Aging is not a wear process (translation)

Hi, Habr! I present to you the translation of the article by Joshua Mitteldorf (2010), the author of the book “Aging is a Group-Selected Adaptation” (2017).


The idea that bodies wear out with age is so old, widespread and deeply rooted that it affects us on a subconscious level. Undoubtedly, many aspects of aging, such as oxidative damage, somatic mutations, and protein cross-links, are characterized by increased entropy in biomolecules. However, for more than a century there was a scientific consensus that there was no physical need for such damage.

Living systems are characterized by the ability to collect order from the environment, its concentration, as well as entropy discharge with waste. In the growth phase, organisms become strong and strong; there is no physical law that could prevent this endless progress. In fact, some animals and many plants are known for unlimited increase and increase of fertility throughout life. The same conclusion is emphasized by the experimental data that various lesions and problems that directly destroy the body or increase the level of wear and tear have the paradoxical effect of increasing longevity. Hyperactive mice live longer than mice from the control group, just as worms with an impaired antioxidant system live longer than wild-type worms. The fundamental understanding of aging should not come from physics, but from an evolutionary perspective: the body becomes eligible for aging when the recovery and regeneration systems, which were excellent at the stage of building and rebuilding the body with a process of constantly increasing elasticity, are now beginning to be reversed. Regardless of the reasons for this extinction, it will be more fruitful to focus on stimulating the effects of the ongoing activity of the recovery and regeneration systems than to try to repair the multiple damage.

“Aging is a physical process of deterioration, because damage accumulates faster than it can be repaired”: this idea is so generally accepted and embedded in the thinking process of gerontologists and practicing doctors, which is rarely called into question. At least since the times of the Renaissance, such an understanding of aging has been accepted by scientists and philosophers, poets, doctors and non-professionals. This remains the basis for a huge amount of current medical research, as well as the core of the SENS (Strategies for Engineered Negligible Senescence) program. But despite its ubiquity and general appeal, this idea was discredited by physicists in the nineteenth century and their analysis remains convincing. Evolutionary biologists take the bar higher and look at the question through profound biological causes,

In this article, the theoretical relationship between life and the Second Law of Thermodynamics will be clarified, and the reasons for believing that physics requires aging from living things will be deconstructed. Also in the future will be cataloged some predictive failures of the “Theory of Destruction”. In the final, if a huge range of natural age rates — at least six orders of magnitude — if this is not a sufficient reason to discredit the idea that aging is inevitable, then the existence in nature of organisms that do not age at all should definitely be refuted.

History of Thermodynamics

The idea that order spontaneously and universally collapses to disorder is very old, but in 1850 it was quantified quantitatively as the Second Law of Thermodynamics. The merit of Clausius was in the inclusion of entropy as a quantitative physical variable. He distinguished the ideal “reversible” from the “irreversible processes” that take place in the real world and demonstrated that the ideal processes retain entropy. whereas in real cases the entropy should always increase. The Second Law of Thermodynamics is sometimes formulated as follows: in any closed physical system, the entropy will increase until its maximum value is reached. The state of the system in which the entropy reaches its maximum value is called “equilibrium”.

The second law explains why the stone seeks to roll the hill down turning its potential energy of gravity into insignificant heat. Metal fatigue and oxidation are similar examples of irreversible processes in which entropy accumulates. But the law applies only to closed (isolated) systems, and it is possible for processes to accumulate information in a single object, while entropy is scattered elsewhere. For example: when the pool of water evaporates, the liquid can be cooled (low entropy) because the gas dissipates with high entropy, which exceeds the compensation. If the water contains salt, the salt may solidify in the crystal after the water has dried. Crystal has a much lower entropy than dissolved species. This water vapor carries high entropy. Disrupting the balance between liquid water and heat,

Living things penetrated this loophole of the Second Law and are designed separately. The continuing ability to collect free energy from the environment and concentration in order, rejecting entropy as waste is a characteristic property of living systems. Each multicellular organism is able to grow from a seed into a fertile adult. Characteristically, the risk of death for an adult is lower than for the immature stage and of course the fecundity (by definition) is higher. Therefore, growth and development establishes “negative aging” in both biological and thermodynamic values. There is no theoretical justification for the impossibility of this infinitely continuing process. An organism can continue to grow larger, become more prolific and more resistant to mortality of all varieties upon reaching maturity, and some, in fact, so do. To explain the decrepitude we will turn to evolutionary theory, and not to thermodynamics.

