast to this, about 15 years ago, Prof. Jan Wijeg and other researchers proposed a completely different approach. Inside every living cell there are thousands of genes whose activity is precisely controlled, like an orchestra with thousands of musical instruments. Prof. Wijag claimed that in aging many cells are damaged only a little and lose only a little the exact control of genes, but the ability of the cells to act together as tissue is significantly damaged. According to Prof. Vijay, in old tissue each cell plays a slightly different symphony.
This theory was hard to digest. Instead of putting the finger on specific failures, she spoke of a general disorder, not really defined, involving all, or a large part of the cells. This difference is very significant when we think about developing an anti-aging treatment. It is possible, at least in principle, to remove a few rotten apples from a pile of good apples, but what can be done when all the fruits are not rotten but also not fresh?
Beyond that, it was difficult to find results that support the theory. In the last ten years, scientists have been able to measure the activity of the genes in each individual cell and it was expected that this would make it possible to identify the same general disorder. But the results were confusing. In some tissues and in some cell types the aging effect was seen, but in others - not. It would seem that the theory does not really describe the basic process of aging.
This is where we came into the picture. Physicists have experience with phenomena resulting from the joint action of many elements, in particular when they have random characteristics, in fields called statistical physics and network science. It turns out that in many examples, from computers on the Internet to the network of neurons in the brain, the functioning of the system mainly depends on the connections between the elements and their coordination.
The proper functioning of biological tissue also depends not only on the exact activity of each gene but on the coordination between them. As in an orchestra, each instrument will be tuned independently, without precise coordination between them - the melody will be jarring. In a biological cell, coordination is achieved by a network of interactions between the genes. We wanted to check: during aging, do injuries accumulate in the coordination mechanisms that cause a decrease in the ability of the genes to work together? Does the orchestra of the gardens begin to forge with age?
The way to answer this question is not easy. We do not have the full map of that network of interactions that is responsible for the coordination between the genes, so it is also difficult to identify if it was damaged. But, fortunately, sometimes you don't need to know all the details to understand the big picture. In the research, we developed a new computational method that can measure the level of coordination between the genes even without having the detailed picture of the entire network. We used this method to study gene activity in individual cells and compared the coordination levels as measured in "young" cells (from a young mouse) to "old" cells (from an old mouse).
With the new method, we saw what they could not see with the previous methods. The old cells started to lose the ability to coordinate between the genes. To check how consistent this phenomenon is, we went back and analyzed data collected from no less than twenty experiments conducted in six different laboratories around the world. In all cases we saw the same phenomenon of the loss of coordination between the genes in old cells, whether it is fruit flies, laboratory mice or humans. For the first time we saw that Prof. Vijag's theory from 15 years ago is actually happening.
Later in the study we saw that the same decrease in coordination between the genes is directly related to the accumulation of genetic damage. If so, the picture that emerges is this: during aging, damage accumulates randomly in the control mechanisms of the cells and impairs the ability to coordinate between the genes. As a result, there is a general decrease in the coordination between the genes in old tissues.
Such a picture opens the door to new directions of practical importance. Is the same decrease in coordination between the genes that we have seen that returns consistently, indeed a significant factor that actually leads to the aging phenomena? If so, the efforts to develop treatments for healthy aging should focus not on searching for specific cells that have been severely damaged, but on developing methods to delay the accumulation of damage in the first place, for example by strengthening the natural repair mechanisms.
What can be done to prevent aging? Dr. Amir Bashan: "If it is just a few 'weeds', a few cells that have been severely damaged - then they must be treated." But in the article we found for the first time broad evidence of a phenomenon that may be much more problematic - that the decline in tissue functions in aging is caused as a cumulative effect of all the small damages that happened to many cells, perhaps to all of them. In other words, it is not about point failures but about a phenomenon that affects all the cells horizontally. This has significant implications for the whole approach of how to repair. If this is indeed the case, we have two options: one, to find ways to reduce the rate of damage accumulation through prevention - for example, nutrition, a healthy life span, reducing mental stress, reducing exposure to certain substances, etc. [By the way, this is very similar to the two strategies for fighting cancer: treating malignant cells - which have already accumulated too many mutations, or preventing mutations by reducing exposure to risk factors. The image between aging and cancer is not accidental. These can be two results of the same process - random damage accumulation]
A second option is to take advantage of the natural repair mechanisms that exist in the cells. Our cells have maintenance mechanisms that know how to deal with damage. When the rate of damage (for example, the rate of mutations) exceeds the rate of repair then the damage starts to accumulate more and more. If we find a way to strengthen these mechanisms - we may be able to prevent, or delay, the process."
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