How to let the years “kill pig knife” knife to stay under the people? It’s going to keep people young forever.

All said that “the years are the killing of pigs knife”, so that the young beautiful girl into a wrinkled old lady, so that the lively young man into a hobbled old man. As the years go by, how has our bodies changed? When did we get old? Can human beings achieve long-lasting and eternal youth? This is the mystery that people have been exploring for thousands of years. Ancient emperors such as Qin Shihuang and Han Wudi pursued the long-term life by seeking immortality and taking a panacea, and many well-known multinational companies invested in anti-aging research, such as Google investing $1.5 billion to set up Calico, a company that studies aging.

At present, with the increase of human life expectancy, the aging of the population is becoming more and more serious, aging-related degenerative diseases, including Alzheimer’s disease, cancer, Parkinson’s disease, diabetes and other incidence has increased, anti-aging research is becoming more urgent.

History and status of aging research

Although people have been pursuing the pursuit of long-term life for thousands of years, the modern sense of scientific research on aging does not take long. The key starting point was in the late 1930s, when scientists found that restricting diet sedatages could extend the lifespan of mice and rats, suggesting that aging is a malleable process. With the emergence of new experimental methods, people have further understanding of the phenomenon of aging from the individual to the cellular and molecular level, scientists have put forward a number of theories to try to explain aging. Some of the representative theories are George C in 1957. Williams proposed the theory of aging evolution with the multi-effects of antagonistic genes, arguing that evolution would choose genetic mutations that are beneficial for early life development and reproduction, but that these mutations accelerate aging later in life. 1961 Dr. Hayflick found that cell aging, in which cell division has limits rather than eternal life, enters an aging period after a limited number of cell divisions. It was further discovered that every time a somatic cell passes through a filament division, the telomeres at the end of the chromosome will be shortened a little, and when the telomere length is shortened to a certain limit, the cell stops dividing into the aging stage, which is the telomere hypothesis of aging. In the 1950s and 1980s, scientists also proposed a number of theories that explain aging, which can be divided into two main categories: the theory of injury/error accumulation, represented by the free radical hypothesis, the accumulation of DNA damage and the cell or tissue wear hypothesis, emphasizing that the erosion of molecules or cells by the environment leads to the accumulation of damage, which in turn leads to aging. “Just as machines can be bad for a long time” is an uncontrollable process; the other is a programomic aging theory, represented by immune theory and endocrine theory, which holds that aging follows a procedural biological schedule like a developmental process that relies on timing to turn on or turn off the expression of specific genes to control the rate of aging. However, these theories usually explain only part of aging.

With the development of molecular biology in the 1990s, the study of aging entered the genetic age, and there was a causal relationship between genes and aging. Two milestones: In 1983, scientist Klass identified the first longevity mutine in model animal nematodes, a genetic mutation called age-1, which extended nematode life by 40-60 percent. The discovery surprised many scientists that a mutation in a single gene could change the length of life. In 1993, Professor Cynthia Kenyon of the University of California, San Francisco, found that mutations in a single gene, daf-2, doubled the life span of nematodes, and she came up with the theory that life expectancy is controlled by genes. Over the next three decades, scientists discovered hundreds of longevity genes that form a complex and orderly network of signal regulation within cells. People have a certain understanding of the mechanism of life-long regulation.

Aging is also accompanied by the degradation of behavior and cognitive function, extending life expectancy while maintaining various physiological functions (i.e. healthy and long life) is the good wishes of human beings. Longevity and healthy aging have been found to be closely related in the past, but recent studies have shown that they can be regulated by different mechanisms. Therefore, extending life is no longer the only goal of anti-aging. If you live long and you can’t be healthy, it’s a torture to keep a weak and sick life in the middle of a windy, sick year. We also hope that the quality of life in old age will improve and that the old age will survive. In recent years, the mechanism of healthy aging has been paid more and more attention by scientists, but there is still little research in this area. Finding effective ways to delay behavioral ability and cognitive function degradation in the aging process has become the focus and difficulty in the field of anti-aging research.

After setting up the laboratory, Researcher Cai Shiqing of the Center for Excellence in Brain Science and Intelligent Technology (Institute of Neuroscience) of the Chinese Academy of Sciences first analyzed the relationship between longevity and behavioral degradation, and found that some longevity genes, while prolonging life, did not necessarily delay the degradation of animal behavior function. To explore the mechanism of behavior degradation related to aging and to find ways to achieve healthy aging has become a clear research direction in the laboratory. The first work also expounds that improving neurotransmitter stoicism can improve the behavior of elderly animals, and lays the foundation for the future study of the regulatory mechanism of behavioral degradation.

