Why do some animals live that long?
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It is well known that the classical model organisms adopted in biological experiments tend to be fruit flies, nematodes, mice, or rats because of their short lifespan and rapid generations. However, in the field of aging research, there is a small group of scientists who have found another way to observe the "life stars" of the animal kingdom. Whatever the evolutionary purpose, some animals did acquire the "longevity code," living longer than their own close relatives. So scientists are determined to take a peek, understand the genes and biochemical pathways in their bodies, and open the door to longevity.
"Longevity secret recipe" which is strong
Regarding aging, we ourselves have more or less intuitive experiences. As I grew older, my skin rebounded slowly, I began to soften, my gray hair gradually rose and I could no longer hide it, my joints were no longer flexible, and it was difficult to recover my energy after a full sleep... It is difficult for the body to return to a youthful state from the outside to the inside. At the same time, molecular damage in the body continues to occur and accumulate, triggering a series of chronic diseases: diabetes, cardiovascular disease, cancer, Alzheimer's disease, etc., ultimately affecting the length of life.
Although the occurrence of the above varies between different species, there is an overall pattern that is not absolute but more obvious: larger animals tend to live longer than smaller animals. But even between species of similar size, the difference in lifespan is sometimes not small. The average lifespan of mice ranges from 2 to 3 years, while naked mole rats live at least 35 years. Bowhead whales are the second largest mammal in the world, and they can live up to 200 years.
The mysterious undersea birthday star - bowhead whale 丨 Image source: university of british columbia / pangnirtung hto via nunatsiaq news
Emma Teeling, a biologist specializing in bat evolution at University College Dublin, once caught a myotis brandtii and found a label on it that had been labeled 41 years ago. After a long time, this little bat is still alive and well, and she can't help but wonder: "This bat is equivalent to the age of 240 to 280 years old for humans, it's amazing, there is no sign of aging, why?" ”
This question can be answered from two lines of thought:
First, from an evolutionary perspective, what is the reason why certain animals live particularly long? Or rather, why did they live so long?
Second, what are the secrets of heredity and metabolism that make them particularly long-lived? Or rather, how do they survive?
The first question is not difficult to answer. According to the classical evolution of aging, the energy input of living organisms must not only strike a balance between reproducing offspring and maintaining their own survival, but also consider which aspect brings greater benefits. When faced with a higher risk of extrinsic mortality (e.g., natural enemies)[1], natural selection causes animals to devote more energy to reproducing offspring and less energy to sustain themselves. Taking rats as an example, it may become the mouth food of other animals one day, and there is not much benefit in investing too much energy in their own maintenance, so rats tend to age rapidly after breeding, and life is coming to an end. In contrast, giant mammals that are not afraid of natural predators, such as whales and elephants, as well as nocturnal bats that can fly flexibly, and naked mole rats that have long lived in the dark underground away from natural enemies... The survival and reproduction of these animal populations benefit more from the maintenance of their own cells. Under constant natural selection, these animals age more slowly and live longer.
What humans want to know more is the answer to the second question.
At the microscopic level, what kind of "anti-aging secret" do long-lived animals have? Scientists have tried to compare organisms with different lifespans and come to some conclusions. In 2013, the team of biologists Vera Gorbunova at the University of Rochester published a study in PNAS (Proceedings of the National Academy of Sciences) that explored the molecular mechanisms of differences in animal lifespans, targeting naked mole rats. They found that the ribosomes responsible for assembling proteins in naked mole rats functioned very precisely and produced fewer abnormal proteins. By ensuring proper folding and stability of proteins, aging can be delayed [2]. Subsequently, gorbunova further studied and continued to compare 17 different lifespan rodents, and found that the longer the animal lifespan, the evolution of ribosomal translation process is more accurate, which can reduce protein synthesis errors, and reduce the occurrence of abnormal proteins, accumulation proteins, and protein toxic stress [3].
Low-key longevity naked mole 丨 Source: john brighenti/flickr/cc by 2.0
Comparator Rochelle Buffenstein, a geriatrician from Google's Calico Biotechnology company, also set his sights on naked mole rats early on. Their team has published an article showing that the proteins in naked mole rats are not only more stable than in other animals, but also have more chaperones that can assist in the correct folding of proteins, as well as more active proteasomes that can more effectively "crush" misfolded proteins under conditions of oxidative stress. In contrast, the mice had lower proteasome activity, allowing erroneous and damaged proteins to accumulate in the body, preventing cells from functioning properly, triggering signs of aging [4].
Gorbunova's team also went deep into the DNA field to test the theory that "gene repair involves longevity." The team compared the ability of 18 species of rodents with varying lifespans to repair DNA double-strand breaks and found that the longer-lived animals showed more ability in this regard than short-lived animals such as mice and hamsters. It also revealed the main reason for this difference: stronger expression of the sirt6 gene promotes DNA double-strand break repair, leading to longer lifespans. The study was published in cell (Cell) in 2019 [5].
