Short- and long-livers

Be born a baobab

Alexander Grafodatsky, Vladimir Trifonov, "First-hand Science"

Envy, perhaps, is the most important factor in the biological and social evolution of man. He will sit down in the shade, for example, a baobab and think: "When our tribe came here, this old baobab was standing, my great-great-grandfather was sitting under it, and my great-grandfather was sitting, and my grandfather and father. Now I'm sitting, and my son will be sitting, and my grandson, and my great-grandson. Then everyone will die, or will the tribe leave, and the tree will still live? It's a shame, yes!". Mankind's envious interest in long-lived species is completely understandable: suddenly it will be possible to learn something that will allow us to live longer, like the same baobab. That is why a lot of attention of scientists is attracted by a huge number of natural models of both delayed and accelerated aging. And, as in the study of many other biological phenomena, the further these "models" are from the usual laboratory animals, the more amazing ways they use to solve the problem of aging.

Most often, the term aging is used for multicellular organisms. It is believed that most unicellular organisms are potentially immortal, since during reproduction they divide symmetrically into two organisms identical to the parent. However, recently, even in some bacteria, unequal division processes have been discovered. So, the inhabitant of freshwater reservoirs is a bacterium Caulobacter crescentus divides asymmetrically, forming one large cell attached to the substrate and a small one floating freely in the medium. Over time, the first "mother" cell slows down the division process, showing signs of aging (Ackermann et al., 2003).

During reproduction in baker's yeast, small daughter cells bud off from a large mother cell, and the mother cell itself, having undergone a certain number of divisions, dies. Signs of aging of a yeast cell are an increase in size, loss of turgor (intracellular pressure), lengthening of the cell cycle, weakening of protein synthesis, accumulation of extra-chromosomal DNA, etc. (Clay and Barral, 2013). Interestingly, maternal cells selectively give their "daughters" more efficient mitochondria (organelles responsible for energy production in the cell).

In another type of yeast – beer – cells divide symmetrically and are potentially immortal, but only under favorable conditions. Under thermal or oxidative stress, all large non–functional aggregates of proteins are collected in one of the daughter cells - such a cell subsequently dies (Coelho et al., 2013). So even single-celled organisms can serve as important natural models for the study of aging processes.

Multicellular cells also have potentially immortal sex cells, but somatic cells are programmed to die. One of the important features of aging in these organisms is the gradual loss of stem cells, which are capable of self-renewal and can transform into all other types of somatic cells during differentiation. Therefore, the loss of stem cells greatly slows down or makes it impossible to renew various tissues.

How the cell ages

Currently, researchers are increasingly wondering how aging occurs at the level of a single cell. Let's look at some of the most important mechanisms involved in this process.

Firstly, these are violations of the primary structure and epigenetic (not affecting the structure) the status of genomic DNA. A huge number of both external and internal factors affect the genome, causing many DNA mutations: point substitutions of individual nucleotides, double–stranded breaks, chromosomal rearrangements (for example, inversions - 180° rotation of a chromosome section), shortening of the terminal (telomeric) regions of chromosomes, etc.

DNA repair systems make it possible to successfully cope with many such disorders – the ability of the body to resist natural damage to the genome depends on the reliability of their work. The weakening of repair systems invariably leads to a reduction in life expectancy. Mitochondrial DNA is particularly sensitive to mutagenic processes, since the repair processes in these cellular organelles are weakened, moreover, they are characterized by high concentrations of reactive oxygen species and other dangerous metabolites.

There are many genes whose activity naturally changes with age for reasons related to epigenetic changes, in particular, with DNA methylation, which prevents the reading of genetic information from it. So, today there are about 400 epigenetic markers (CPG-dinucleotide sites), the level of methylation of which reflects the aging processes of the body. In most of these genes, the value of this indicator increases with age, and their activity, respectively, decreases. This group includes, for example, genes responsible for the formation of nerve synapses and differentiation of neuroepithelial cells. In other genes, the level of methylation decreases with age, on the contrary. These genes are related to leukocyte differentiation and nucleic acid metabolism (Horvath, 2013; Thomson, von Holdt, Horvath et al., 2017, etc.).

Recently, epigenetic processes such as the modification of histones, an extensive class of cell nucleus proteins involved, among other things, in the packaging of DNA strands, as well as methylation, have been assigned a rather large role in cellular aging. (addition of a methyl group (–CH3) without changing the nucleotide sequence) DNA (Han and Brunet, 2012).

The second important mechanism of aging is the accumulation of proteins with an irregular structure. Aggregation of improperly folded proteins with the formation of amyloids is associated with the development of age-related progressive neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases.

