Why do we get older?

After years of evolution, today’s eukaryotic cells contain two separate sets of genomes, of which the nuclear genome encodes the vast majority of proteins that make up mitochondria, and the mitochondrial genome encodes the most important proteins in mitochondria, both. Must be combined to assemble a complete mitochondria. However, the two sets of genomes are independent after all, so the mutual cooperation between them becomes a problem.

According to Nick Lane, a biochemist at University College London, the core of aging is the mismatch between the nuclear genome and the mitochondrial genome, which is why only eukaryotes have aging, and prokaryotes are eternal.

Let’s first examine the heterogeneity in eukaryotes: the Sponge, which is almost never aging. This is the world’s simplest multicellular animal with very low levels of somatic differentiation. Sponge usually does not require action, so the number of mitochondria in sponge cells is small and the work efficiency is not high. Therefore, the mutation rate of sponge mitochondria is very low, and it is not easy to have bad mutations.

The reproductive parts of the sponge are both asexual and sexual. In asexual reproduction, any part of the sponge body can develop into a new individual alone; similar to sexual reproduction, most of the body’s body cells can be transformed into germ cells, and then mated together to produce fertilized eggs. Therefore, even if there is a problem with a certain part of the sponge body, other healthy parts will immediately regenerate a new one. This process can continue without affecting the health of the next generation, because the bad genes are all in the process. Eliminated.

If eukaryotes are simple creatures like sponges, then aging may not occur, but because of the contribution of cyanobacteria, the Earth’s atmosphere first appeared oxygen in 2.4 billion years ago. This is a very active gas, its presence has greatly improved the energy efficiency of life, and higher animals with walking ability finally emerged, and soon gained an evolutionary advantage. At this time, we will look at the mitochondria and find that higher animals cannot be propagated in the way of sponges. Because the body structure of higher animals is too complicated, higher requirements are placed on the quality of mitochondria.

Take humans as an example. Human cells are highly differentiated, and each organ divides and works together, and one less will not work. If there is a problem with the mitochondria of an organ that causes this organ to go wrong, then the whole person will not survive. In order to prevent this, the human fertilized egg is getting bigger and bigger, and the number of mitochondria contained in it is astonishing about 100,000. This is because when the fertilized egg is split, the mitochondria are randomly assigned to two daughter cells. Going in the middle. If the number of mitochondria in the fertilized egg is too small, the bad mitochondria mixed therein may be concentrated in a certain offspring cell during embryonic development, causing problems in a certain tissue or organ. It is only possible to avoid this when the number of mitochondria in the fertilized egg is large enough.

In other words, the highly differentiated body structure of higher animals places high demands on the early development of the embryo. No cell in the embryo can drop the chain, otherwise it will affect the whole organ and then spread to the whole body. So higher animals have evolved super-large eggs containing a lot of mitochondria, which solves the mitochondrial quality control problem of embryo development.

In addition, terrestrial animals like humans need to run around, this kind of lifestyle requires a lot of energy, so the human mitochondria work very efficiently, the reproduction speed is very fast, and the mutation rate is greatly improved. It is known that the mutation rate of the human mitochondrial genome is 10 to 50 times higher than that of the nuclear genome, which is much higher than that of the sponge. Therefore, the possibility of mitochondrial dysfunction in human somatic cells becomes very large, and it is impossible to casually take it from the body like a sponge. You can regenerate a new person by cutting a piece of meat.

Therefore, in order to ensure the health of the mitochondria of the offspring, humans have evolved specialized germ cell lines, freeze them shortly after birth, no longer participate in any physiological activities, and minimize the possibility of genetic mutation. For example, human oocytes are protected in the early stages of female embryo development. Each adult’s eggs are separated from these protected oocytes, and the mitochondria quality is guaranteed.

Ryan summed up this phenomenon into a sentence called ” Immortal germline, mortal body.” The general idea is that life is like a river, and the water molecules flowing through it are different every moment, but the name of the river will never change.

In short, Ryan believes that the active lifestyle of higher animals places high demands on energy, making the protection of mitochondrial quality an important task, so higher animals have evolved relatively independent germ cell lines that do not participate in any other life activities at all. Concentrate on reproduction. The presence of germ cells liberates somatic cells, allowing the latter to develop into what the body needs, such as muscle cells, nerve cells, and immune cells. These highly differentiated somatic cells do not have to consider their own reproductive problems. Their only job is to help the germ cells to complete the breeding task, and then they can be discarded. This is why the life span of all animals is directly proportional to the developmental period, as long as the development is complete. The body is useless.

So how are these somatic cells abandoned? The answer is apoptosis. The study found that all eukaryotic apoptosis follows the same pattern, the core of which is mitochondria. When the efficiency of mitochondria declines, free radicals will leak out. This is a signal that triggers a series of biochemical reactions that cause respiration to stop, the transmembrane voltage disappears, the cell completely loses its energy source, and is quickly starved to death. .

When the mechanism of apoptosis was discovered, scientists did not understand why mitochondria would kill cells. Ryan believes that this apoptotic system is essentially the same as the apoptotic system that bacteria have evolved against phage. When the archaea swallowed the bacteria 2 billion years ago, the system was brought into the host and took on the task of monitoring the quality of the mitochondria.

There are two sets of genomes in eukaryotic cells, which together encode mitochondria, which is equivalent to the same mitochondria but with two design drawings, which must be closely matched to each other to assemble into a high-quality mitochondria. If the two sides no longer match for some reason, the living body must remove the cell, so as not to trap other cells, which is why free radical leakage will initiate the cell suicide program, because this is a sign of mitochondrial mass decline.

