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Must die?

How and why we age. By Leonard Hayflick. Translated from English: Emmanuel Lotem. Published by Y.L. Magnes, 377 pages, NIS 96

By Zvi Yanai

Albrecht Dürer, a 93-year-old Yeshish head from 1521

"Old age," Hayflick quotes an anonymous source, "is that period of life when more and more things happen for the last time, and less and less things happen for the first time." True. And as if that wasn't enough, we don't know why. The fact that it is the fate of every living being to grow old and die raises a long series of difficulties: Is death a biological necessity? How long can youth be extended? Slow down aging? postpone death? In 15th century Europe, Hayflick writes, old men were advised to suck milk from the breasts of virgins, or alternatively to sleep next to a virgin as a virtue for longevity. With the rise of the power of science in the 18th century, the belief in its possibility to guarantee immortal life increased. "A day will come," declared Condorcet, the secretary of the French Academy of Sciences at the time, "and death will come solely as a result of extraordinary accidents or the science of life forces."
Since then, 250 years have passed, and even though science has increased its validity, the biological limit continues to stand at 115 years. It is not for nothing that the 20th century experienced a flourishing of private clinics that tried to circumvent this rule by injecting fetal cells and testicular extracts of elderly and monkeys into elderly people with unknown appetites. To teach you that fools don't die, they just change.

Hayflick's book reviews at (excessive) length and with the help of detailed tables the various theories proposed for the aging phenomenon. At the beginning of the century, aging was believed to be a consequence of rapid metabolism. For example, a mouse lives for three years, a rabbit for seven, an elephant for 60 and turtles for up to 180 years. Raymond Pearl, the father of the "pace of life" theory (1928), believed that every animal is born with a given amount of life energy - which it can spend quickly or sparingly, similar to a water well that can be emptied with a spoon or a bucket. But further studies have shown that the pace of life is not a general principle.

46 years earlier, the German biologist August Weissmann put forward the "wear and tear" theory. According to this theory, death occurs because the rate of wear and tear of body tissues is faster than the rate of regeneration. Another theory attributes aging to the gradual accumulation of waste in the cells. During youth, the garbage disposal mechanisms work with maximum efficiency, but as time passes, their efficiency decreases and the amount of toxic substances in the cell gradually increases, until it collapses.

These and other theories - including two of the most popular - are dismissed by Hayflick on the grounds of a lack of solid evidence. The first is the free radical theory, which was first proposed in the 50s. According to this theory, certain molecules break down and combine with oxygen, which gives them increased chemical activity to the point of disrupting the operation of DNA and other substances in the cell with which they come into contact. Indeed, laboratory animals that received anti-oxidizing substances (antioxidants), such as vitamins C and E as well as beta carotene and melatonin, extended their lives up to 30% and more than the control groups.

Hayflick treats these findings with caution, since it is impossible to know for sure whether the animals that were fed with anti-oxidant vitamins were averse to it and therefore consumed less food. And if they did avoid overeating, then the reason for their longer life should be sought in a lower consumption of calories, which is another hypothesis for longevity. The second theory places the cause of aging in the error and malfunction repair mechanisms operating within the cells. This theory, proposed by Leslie Orgel in 1963, pointed to errors and breakdowns that occur in the process of protein production in the cell, a process that begins with the copying of the protein's genetic code from DNA to RNA and ends with the production of chains of amino acids in ribosomes.

Indeed, in the course of evolution, no less than six different systems were developed to correct the disruptions of copying and replication in the cell. However, as time passes, these repair mechanisms lose their effectiveness, and their activity goes awry. The problem with this theory, Hayflick says, is that it has not been shown that old cells necessarily contain a greater number of errors than young cells. What is surprising in Hayflick's lengthy review is his partial reference to later findings related to his own discovery. Because that's how we should expand on it.

Hayflick's discovery is related to the question of whether death is a biological necessity or the result of biological mechanisms that can be repaired, renewed and perhaps even eliminated. The very fact that six cellular mechanisms were found whose job it is to locate the errors and malfunctions in the copying and replication of the genetic material, is to testify that if we knew how to maintain their normal activity, it might be possible to slow down the aging process.

Behind these mechanisms stands an interesting problem: why did evolution not develop fail-safe mechanisms for correcting the copying and replication errors in the genetic material of the cell? After all, natural selection faced two equally plausible options: one was to ensure eternal biological life for the individual, with the help of inexhaustible repair mechanisms, which would have allowed the individual to give birth to an unlimited number of offspring; The second strategy is to put the emphasis on developing rapid and intensive reproductive capacity at a young age, at the expense of sophisticated maintenance mechanisms. Natural selection chose the second option: it gave the animals a short, healthy and very fertile youth, but after the birth of the offspring, a gradual disintegration of the life mechanisms begins.

The choice of the second strategy raises three central questions: A: If death results from the activity of biological mechanisms, how do these mechanisms know when to activate the aging and wear and tear process? B: Do biological clocks work in cells, counting their lifespan? C: If such biological clocks do exist, is it possible to slow them down, or even stop them? These questions stem from an experiment conducted in 1912 which showed that cell tissue taken from the heart of a rooster could divide in culture without limit for decades. This was seemingly conclusive proof of the view that cells are immortal by nature of their creation. Meaning, if every living being is destined to grow old and die, the blame should not be sought in the cells but in external factors, perhaps hormones and perhaps other environmental factors. And here, in 1959, Hayflick grew a cell culture taken from human fetal tissue, with the aim of finding cancer-causing viruses, but to his surprise, he found that these fetal cells divide about 50 times and die. Furthermore, when they took tissue from an older person, they found that the number of cell divisions was reduced accordingly.