The role of Weismann

If living organisms wear out like machines, then there is no evolutionary need for aging. But multicellular life succeeds in an outstanding feat of constructing complex systems of fragments found in the environment, using only genetic design to simply fall apart due to the inability to perform the much more modest task of supporting the completed soma in a reasonable working order. A generation after Charles Darwin, Augustus Weismann articulated the necessary biological puzzle of aging and saw the explanation not in physics, but in evolution. Weismann is known for his first evolutionary theory of aging, but his departure from physical aging was not so clear. His original theory was based on the assumption that the destruction of the adult catfish was inevitable and that the destruction should accumulate over time.

Weismann retreated from this theory at the end of his life, and instead wrote about the loss of the immortality of somatic cells when it becomes an unnecessary luxury. But this persisted until Peter Medavar formulated the necessary logical flaw in Weismann’s theory: “Weismann believes that the oldest in his race wear out and become decrepit — a very characteristic state of affairs, which he tries to comprehend the reasons for — and then starts arguing that because these feeble-minded animals they take the place of the healthy, the healthy must replace the old by natural selection. ”

Medawar was well aware that there is no need for thermodynamics for wear and accumulative destruction. He saw an explanation of aging not in physics, but in evolution, based on the declining power of natural selection with age. The evolutionary community does not look back, and today there is wide agreement that aging cannot be explained as a physical necessity, but must be understood as any biological phenomenon in terms of natural selection.

Is somatic recovery a complex or costly process?

It was argued (largely due to Hamilton) that the recovery of an adult organism cannot be flawless, and that recovery errors and support must inevitably accumulate, eventually leading to death of the organism. Such a premise also exists in Kirkwood's “One-time Soma" theory. But the rationale is logically nekkorektno as James Waupel demonstrated. There is nothing flawless in the new adult organism as well as in supporting it; this is not the process that requires flawlessness. together it will take several weeks. The bone was not perfect until it breaks and will not be after its healing. But the repaired bones are stronger than the original bones and will not be broken again in the same place. bones will improve its initial effect exceeding the initial 100%,

The bodies of mammals are equipped with an impressive set of recovery mechanisms, ranging from the molecular level to the level of tissues. Proteins are converted into compound amino acids when they are damaged; but in old animals this process becomes ineffective. DNA is constantly being examined and restored. Ineffective mitochondria will be eliminated and replaced under the control of the cell nucleus. Like whole cells are regularly destroyed by apoptosis and replaced when they are damaged. All these processes correspond to youth and keep the body from loss of function, but over time they begin to progressively refuse as a result of aging, causing accumulated senile damage. However, the effectiveness of these processes in youth indicates the fact that recovery can be as effective as necessary.

Free analogies may indicate that at some point in the life of an organism, damage accumulates at the point where the recovery of the body becomes less energy-intensive than updating through reproduction. This idea underlies the theory of disposable soma. Our experience with artificial devices adds credibility to this idea; There are many reasons why a ten-year-old car can be replaced by a cheaper one than its restoration would cost, but it has no analogies in the world of biology. Cars must be disassembled before they can be repaired and reassembled later, when both biological organisms recover from the inside. Automakers appreciate the new car with a low margin and overestimate the price tag on the details, because the buyer has no choice. Auto repair service at the European and American salary working rate, when as a cheap Asian labor and cheap robots are used in production where the car itself appears. Thus, we cannot rely on our intuition using the automobile analogy in relation to living bodies.

The energy cost of restoring the old part is significantly lower than the total energy cost of reproducing one new adult. DNA repair and amino acid folding together are two processes with their inherent low thermodynamic cost, and both are well optimized for energy efficiency. In contrast, the cost of anabolism is quite high, and the cost of reproduction is multiplied by the high mortality rate at a young age. As an example, a female mouse consumes 2 times more calories during pregnancy and lactation. All this hints that a huge amount of resources were consumed to create one mature adult, as well as efforts were put into countering evolutionary pressure to protect and preserve it.