When eukaryotes evolved into a multi-cell stage, a penal mechanism was urgently needed to manage cells that did not obey the big picture, and this mechanism of apoptosis was requisitioned and played an important role in many other occasions. For example, our hand is a uniform mass of meat in the early stage of embryonic development, and then the four cell clusters on the surface of the meat ball start the suicide mode, and the rest continue to grow, which gives rise to five fingers. If this process is not controlled, the cell group that starts the suicide mode has one more, and eventually a six-finger will be born.

Adult multicellular organisms also often need to rely on apoptotic function to remove unqualified cells, and most cancer cells are eliminated. According to statistics, an adult has 60 billion cells removed every day through apoptosis, accounting for about one-thousandth of the total number of human cells.

From this example, we can see how important mitochondria are. Ryan believes that life is the process of constantly resisting the entropy increase. This process consumes a lot of energy all the time. Once the energy supply can’t keep up with the energy demand, the result is aging and death. As the sole supplier of energy required for eukaryotic cells, mitochondria govern the eukaryote’s life and death, and the health limit of mitochondria is the life limit of eukaryotes.

In this case, can animals live longer if they evolve high-quality mitochondria? The answer is not as simple as everyone thinks. The genetic pattern of mitochondria is different from the nuclear genome, and both sides must cooperate with each other.

The mitochondria in the fertilized eggs of higher animals all come from the egg, but half of the nuclear genome comes from the sperm. Therefore, every fertilization of the egg is a big hit. It is a joy to meet the right sperm. If it is not suitable, it will be unlucky for a lifetime. Most higher animals have learned to pre-screen fertilized eggs, that is, to remove unqualified embryos, so that no resources are wasted.

For humans, this is a miscarriage. According to statistics, about 40% of human pregnancy ends in miscarriage, and many abortions are not even noticed by the mother. Ryan believes that many of the miscarriages are caused by a mismatch between the mitochondrial genome and the nuclear genome, leading to problems with mitochondrial quality.

However, there is no better match between the genomes. What is the standard for the quality of mitochondria to be screened out? The answer must be determined by the lifestyle of the animal. For example, flying requires a lot of energy, so all flying animals have very high requirements for mitochondrial quality, which is why most birds are extremely picky about their spouses.

Many evolutionary biologists are puzzled by why the male bird evolved such a gorgeous feather. Darwin once said that he felt “disgusting” every time he thought of the feathers of the peacock, because it was too inconsistent with the expectations of evolution. . But in Ryan’s theoretical system, this matter becomes very easy to explain. Pigments on male feathers are difficult to synthesize and require high-quality mitochondria to provide energy, so Ryan believes that male feathers are actually a billboard that shows the quality of their mitochondria.

It is also important that the male’s sex chromosome is ZZ and the female is ZW, as opposed to humans. Many of the genes involved in mitochondria are on the Z chromosome, so the mitochondrial genes of the females are mostly from the father, which is why the mother must be very picky when choosing a spouse, otherwise her daughter will suffer. However, the result of the picky is that the reproductive capacity of birds is relatively low, and a female can often only have one litter a year.

Let’s take a look at the situation of mice. The mice have a small range of life and do not fly. They do not need special high-quality mitochondria to live well. If the mother is as picky as a bird mother, it is not necessary. As a result, mice have much lower embryo quality requirements than birds. As a result, although the horse’s physical strength is not as good as that of birds, its fertility is stronger than that of birds.

In short, the life of eukaryotes is a contest between fitness and fertility. The two are a natural contradiction. Fish and bear’s paws can never be combined. This competition will eventually reach a certain balance, and the position of the balance depends on the survival strategy of the creature.

Ryan’s theory explains why pigeons and mice weigh almost the same, the metabolic rate is similar, but the absolute lifespan is 10 times different. The reason is that the mitochondria of birds are of high quality, and the rate of free radical leakage is the same weight. One tenth of the mammal. Interestingly, the mitochondrial mass of the only flying mammalian bat is more similar to that of birds, and the lifespan is correspondingly much longer than that of mice of the same weight.

The theory also explains why hunger therapy, exercise and a low-carb diet delay aging, all of which are free radicals. The results of the study show that when people are hungry, exercise and low-carb diet, their mitochondria work more efficiently, and free radicals are less likely to leak.

In short, Ryan believes that the cause of aging is the decline in mitochondrial mass caused by a mismatch between the mitochondrial genome and the nuclear genome, and the loss of free radicals, which damages cells and triggers apoptosis. After that, if the suicidal cells are replaced by new ones, they are all happy, this is the state of youth; if there is no time to replace, the number of living cells will be less and less, this is the state of old age; if there is a problem with the process of apoptosis This causes the cell to not die, but loses its ability to divide, and it becomes aging cells, causing a series of problems.

Is mitochondria likely to remain healthy forever? the answer is negative. Because the genes always mutate, the two sets of genomes do not match. But the human body does not care about this, because germ cells have long been protected. When the breeding task is completed, it doesn’t matter how the body ages.

Let’s take an analogy with the development of human civilization. During the safari collection phase, human beings lived in small groups. The group size has not changed for a long time. This is the prokaryote. When humans invented agriculture, the source of food was guaranteed, so large tribes emerged, and then the country emerged, which is eukaryotes and higher animals. The complicated mechanism within the country will sooner or later cause chaos, so when a strong country is also destroyed, this is the death of the body. But human civilization will not be interrupted because people are still alive, just changing a national number, this is the eternal life of germ cells.

Someone who asks here may ask why nature has not evolved another set of energy production methods to prevent mismatch between the two sets of genomes. Ryan believes that this result just shows that evolution is not far-sighted, but lacks top-level design, taking a step by step, solving a problem after a problem arises, and then welcoming new problems. The final result is the one we see today. The group is chaotic. Life is step by step to this day, and will continue to go step by step in this way in the future. What will the future world be like? No one can predict, this is the most attractive place of life.