These findings contradicted the dogma regarding the eternity of the cells and their non-involvement in the aging process, as they indicated that all the cells of our body are assigned a limited and predetermined book of divisions. In 1961 Hayflick sent the results of his research to a scientific journal. The article was returned to him a few months later on the grounds that his findings were inconsistent with existing knowledge.

It took ten years for the scientific community to digest the fact that our body cells are not immortal, and no less importantly, that they probably contain a clock (of which no one knew anything at the time), which starts ticking even before we are born and counts the number of divisions left for them to divide until the final extinction of the body The mechanism of this clock was only revealed in 1990 in the form of telomeres - repeated sequences at the ends of chromosomes, built from three of the four chemical letters of DNA. Each time the cell divides, the chromosomes shorten by several layers of telomeres, until the remaining amount of telomeres cannot prevent the chromosome from breaking apart, similar to a shoelace that has lost its plastic end.

The discovery of telomeres in turn raised two central questions: can this biological clock be stopped, and alternatively - can it be set again?
The inspiration for these questions comes from two types of cells that divide indefinitely:

Germ cells and cancer cells, whose eternal youth generate opposite results (the germ cells produce new life while the cancer cells cause the death of the owner of the cells), but is it possible that they are activated by a common factor? It turns out that it is. The common factor is a gene for a cellular enzyme that is activated in cancer cells and sex cells, called telomerase. Whenever these cells divide, telomerase renews the layer of telomeres that was cut during division and thus preserves their original length.

For some reason, the activity of telomeres and telomerase is given by Hayflick but a brief and partial mention (in the introduction to the second edition of his book and on page 149). No less surprising is his disregard of the crucial role played by the P53 gene in protecting the body from turning malfunctions in the cell into cancerous processes, as well as the phenomenon of apoptosis - which is a kind of cell suicide program, which is activated following the invasion of the cell by violent viruses and its damage from various environmental factors, such as radiation, chemicals and over-oxidation from free radicals .

Hayflick's lack of reference to the interplay between telomeres and telomerase is particularly surprising, since if the clock that sets our days is embodied in the telomeres, and if the telomeres maintain their original length, then there is a chance in principle to activate the telomeres or silence them in a controlled manner, thereby extending our lives. That is, if we manage to prevent the activity of normal telomerase cells, it may be possible to prevent their cancer. Alternatively, if we know how to suppress telomerase activity in cancer cells, it may be possible to cause their death and thus prevent the spread of cancer. Two studies were recently published that illuminate these prospects in a new light.

Researchers from the "Gron" company in the USA managed to make a culture of skin cells divide 400 times or more with the help of a piece of DNA that was inserted into the cells. This stimulated the production of telomerase in them and caused them to function like young skin cells with extreme division potential. The interesting thing about this experiment is that when the production of telomerase was stimulated from the outside, the skin cells renewed their youth, while when the telomerase was activated from the inside, the cells became cancerous. If this research fulfills the hopes placed in it, in the future we will be able to apply an ointment to old and wrinkled skin that will externally stimulate the production of telomerase in its cells and renew their youth. In a second experiment, they succeeded in developing a substance that prevents the production of cellular telomerase. Introducing this substance into cancer cells could possibly suppress the production of telomerase from the inside, thereby slowing down the cancer process.

Despite the great interest these findings arouse, one should not conclude from them that telomeres and telomerase hold the sole key to the fountain of youth. In fact, nerve and muscle cells also die, even though they do not divide. Furthermore, mice are equipped with longer telomeres than ours and yet they only live three years, while fruit flies continue to function well even when their telomeres are running out. Indeed, Hayflick does not support the view that we grow old or die because we have not exhausted the number of divisions allotted to them. He finds reinforcement for this assessment in the fact that cells of very old people can multiply themselves several more times.

It is not that aging is not the result of a single biological mechanism, and this is without a doubt one of the reasons why the puzzle of our aging and death remained the same even at the end of the 20th century. And perhaps it is good that we have not solved this great puzzle, because the extension of life inevitably creates dilemmas for society that are no less difficult than these that death placed before us.

According to Hayflick, "the debates going on today about the use of sophisticated systems to sustain life and the right to abort, are nothing compared to the ethical dilemmas that will arise if we are given the ability to slow down the aging process or extend life." For example, eliminating cancer and heart disease would extend our life expectancy by 17 years. This means increasing federal spending (in the US) on health (and nursing expenses) by $85 billion per year (at 1983 dollar prices). Furthermore, if each person could choose for himself at what age to stop his aging process, no small dilemma would arise, since, Hayflick asks, "How should I treat my parents who are younger than me, my children who are older than me, and my brothers who are aging at different rates?" Hence: "The problems caused by the ability to slow down the aging process, or even slow it down, will be enormous and harmful to the individual and to society at large."

And as if that were not enough, Hayflick warns that these problems will be nothing compared to mass mortality from malnutrition, wars, poverty and demographic and ecological holocausts, which will be our lot if and when we become immortal. Instead of dealing with slowing down aging, Hayflick recommends striving "to maximize human life expectancy through the elimination of the leading contemporary causes of death." The desired scenario in his eyes is this, "where all human beings reach the maximum life span, while they are still gifted with all their physical and mental powers, and death will come quickly when we approach, say, our birthday."115

If this scenario does materialize, we will have 3,473,840,000 seconds, which are 60,474,240 minutes, which are 41,996 days. That's a lot of time for those who know how to turn chronological time into quality time.
Zvi Yanai's book "The Endless Search: Conversations with Scientists" was published in Ofakim Library, published by Am Oved

{Appeared in Haaretz newspaper, 5/7/2000{

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