Two more anti-aging genes found, possibly related to Alzheimer's disease

Author: Yuan Jie

The article comes from the Science Academy official account (ID: kexuedayuan)

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How to grow old healthily? Rather than simply extending lifespan, people hope to achieve longevity and improve the quality of life in old age.

(Photo source: veer photo gallery)

In the past, people believed that longevity and healthy aging were closely related, but recent studies have found that the two are not the same thing. Although some genes can extend lifespan, they do not necessarily delay the deterioration of animal behavioral functions [1]. So, which genes can affect both lifespan and the deterioration of behavioral abilities and cognitive functions during aging? This is the key and difficulty in the field of anti-aging research.

Cai Shiqing's research team from the Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences used two model animals, nematodes and mice, as well as the human brain gene expression database to discover new anti-aging target genes through whole-genome screening, clarifying the regulatory mechanism of cognitive aging and providing new clues for achieving healthy aging. The related paper "Two conserved epigenetic regulators prevent healthy ageing" was published online in Nature magazine on February 26, 2020.

How to find potential anti-aging genes?

In biology, in order to study the function of a gene, the gene can be removed from the genome to observe what abnormalities occur in the organism, so as to infer what physiological function the gene plays in the organism. When we want to find a gene that specifically regulates a physiological process (such as development, aging, etc.) from thousands of genes, genetic screening is a very important and effective method.

Among the model organisms commonly used for genetic screening, researchers chose nematodes as the research object because nematodes are tiny (only 1 mm long), easy to culture, have a clear genetic background and are easy to genetically manipulate, and have a short life cycle. They can mature and produce offspring in 3.5 days, and their entire life cycle is about 21 days. Nematodes are an important model organism for studying aging. Many important signaling pathways that regulate lifespan were first discovered in nematodes, and these signaling pathways are also conserved in mammals. (Why is your forty different from her forty? We found the answer in nematodes)

Caenorhabditis elegans (Photo source: Sohu.com)

But even in nematodes, detecting behavioral changes during aging is not so simple and requires complex experiments. Is there a biological marker of aging that is easy to track, can reflect the degeneration of behavioral function, and is suitable for large-scale screening? The researchers cleverly simplified it and thought of the neurotransmitter system. Neurotransmitters are chemicals that mediate signal transmission between neurons in the brain. During the aging process, abnormal neurotransmitter function will lead to behavioral function degeneration. Improving neurotransmitter function can improve the behavioral ability of the elderly. For example, dopamine signals decrease with aging, and improving dopamine neurotransmitter function can improve the cognitive function of the elderly.

Cai Shiqing's laboratory has previously found that the expression of dopamine decarboxylase, an enzyme that catalyzes dopamine synthesis in nematodes, decreases during aging, leading to decreased dopamine levels and the deterioration of some related behavioral functions [1]. Using this as a clue, the researchers tagged dopamine decarboxylase with fluorescent protein, using fluorescence intensity to indicate changes in dopamine synthesis during aging. Through reverse genetic screening (a technique that uses interfering RNA to reduce the function of target genes), they knocked down more than 16,000 genes in the nematode genome one by one to find genes that improve dopamine function and thus improve the behavioral abilities of elderly animals.

After several rounds of repeated experiments to confirm the screening results, the authors finally found 59 candidate genes, 10 of which have been reported to be related to degenerative diseases or cell aging, and the remaining 49 were discovered for the first time to affect the aging process.

By constructing an interaction network of 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 tested the behavior of nematodes and found that the feeding ability and other behavioral abilities of mutant nematodes lacking the baz-2 and set-6 genes deteriorated much more slowly with aging than wild-type nematodes, and they also extended their lifespan. These results indicate that these two genes accelerate aging, and reducing the function of these two genes can delay aging.

How do genes regulate aging? Through mitochondria

The most difficult part of research is usually not to discover a biological phenomenon, but to study the biological mechanism behind the phenomenon. At the beginning, the researchers had no idea how the proteins BAZ-2 and SET-6 encoded by the baz-2 and set-6 genes regulate aging. Through sequence analysis, they found that these two genes may be epigenetic regulatory factors. So, they found the laboratory of Jiang Lubin, a researcher at the Shanghai Pasteur Institute of the Chinese Academy of Sciences, who is good at epigenetic research in lower eukaryotes, to cooperate.

Epigenetic regulation is different from the well-known genetic regulation. It refers to the heritable changes in gene expression without changing the gene DNA sequence, which ultimately leads to phenotypic changes. Through collaboration, they first proved that SET-6 in nematodes is a histone methylase, and also found that there is an interaction between BAZ-2 and SET-6.