Several mammals and many primitive animals are capable of regenerating whole parts of the body after separation. Ellen Heber-Katz showed that the ability is hidden by a mouse and can be turned back on by a simple blood factor. Almost all plants and many animals are able to recover. The process is costly to restore. but cheap compared to the total cost of reproducing a new adult individual. The starfish has a legendary regeneration ability, when half the star can grow the second. But also, the starfish has a life expectancy of about 8 years. If the limb was separated from the star of 6 years of age, it will restore the whole animal that will remember its age so that the animal will have 2 expected years of life.

The wear of teeth is an example of the present accumulation of destruction leading to the decrepitude of an elephant. Elephants can grow 6 complete sets of teeth throughout their lives. but if they survive their last set of teeth (and some were found in nature), they will become toothless and will have to die of hunger. Wear theory must be strange in its ability to explain how this elephant becomes incapable of recovery after the sixth set of teeth.

Theories of oxidative damage

It has been 50 years since Denam Harman first suggested that aging is caused by the progressive destruction of body chemistry due to active forms of oxygen (ROS), which are an inevitable product of respiration. The theory has inspired thousands of research projects and continues to have a large prevalence today. The continuing attractiveness of the theory is that there is widespread evidence that oxygen damage is key to protein aging. Extensive experiments have investigated the use of antioxidants as a measure against aging. Studies were conducted both in labarotor conditions and according to the results of epidemiology. The results of this large amount of research have been disappointing, in fact showing an increase in mortality for antioxidant users. The emerging picture of the relationship between oxidation and aging is complex: peroxide is an important signal on the path of apoptosis. Apoptosis has two faces: it is a necessary mechanism for cleaning from infected, cancerous and damaged cells, but it is also embroiled in emptying sarcopenia, as well as the loss of brain cells in Alzheimer's and Parkinson's diseases. With age, important oxidative properties are less pronounced, for example, in two cases an increase in oxidative damage is observed (27 , 28 ) which suggests that oxidative damage is a secondary effect rather than the source of the cause of aging.

Theories of oxidative damage are elegant and attractive, but some experimental results seem to almost make fun of theoretical predictions. Physical activity generates an abundant amount of free radicals, but also such activity is mainly associated with prolonged, not shorter than average life expectancy. Hanson and Hakimi reported a genetically modified mouse that had an additional mitochondria. These mice are phenomenally active, eat much more wild and burn everything, they also live and remain reproductively active for 2 years longer than wild-type mice. The two most important antioxidants are superoxide dismutase (SOD) and ubiquinone. Mice in which one copy of the gene for SOD was turned off have half as much SOD in their tissues, and measurements of oxidative DNA damage show that it is much more than in the control group; still heterozygous Sod2 ± mice live a little longer than controls. The suppression of SOD in worms also prolongs life together with elevated markers of oxidative stress. clk-1 is a gene originally found in worms, the suppression of which leads to an average life extension of 40%. The homologue of this gene in a mouse is mclk1 and its removal also leads to an increase in the lifetime. Only later was it discovered that the action of clk-1 is necessary for the synthesis of ubiquinone, with the result that the clk-1 mutants are less able to quench the ROS products of mitochondrial metabolism, but still live longer. The first data were found in heterozygous clk-1 ± worms and it was believed that homozygous - / - mutants are not viable. A more thorough study found that - / - worms developed with a delay, subsequently alive at a record 10 times longer than normal Caenorhabditis elegans. This worm does not have the ability to synthesize ubiquinone, and its exorbitant lifespan is a paradox for theories of destructive aging. Bare diggers live 8 times longer than a mouse of comparable size, and recently it seemed to be better protected against oxidative damage. As a rule, a mouse's lifespan is several years, while bats live for decades despite higher metabolism and a greater burden from mitochondrial ROS. better protected against oxidative damage. As a rule, a mouse's lifespan is several years, while bats live for decades despite higher metabolism and a greater burden from mitochondrial ROS. better protected against oxidative damage. As a rule, a mouse's lifespan is several years, while bats live for decades despite higher metabolism and a greater burden from mitochondrial ROS.