Then they used the changes in the neurotransmitter system in aging as a marker of aging, on the one hand, analyzed the genetic basis of the difference in the rate of aging between individuals, and found a new glial cell-neuron signaling pathway to regulate the rate of aging; On the other hand, the combination of nematodes and mice, as well as the human brain gene expression database, through genome-wide screening to find new anti-aging target genes, the cognitive aging regulation mechanism, to achieve healthy aging provides a new clue. The work was published online recently in the journal Nature.

Genome-wide genetic screening finds new potential anti-aging genes

How to find genes that regulate behavioral degradation? In biology, in order to study what a gene can do, it can be removed from the genome and observe what abnormalities occur in the organism, so as to speculate on what physiological function the gene performs in the organism. Genetic screening is a very important and effective method, often with unexpected results, when we want to find genes from thousands of genes that regulate a specific physiological process (such as development, aging, etc.). In the model organisms commonly used for genetic screening, the researchers used nematodes as their subjects because they were small (only 1 mm in length), easy to culture, have a clear genetic background and are easy to operate, have a short life cycle, and can mature in 3.5 days to produce offspring, with a life cycle of about 21 days. Nematodes are important model sage-study organisms, and many of the important signaling pathways that regulate life span are first found in in-line insects, and these signaling pathways are conservative in mammals.

But even in online bugs, detecting behavioral changes in the aging process is not so simple and needs to be tested through complex experiments. Is there a biological marker of aging that is easy to track, reflects degeneration of behavioral function, and is suitable for mass screening? The researchers cleverly turned into a neurotransmitter system. Neurotransmitters are chemicals that mediate signal transmission between neurons in the brain, and abnormal neurotransmitter functions during aging can lead to degeneration of behavioral function. Improving neurotransmitter function can improve the behavior ability of the elderly, such as dopamine signal decreased with aging, improve dorpamine neurotransmitter function can improve cognitive function in the elderly.

Early work in Cai Shiqing’s laboratory has found that the expression of dopamine, an enzyme that catalyzes dopamine synthesis in nematodes, decreases in the amount of expression during aging, leading to a decrease in dopamine levels and the degradation of some related behavioral functions. Using this as a clue, the researchers used fluorescent proteins to label dopamine assinasers, and to indicate changes in dopamine synthesis in the aging process with fluorescence intensity, and to search for improved dopamine function by vector genetic screening, a technique that uses interfering RNA to reduce the function of the target gene, to improve dopamine function. Genes that improve the behavioral capacity of older animals. After several rounds of repeated experiments confirmed the screening results, the authors finally found 59 candidate genes, 10 of which were reported to be associated with degenerative diseases or cell aging, while the remaining 49 were the first to be found to affect the aging process. By building a network of interactions between these candidate genes, they found that two genes, baz-2 and set-6, were located at key nodes in the network and were mainly expressed in the nervous system. The researchers examined nematode behavior and found that the ability to feed, such as mutant nematodes that were missing baz-2 and set-6, deteriorated much more slowly with aging than wild nematodes, and they extended their lifespans. These results suggest that these two genes accelerate aging, and reducing the function of these two genes can delay aging. The researchers were pleased to see that the screening system was very effective and did identify potential target genes for anti-aging.

Epigenetic-related anti-aging target gene regulation mitochondrial function

So how do these two anti-aging target genes regulate aging? The most difficult part of research is usually not to discover a biological phenomenon, but to study the biological mechanisms behind the phenomena. When the authors first explored the molecular mechanisms of BAZ-2 and SET-6 to regulate aging, there was no clue. Through sequence analysis, they found that the two genes may be epigenetic regulatory factors. So they found a lab collaboration with Jiang Lubin, a researcher at the Pasteur Institute in Shanghai, who specializes in epigenetics of low-level eukaryotic biogenetics. Epigenetic regulation, unlike well-known genetic regulation, refers to genetic changes in gene expression that eventually lead to phenotypes without altering the dna sequence of genes. Since the establishment of the laboratory in 2012, Jiang Lubin researchers have made several important breakthroughs in the study of malaria disease mechanism through epigenetic research. Not only was it the first apparent genetic editing technique for single-cell eukaryotic parasites, but the hetintmethylase PfSETvs and DNA decycloneas POrmac1 were found to be key epigenetic regulatory factors for Plasmodium falciparum to evade human immune response. By working together, they first demonstrated that nematode SET-6 is a histone methylator, and also found that there was an interaction between BAZ-2 and SET-6.