Thirdly, during cellular aging, signaling pathways change – molecular mechanisms that ensure the transmission of signals inside the cell. For example, the so-called insulin cascade / insulin-like growth factor, which affects many cellular processes, such as energy metabolism, stress response, etc. This pathway is involved in the processes of cellular aging in a wide range of organisms, including coelenterates, roundworms, insects and mammals.

As for oxidative stress, which, as shown in a number of works, makes a significant contribution to the aging process, the situation here is ambiguous. There is experimental evidence that small "portions" of oxidative stress, obtained as a result of exercise or impulse fasting, on the contrary, train antioxidant defense mechanisms. And, accordingly, lead to an increase in life expectancy.

Multicellular "koschei"

All multicellular organisms belong to the so–called eukaryotes - organisms with a decorated cell nucleus. And even among these higher organisms, we encounter the phenomenon of complete potential immortality, characteristic of prokaryotes (bacteria and archaea).

Such "koschei immortals" are found in some types of invertebrates devoid of bilateral symmetry. For example, in hydroid polyps/jellyfish of the genus Turritopsis. Representatives of the Turritopsis dohrnii species are considered immortal because they do not show signs of aging associated with age. At the "juvenile" stage, they are a stationary form – a polyp, and at the next stage of sexual reproduction – a free-floating jellyfish. The most amazing thing is that after reproduction, these organisms do not die, but turn back into immature polyps. And such a cycle can be repeated many times.

These multicellular animals always have stem cells capable of differentiating into cells of various tissues and participating in the regeneration of any organs. This is probably what gives them immortality. However, in the process of evolution in more complexly organized forms, this ability was lost, which, most likely, was due to the need to fight the malignant degeneration of cells into cancerous ones.

At the same time, there are no direct links between the complexity of the organization and the life expectancy. So, if sponges, one of the most primitive multicellular animals, live up to 15 thousand years, and whales belonging to mammals, only up to 200 years, then the not too complicated roundworm Caenorhabditis elegans does not have stem cells at all and lives only a couple of weeks.

In general, among multicellular organisms there are very different, sometimes bizarre variants. For example, arthropods, the most numerous group of animals, with all their metamorphoses, larvae, pupae, caterpillars and imagos. There is a lot of everything and different, including in life expectancy at each stage of development. Or plants with their special biology. It was the trees, many of which live for hundreds and thousands of years, that gave the name to our article in the periphrase of the famous song by Vladimir Vysotsky.

But today we will not talk about them. Below we will look at some examples of the diversity of life expectancy in vertebrates, to which humans belong. Many of these species have already become or may become living "models" for a detailed study of the phenomenon of aging, useful in relation to longevity with you and me.

Among vertebrates, fish are distinguished by a special longevity. The champion among them is the Greenland polar shark, a super predator that can live up to 400 years. And the representatives of this species reach puberty only by the age of 150 years. Circumpolar sea bass live up to 150 years or more. Interestingly, all these fish are viviparous. Many other shark species, as well as sturgeon and catfish, live relatively long (50-150 years). At the same time, among the fish there are species that live only a few months, for example, representatives of the Notobranchiaceae family and gobies.

Among amphibians, proteus lives the longest (more than 100 years) – a blind tailed creature that lives only in cold lakes and rivers of caves in the Balkans. The long-lived reptiles are turtles (the Galapagos tortoise reaches the age of 170 years), crocodiles, whose lifespan is more than half a century, and the Komodo lizard.

Most of the bird species also live relatively long. The record holders among them are the Australian resident cockatoo Inca, who has lived for more than 80 years, as well as the Andean condor (79 years old).

Among the unique order of oviparous mammals, the echidna attracts attention, which lives for half a century – twice as long as platypuses. Marsupials have record holders for longevity – a wombat and a giant kangaroo, who live for 25-30 years.

Among the afroteria, a special superorder of placental mammals independently formed in Afro–Arabia, the species that have adapted to an aquatic lifestyle (manatees and dugongs), as well as elephants that live up to 65 years (besides, the number of enemies of these animals, due to their size, is also limited) live the longest. Attention is also drawn to such a feature of elephants and sirens as the constant change of teeth to new ones, i.e. the preservation of high potency of the cells of the corresponding tissues.

This group also includes tenreks, small, hedgehog-like animals, most of which have been living in isolation in Madagascar since the Cretaceous period. It would be extremely interesting to compare genomes, features of cellular differentiation and other characteristics in these species, since their life expectancy differs by six times.

Among the half–toothed, sloths live long enough - more than 40 years. They spend most of their lives in trees, almost without moving, and if necessary, they move at a speed of 1-3 m per minute. Their brains have no convolutions, and the digestive system and bladder are arranged in such a way that the need to satisfy natural needs arises only once a week. Even ocelots and harpy eagles, capable of getting sloths in trees, attack them quite rarely. Not life, but the name day of the heart, the dream of Diogenes. But the life of more active ground-based non-toothed anteaters and armadillos is almost twice as short.

