Causes of aging
David James, Professor of Biogerontology, University College London
The causes of aging are one of the main issues of biomedicine. Now they are unknown, but I can offer you a historical overview of ideas about what researchers think causes aging and what is happening in this area, but this is my point of view. I don't think a consensus has been reached in this area. But what I'm going to tell you is not some crazy personal ideas.
For many years, there has been a general, dominant hypothesis about the nature of aging. This dominant thought about the biology of aging has guided experiments and the formulation of hypotheses in this field. It consists in the fact that living organisms are complex systems and, like other complex systems in the inanimate world, such as mechanisms, they wear out over time. Complex objects wear out. If you look at a person or an animal as they age, it looks exactly like this.
With the development of modern biochemistry and molecular biology, there has been a tendency to seek definitive answers to our questions at the molecular level. There was also an idea that, perhaps, aging is the result of wear at the level of molecular processes, that is, molecular damage. There are many theories about how molecular damage causes aging, but most are united by the idea that it is arbitrary damage, arbitrary wear of molecules. This led to the fact that we began to look at what can cause damage accumulating with age and what their nature is. Evidence that aging is a process of damage accumulation appeared quite early. If you look at proteins and DNA, at lipids of laboratory animals or elderly people, you will see the accumulation of damage: you will see the accumulation of DNA damage, protein oxidation and the like.
For several decades, one idea has been particularly popular – this is the idea that we live in an oxidizing environment and this is the main engine of aging. According to this idea, the body simply cannot help but accumulate oxidative damage, and it is they who cause various diseases associated with aging. This theory has been actively tested for twenty years, especially in the 1990s and 2000s. In the late 1990s, everyone believed in this theory, especially that if you install protection against oxidative damage and damage by free radicals, you can protect yourself from aging. If you go to a health food store today, you can still find antioxidant supplements there, buy superoxide dismutase in capsules and everything like that - as a cure for aging. But in the 2000s, this theory was thoroughly tested on animal models: C.elegans nematode worms, fruit flies and mice. Antioxidants were added to their diet or their genes were changed in such a way as to strengthen their internal resistance to oxidative damage and give them an additional opportunity to neutralize oxidants in cells. The research results obviously contradicted the theory. In my laboratory, we spent about 10 years testing – not continuously, but from time to time – this theory on C.elegans, using a variety of approaches. The theory is simply wrong.
I think the current state of this area is very strange. There is still a lot of interest in the concept of damage as the primary cause of aging, but partly because of problems with this theory about oxidative damage, it has practically been run away from - as well as from the idea that we can determine the causes of aging at all. There was a tendency to just say, "Well, you can't identify the cause of aging! There are so many different processes going on in us, it's naive to put the question like that." I think there is something in this, but it is a very simple solution - just avoiding the problem. Or you can accept the challenge and say, "Can we identify in some form the fundamental causes of aging?"
I think the question of the causes of aging is somewhat similar to the question of the causes of diseases – diseases unrelated to aging, normal diseases that occur in young people. One could say: "This is a stupid question: there is no one cause of diseases." But I think we can answer it. You can say: "What causes diseases? There are various reasons, but they can be divided into classes. Many diseases are caused by infectious pathogens: bacteria, viruses, microparasites. This is one type of the causes of diseases, and it is related to the microbial theory of diseases. There are also hereditary diseases: genetic diseases, congenital diseases, malformations. There are diseases caused by mechanical damage." The number of general categories of causes of diseases is limited, and it gives us a general understanding of the nature of diseases.
I believe we need to do the same for aging: we need to try, we hope, to identify certain fundamental, basic causes, and already a combination of these common causes will give us an understanding of aging. This knowledge is not enough for us now.
Recently, a theory has emerged that has become an alternative or supplement to the theory of aging as a chain of damage. It originated in the last decade and is based on an old idea of an evolutionary biologist, American George Williams. He proposed the theory of evolutionary genetics, according to which aging is controlled by our genes in a certain way: it appears not under the influence of external factors, but as a result of the work of genes, that is, internal factors. You may have genes that are beneficial in youth, but the actions of the same genes in adulthood can cause pathologies. Natural selection is much more important than what happens to you when you are young. Evolutionary fitness is the question of whether you can live to reproductive age and leave offspring. After you have successfully produced offspring, the power of natural selection decreases. If you have a new gene that increases your fitness when you are young and gives you the opportunity to leave more offspring, but the same gene will cause harm later in life, natural selection can leave this gene even if it causes aging.
There is one limitation to this theory. It is sometimes called antagonistic pleiotropy – from the concept of "pleiotropy", when changes in a gene have many effects. Antagonistic pleiotropy means that the same gene change has both positive and negative effects: with aging, positive effects are seen earlier, negative ones later. Over time, it turned out that there is a problem with antagonistic pleiotropy: it does not explain at the mechanistic level the processes taking place in the cell, it is an abstract idea. But in the 2000s, biologist Mikhail Blagosklonny, a Russian scientist working in the United States, found a way to combine recent discoveries in the biology of aging and antagonistic pleiotropy and got a new theory. It is sometimes called the "hyperfunctionalization theory". According to her, antagonistic pleiotropy can be observed in genes affecting entire programs of cellular differentiation and changes. These can be development programs, division programs, tissue regeneration programs, healing, remodeling, and so on. Activation of these programs in late life can explain many pathologies.
We tested this theory in my laboratory, and it turned out that it explains very well the origin of aging-related diseases on C.elegans. In a broad sense, this theory says that the cause of aging is our own genes. It doesn't happen because our genes are defective, and not because they don't work well or mutations appear. Good genes – "wild type" genes – as a result of prolonged action in late life, they create pathologies of old age. It is very interesting. I'm not saying that this theory explains the whole aging process. But now, after research on worms, it seems to me to be one of the main principles by which aging-related diseases appear. I think this is a very interesting trend in the development of biogerontology.
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