A new tool to decipher animal longevity
Powerful biological tools can help scientists solve more mysteries of longevity. The "epigenetic clock" associated with DNA methylation is one of them. DNA methylation is a biomarker that characterizes aging, and methylation is like a gene switch, which determines whether a gene is expressed and functioned in cells. Steve Horvath, a geneticist and biostatistician at UCLA, notes that there is some kind of link between methylation and aging: As we age, methylation of some genes increases, while others decrease. So he speculated that different ages correspond to specific methylation maps, and after basing on gene "methylation" tags and machine learning on a large number of samples, Horvath developed an "epigenetic clock" that uses gene methylation maps to determine the physiological age of organisms. [6]
In March 2021, Horvath's team used dna methylation atlases to analyze 712 bats of known ages and different species, and found that the methylation change rate in long-lived bats was slower than that of bats with shorter lifespans, and that longevity-related methylation changes were associated with innate immunity or tumorigenesis genes, suggesting that bat longevity may be the result of a combination of a strong immune response and tumor suppression [7]. And this type of methylation may also be affected by development-related genes, although detailed associations remain to be explored. Horvath hopes his research will conclusively prove that genes are key to regulating longevity and aging.
In recent years, the development of molecular technology has also provided researchers with excellent tools to help find mechanisms to explain the differences between abnormally long-lived organisms and ordinary-lived organisms. Among them, mrna sequencing can reveal genes (transcriptomes) that are active in the genome at a given moment, depicting the dynamic process of cell activity.
The aforementioned team has been studying myotis myotis bats in five habitats in France for 8 years, and they take a small blood sample for sequencing each year to track how the bat transcriptome changes with age. Subsequently, the transcriptome change process was compared with mice, wolves, and humans. The question teeling wants to solve is: Does the aging process of rat-eared bats also occur in disorders like us humans?
Myotis myotis bats 丨Source: eurobats.org
The answer is no. In general, the older mammals get, the fewer MNA molecules they produce in their bodies that are related to functional maintenance. But rat-eared bats are the opposite, and their DNA repair, immune system, tumor suppression, and other functions seem to become more and more powerful, and more repair-related mna [8].
However, this conclusion is still controversial because the presence of more MNA molecules does not necessarily mean that it is more effective in its own maintenance function, and the relationship between the two still lacks key evidence. Steven Austad, a biogeriatrician at the University of Alabama, believes: "This is an important first step, but it is limited to that. ”
In addition, in the same study, the teeling team also found 23 genes in mouse-eared bats, which become more active as they get older, compared with the opposite in other mammals. They are now working on these genes with great interest, hoping to discover new "switches" that change the aging process.
The study by Vadim N. Gladyshev's team from Harvard Medical School, published in the journal Aging Cell, sequenced transcriptome expression patterns in liver, kidney, and brain cells in 33 mammals and looked for patterns associated with longevity, and found that for animals of different lifespans, there were a large number of differences in gene activity involving cell maintenance functions, including DNA repair. Antioxidant defense and detoxification [9].
Which path to longevity is right for humans?
The reason why scientists conduct comparative research is because different animals take their "own path", and the secret of longevity is not the same. In addition to the previously mentioned, all long-lived mammals delay the onset of cancer, but the method is different for each animal: African elephants have more than 40 copies of the tp53 gene in their bodies, which encodes the p53 protein, which prevents cells carrying damaged DNA from continuing to divide, and is a key tumor suppressor, so even if the gene ruptures during life-consuming processes, the cells have plenty of copies [10]; naked mole rats obtain cancer resistance through an unusual molecule Bowhead whales enhance their cancer tolerance and DNA damage repair pathways through genetic mutations [11].
The world's longest-lived black-backed albatross. In 2020, she laid an egg at an ancient age, achieving the so-called "graceful aging". 丨Source: jon brack / friends of midway atoll nwr
So, the question arises: If we learn more and more about the longevity secrets of animals such as naked mole rats, bats, and bowhead whales, will humans have a way to make themselves live longer and healthier? At the moment, we may not be able to get a definitive answer, but early research and reflection on these long-lived animals does offer a glimmer of hope for humans.
Original: https://knowablemagazine.org/article/health-disease/2021/genetic-tricks-longest-lived-animals?xid=ps_smithsonian
Resources
[1] https://www.annualreviews.org/doi/10.1146/annurev-animal-022516-022811
[2] https://www.pnas.org/content/110/43/17350#sec-6
[3] https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12628
[4] https://www.pnas.org/content/106/9/3059
[5] https://www.cell.com/cell/fulltext/s0092-8674(19)30344-7
[6] https://www.nature.com/news/biomarkers-and-ageing-the-clock-watcher-1.15014
[7] https://www.nature.com/articles/s41467-021-21900-2
[8] https://www.nature.com/articles/s41559-019-0913-3
[9] https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12283
[10] https://jamanetwork.com/journals/jama/fullarticle/2456041
[11] https://www.cell.com/cell-reports/fulltext/s2211-1247(14)01019-5