Relatively recently, it turned out that whales are artiodactyls that have changed a dangerous life on land for a more comfortable and, consequently, longer existence in the seas and oceans. It is among cetaceans that we note such a species as the bowhead whale – the record holder for longevity among mammals (Moskalyov et al., 2017).

Hippos, the closest conditionally terrestrial relatives of whales, also live for a long time. It should be noted that they are the most dangerous animals in Africa for humans. It is when colliding with hippos that many more people die than from the teeth and claws of other species. Recently it was discovered that they are able to eat fresh (and rotten) crocodile, antelope and lion meat. And then peacefully graze grass along the banks of swamps and rivers. Lips, since teeth are used exclusively for bloody fights and attacks on other animals.

Ungulates – horses, rhinoceroses and tapirs - live for quite a long time, and a horse reaching the age of 60 years is the leader among them.

Among the predators, pinnipeds live for a long time, having changed from a dangerous life on land to a more comfortable one in the seas and oceans. And among pinnipeds, the Baikal seal lives the longest, having managed to get far away not only from terrestrial, but also from marine predators. Bears live for a long time, and who can object to a polar bear in his desire to live up to forty with a tail? Cats generally live longer than dogs.

Bats are a group that abruptly changed their habitat and said goodbye to all ground aggressors. The record holder for longevity is Brandt's Siberian moth, a flying creature weighing less than 10 g that can live for 40 years. But most other bat species also live much longer than their insectivorous ancestors and relatives.

But the life of true insectivores is saturated (round-the-clock sex and food), but very short. Three times longer than shrews (up to 12 years), the poisonous Cuban and Haitian schelezub lived, until cats, dogs and mongooses were brought to the islands of their habitat, which exterminated these animals almost completely. Hedgehogs can live almost as long, besides having a well-known natural and effective protection from predator attacks.

Among the hares twice as long (up to 18 years!) in comparison with the peepers and rabbits, it is the hares that live, in particular, the white hare.

The record holder among rodents is the naked digger, with all its unique and repeatedly described features of the activation of many genes, repair systems, etc. However, it should also be remembered that diggers have a special form of "social protection" of their colonies, with a caste division of individuals. The life of many "colonists" can be short, ending up in the stomach of snakes, which, however, gives other individuals the opportunity to live extremely long – over 30 years, which is a record for small rodents. It would be extremely interesting in every study of the organization and functioning of the genomes and cells of a naked digger to compare this species not only with a mouse, but also with animals much more close to it. For example, with sandworms, whose life is significantly shorter (about 11-15 years).

Porcupines with their spines, squirrels that have climbed trees, and beavers that have mastered the aquatic environment live for a long time. And very few (2-4 years) live species of the most numerous group among mammals – mouse-like rodents.

How are things with us? Tupayas, close to the ancient ancestors of primates, and semi-monkeys live noticeably less than real monkeys. The maximum age of the latter is about 40 years. Great apes, including gibbons, have been living for quite a long time, about 60 years. Obviously, this is the maximum biological age resource for humans, while according to recent estimates, the average life expectancy for our species is close to 38 years (Mayne et al., 2019). The next 60 years of our life, before reaching the maximum fixed age of 120 years, obviously have a "supra-biological" character and are mediated by changes in the social structure of society, advances in medicine, etc.

Whether the latter is a blessing is a very controversial question. Nature has put up mighty barriers to useless, from a biological point of view, longevity. First of all, this is oncopathology. This barrier significantly limits any attempts to "rejuvenate" and "improve" the genome. Embedded stem cells where their tissues have exhausted their potential, or edited the work of any genes - nature will respond to you with the growth of cancers. Don't get into a working mechanism with a sledgehammer, don't break something that you didn't build.

But while humanity has left its scientific biological part objects for research and comparison, the following conclusions suggest themselves, at least for vertebrates. Longevity is the essence of attempts by certain species and groups to drastically reduce the number of their enemies. To this end, the land ancestors of whales, sirens and pinnipeds went to live in the ocean; birds and bats took to the air. Many species have become super-dangerous creatures themselves (sharks, bears, hippos) or have dramatically increased their size (for example, an elephant), or have climbed trees like primates and squirrels. Or they hid in inaccessible caves and burrows, like proteus and a naked digger, or even "pretended to be a rag", like a sloth. Hence, it is clear that increasing life expectancy is one of the survival strategies of species. But obviously not the best.

The most numerous group among mammals, in fact, "conquered the world", are mouse-like rodents, whose life is very short. In order to understand the essence of evolutionary success, it is enough to compare the number and prevalence of a house mouse, vulnerable, susceptible to all possible types of cancer, very short-lived, and the prevalence and number of living individuals in a naked digger. Man is the only species among vertebrates trying to implement both survival strategies: to be both a large mouse and a small "immortal" digger.

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