Then, using a variety of high-throughput sequencing methods, they found that BAZ-2 and SET-6 regulate their expression by regulating epigenetic modification of mitochondrial function-related genes. Since mitochondria are the main site of cell metabolism and the energy plant, a large number of studies have shown that the decline of mitochondrial function is the main cause of tissue function degradation. By detecting nematode stoma function, they found that knocking out the baz-2 and set-6 genes did improve mitochondrial function, and that knocking out both genes delayed behavioral degradation by improving mitochondrial function. These results show that in order to improve the behavior function of the elderly individual, it is necessary to activate the vitality of the mitochondria. The process of exploring the causes of anti-aging is very difficult, and the two laboratories, through several years of collaboration, finally elaborated on the principles of the role of these two new anti-aging target genes.

Anti-aging target gene regulation mice cognitive aging

After all, nematodes are far from human kinship, do these two anti-aging target genes have the same effect in mammals? With the development of high-throughput sequencing technology, there are many databases of gene expression of human tissue samples available for scientists to study. The authors made full use of this resource to analyze how the two new anti-aging target genes were found to change in the aging brain. Interestingly, the researchers found that baz-2’s human homologous protein BAZ2B expression increased with aging.

To test whether reducing baz2B function is also anti-aging, the researchers built mice with the Baz2b gene knockout. Three years passed because the mice had a long reproductive cycle and a life cycle of up to three years, from starting to build genes to knock out mice, to removing background mutations, and finally growing the mice into old age. After a long preparation period, the authors were pleasantly surprised to find that reducing Baz2b function in mice could slow weight gain in mice with age. Wild mice were “well-off” in middle age, while Baz2b-knocked mice were able to maintain a slimmer figure during the aging process. What’s more, behavioral tests showed that older Baz2b knockout mice maintained better cognitive abilities than wild mice. It is shown that BAZ2B also regulates the aging process in mammals and is a new anti-aging target gene.

Tips for the treatment of neurodegenerative diseases

Numerous studies have shown that mitochondrial deficiency plays an important role in the development and development of Alzheimer’s disease. Alzheimer’s disease, commonly referred to as Alzheimer’s, is the number one killer of cognitive impairment in older people, half of those over the age of 85 are at risk of developing Alzheimer’s disease, and there are currently no drugs to treat the disease. Because the human homologous protein EHMT1 of BAZ2B and SET-6 conservatively regulates mitochondrial function, the authors also explore the changes in Alzheimer’s disease in these two anti-aging target genes. They found that expression of BAZ2B and EHMT1 in the brains of Alzheimer’s patients was positively correlated with the course of the disease, and negatively associated with the expression of key mitochondrial proteins. These results suggest that increased expression in the aging brain by BAZ2B and EHMT1 may be a major cause of mitochondrial function deficiency in Alzheimer’s disease and play an important role in the occurrence and development of Alzheimer’s disease.

In summary, through genome-wide screening, the work identified a series of genes that potentially regulate behavioral degradation, and identified two epigenetic regulatory factors BAZ-2/BAZ2B and SET-6/EHMT1, which hinder healthy aging, and reduced the function of these two genes to improve mitochondrial function and thus improve cognitive aging.

The Meaning of The New Discovery

Aging is the most important risk factor for the occurrence of neurodegenerative diseases, the occurrence and development of neurodegenerative diseases in the aging brain in the molecular cell environment, understanding the brain aging regulation mechanism is essential to prevent and control these diseases.

Through genome-wide screening, the work presented for the first time a broad genetic map for regulating the degeneration of aging-related behaviors, identified a series of genes that potentially regulate behavioral degradation, and identified two epigenetic regulators BAZ-2/BAZ2B and SET-6/EHMT1, which hinder healthy aging and reduce the function of these two genes to improve mitochondrial function and thus improve cognitive aging. The study sheds light on the role of BAZ2B in cognitive aging and discovers baz2B as a new anti-aging gene target.

The work also combines a variety of model animals, from a multi-level interpretation of cognitive aging regulation mechanism, for the future more comprehensive understanding of the mechanism of healthy aging has laid a good foundation, the study provides a new explanation for the brain aging mechanism, for the delay of brain aging provides a new theoretical basis and role target.