The Arlan Richardson Laboratory (Barshop Institute of the University of Texas) reported the result of an eight-year systematic study of a wide variety of genes encoding antioxidant enzymes. For each target gene, they examined a mouse with a modified version and a mouse with an extra copy of the gene to analyze the lifespan under standard conditions. The only impact was made by the sod1 gene. They published their study under the provocative heading “Is the Theory of Oxidative Aging Dead?” Circling like black beasts, LePont and Hekimi gave a parallel conclusion from their own experiments, in an article entitled “When The Theory of Aging Is Badly Aging”.

There is a certain truth that most of the damage we associate with aging can be traced to the processes of oxidative destruction caused by ROS as a by-product of mitochondrial activity; However, protective biochemistry may be suitable for protection against these threats with rather high efficiency.

Theory of disposable soma

The theory of one-time Kirkwood soma is the only dominant theory that is associated with the idea of ​​accumulative destruction. The idea of ​​Kirkwood is that the damage is accumulated because the body must conserve energy for the benefit of the restoration of reproduction, which is a compromise to optimize the reproduction rate. The huge problem with this theory is that it predicts the relationship between food energy and aging. If aging mainly depends on insignificant food energy for productivity and recovery, a larger calorie content will reduce the need for compromise, which means the body will not only be able to live longer, but also increase fertility. Caloric restriction is the oldest, most stable and completely incompatible with the theory of disposable soma practice.

The theory of a one-time catfish also has a strong prediction that the lifespan is reduced due to high energy costs for reproductive activity. If we look at animals, we will not find confirmation of this; in the case of people, there is only a small positive correlation between birth rate and life expectancy.

Aging, Minor Aging, Negative Aging and Post-Aging

If aging is a process of stochastic destruction, then this destruction will accumulate inexorably, regardless of the species, the environment or the lifetime. Many ageless examples demonstrate that aging is not a physical necessity. The whole multicellular life is able to build itself from the seed. During growth, aging is usually absent. In fact, aging is defined demographically as increasing mortality along with decreasing fertility, while an early period of growth is a time of negative aging.

Single-handed organisms from mayflies to octopuses can be noted as a subcategory of animals that do not suffer from aging before they die rapidly. Many plants and some animals do not age to a certain extent for hundreds of years. The vaupel collected examples of negative aging, including corals, sea urchins, some molusks, and desert lizards. Fahey provided unique details and added more examples including cartilage fish and turtles.

The phenomenon of the “plateau of mortality at the end of life” was not predicted by any evolutionary theory of aging, and even more so by theories of wear. In the 90s it was found that the mortality of Drosophilus, C. elegans and humans ceases to grow exponentially and levels out at the end of life (there are only three species of animals for which there is sufficient sampling to detect this phenomenon). This phenomenon is difficult to reconcile with the destructive theory of aging. It is paradoxical that destruction will stop the unrelenting movement at the weak point of the life cycle, the moment when the recovery mechanisms are the weakest.

If not destruction then what?

The thesis of this work was negative: the aging of living organisms must be distinguished from the damage accumulation processes that occur in lifeless machines that wear out over time. If aging cannot be explained through the process of accumulative destruction, then what can? The answer must be considered in the evolutionary process that created life. Due to the ubiquity of the aging phenomenon in the biosphere, as well as the separation of genes by classes (taxa), it is prerequisite to consider a single answer to the question of why organisms age.

But the phenomenology of aging is diverse and often paradoxical. refusing to be tamed by simple universal theories. The evolutionary community has no consensus on the original source of aging. On the contrary, there are competing theories with well-accepted ideas derived from Medawar's original intuition about the declining power of natural selection. This may be phenomenologically paradoxical, include the results cited here, since they are incompatible with the prevailing remarks about individual suitability and that evolutionary theory will stretch to fit the evidence.

Fortunately, there is a clear signal for research that does not depend on the preferred evolutionary theory. This is the idea that aging is controlled by the body. If there is no physical need to accumulate damage, then there is no need for bioengineers to develop solutions for the recovery of these damage. In the future, it will be easier to reprogram the signaling apparatus of the body, including mechanisms that are excellent for supporting the state of the body in a state of vigorous youth.

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