Subsequently, they used a variety of high-throughput sequencing methods for comprehensive analysis and found that BAZ-2 and SET-6 regulate the expression of mitochondrial function-related genes by regulating their epigenetic modifications. Since mitochondria are the main site of cell metabolism and energy factories, a large number of studies have shown that the decline of mitochondrial function is the main cause of tissue function degeneration.

Schematic diagram of mitochondrial structure (Image source: Wikipedia)

By testing the mitochondrial function of nematodes, they found that knocking out the baz-2 and set-6 genes can indeed improve mitochondrial function, and knocking out these two genes slows down behavioral degeneration by improving mitochondrial function. These results show that in order to achieve improvement in the behavioral function of elderly individuals, it is necessary to activate the vitality of mitochondria.

The process of exploring the causes of anti-aging is very difficult. After several years of collaboration, the two laboratories finally elaborated in detail the working principles of these two new anti-aging target genes.

From nematodes to mice

After all, nematodes are not closely related to humans. 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 in human tissue samples available for scientists to study. The researchers made full use of this resource to analyze the changes in the two new anti-aging target genes found in the aging brain. Interestingly, the researchers found that the expression of BAZ2B, the human homologous protein of nematode BAZ-2, increased with aging.

To verify whether reducing Baz2b function can also fight aging, the researchers created mice with Baz2b knockout. Since mice have a long reproductive cycle and a life cycle of up to three years, it took three years from the beginning of constructing knockout mice to removing background mutations and finally raising the mice to old age.

After a long preparation phase, the researchers were pleasantly surprised to find that reducing the function of Baz2b in mice can slow down the weight gain of mice with age. Wild mice will show the phenomenon of "middle-aged obesity", while Baz2b knockout mice can maintain a more "slim" figure during aging. More importantly, the results of behavioral tests showed that old Baz2b knockout mice maintained better cognitive abilities than wild-type mice. This shows that BAZ2B also regulates the aging process in mammals and is a new anti-aging target gene.

Anti-aging target genes regulate body weight and cognitive behavior in aged mice (Image source: provided by the author)

Perhaps these two genes are linked to Alzheimer's

Numerous studies have shown that mitochondrial dysfunction plays an important role in the occurrence and development of Alzheimer's disease. Alzheimer's disease is the number one killer causing cognitive impairment in the elderly. Half of the elderly over 85 years old may suffer from Alzheimer's disease, and there is currently no drug that can effectively treat this disease.

Since the human homologous protein EHMT1 of BAZ2B and SET-6 can also regulate mitochondrial function like nematodes, the researchers also explored the changes of these two anti-aging target genes in Alzheimer's disease. They found that in the brains of Alzheimer's patients, the expression of BAZ2B and EHMT1 was positively correlated with the disease process, and negatively correlated with the expression of key mitochondrial proteins. These results indicate that the increased expression of BAZ2B and EHMT1 in the aging brain may be an important cause of mitochondrial dysfunction in Alzheimer's disease and play an important role in the occurrence and development of Alzheimer's disease.

Schematic diagram of the regulatory mechanism of healthy aging (Image source: provided by the author)

The significance of new discoveries

Aging is the most important risk factor for the occurrence of neurodegenerative diseases. The occurrence and development of senile neurodegenerative diseases take place in the molecular and cellular environment of the aging brain. Understanding the regulatory mechanism of brain aging is crucial to the prevention and treatment of these diseases.

Through whole-genome screening, this work has for the first time demonstrated a broad gene map regulating age-related behavioral degeneration, discovered a series of genes that potentially regulate behavioral degeneration, and identified two epigenetic regulatory factors, BAZ-2/BAZ2B and SET-6/EHMT1, that hinder healthy aging. Reducing the function of these two genes can improve mitochondrial function and thus improve cognitive aging. This study clarifies the role of BAZ2B in cognitive aging and discovers BAZ2B, a new anti-aging gene target.

This work also combined a variety of model animals to clarify the regulatory mechanisms of cognitive aging from multiple levels, laying a good foundation for a more comprehensive understanding of the mechanisms of healthy aging in the future; this study provided a new explanation for the mechanisms of brain aging and provided a new theoretical basis and target for delaying brain aging.

References:

1.Yin, JA, et al., Longevity manipulations differentially affect serotonin/dopamine levels and behavioral deterioration in aging Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. 34(11): p. 3947-58.