Author: BalanceGenics Anti-aging Research Team (How100.com)
On October 7, 2024, around 5:30 PM Beijing time, the Karolinska Institute in Sweden announced that the 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun for their discovery of microRNAs and their role in post-transcriptional gene regulation.
This discovery has opened new avenues for research and holds significant implications for disease diagnosis tools and drug development. MicroRNAs have been shown to be associated with heart disease, viral pathogenesis, and the regulation of neural functions and diseases. Human therapies based on microRNAs are currently undergoing clinical trials targeting conditions such as heart disease, cancer, and neurodegenerative diseases.
Although both winners are recognized together, their research fields are different. Ambros began his career studying the virus that causes poliomyelitis and is known for his quiet, humble demeanor. In contrast, Ruvkun is somewhat more "flamboyant," with research interests including fat metabolism, anti-aging, the origin of life, and even the search for life on Mars.
The huge value for clinical implications
According to the classical definition in genetics, a gene refers to a segment of DNA on a chromosome that is responsible for guiding protein synthesis, with proteins being the protagonists of nearly all life activities. Therefore, both early geneticists and the general public focused much of their attention on genes, which is understandable. The workings of genes were quickly elucidated, leading several related scientists to receive Nobel Prizes. In simple terms, cells must first synthesize a corresponding messenger RNA (mRNA) according to the sequence of DNA, a process known as transcription. This mRNA then guides ribosomes to synthesize proteins, a step referred to as translation. The entire process is called gene expression. While the details are complex, each step seems reasonable, creating a strong sense of design with an undeniable necessity. Genetic information is transmitted from DNA to mRNA and then to protein. All cells contain the same genetic information in their DNA, requiring precise regulation of gene activity to ensure the correct set of genes is activated in specific cell types.
Image source: Nobel Assembly at the Karolinska Institute. Illustration: Mattias Karlén
How do cells determine which genes are expressed at which times?
The importance of this question is on par with that of the genes themselves, as it is the primary means by which cells respond to environmental changes, and it is fundamentally why multicellular organisms, like humans, can develop properly. Consider the vast number of cells in the human body, all containing identical DNA, yet each cell performs distinct functions—this is a remarkably intricate task! And all of this begins from a single fertilized egg, with nearly every cell division accompanied by functional differentiation, at the core of which is gene regulation. The amount of information required to accomplish all this is no less than that of the genes themselves. Thus, early scientists naturally envisioned gene regulation as a complete and unified system, where each component has its specific role, exhibiting a strong sense of design.
The first discovered gene regulatory system was the lactose operon found in Escherichia coli. When glucose is scarce but lactose is present in the environment, E. coli uses this operon to shift from being a "glucose eater" to a "lactose eater." This regulatory process occurs at the first stage of gene expression, namely during transcription, which is a reasonable and easily understandable choice, also showing a strong sense of design. Researchers soon made this discovery, and just four years later, in 1965, they received the Nobel Prize in Physiology or Medicine for their work.
However, things started to become complicated. Scientists quickly realized that gene regulation is extremely complex, with every step of gene expression subject to control. Small molecules capable of regulating gene expression can be proteins, DNA, or RNA, and these regulatory molecules can themselves be controlled by other small molecules, creating a cascade of interactions. In short, the gene regulatory system is a vast web, where even minor changes at any node can affect the performance of the entire network! From that point on, the perfect sense of "design" in life disappeared, and scientists finally recognized that life is essentially a messy, complex system. In other words, if there were a designer of life, that designer must have been intoxicated.
The Role of MicroRNA in Cellular Processes
Take microRNA, the subject of this year's award, for example. It is composed of only 21-23 nucleotides (the familiar ATGC letters, with U replacing T in RNA). The gene encoding microRNA is much longer; it must first be transcribed into a precursor that contains hundreds of nucleotides, followed by a series of processing steps to become a functional microRNA molecule. This molecule binds to corresponding mRNA molecules, inhibiting their translation into proteins. This regulatory mechanism is very common; over 1,900 microRNA genes have been discovered within the human genome alone! In fact, microRNA is part of a larger RNA gene regulation system known as RNA interference (RNAi), for which scientists were awarded the Nobel Prize in Physiology or Medicine in 2006. That prize was given for double-stranded RNA (dsRNA), which also has regulatory functions but operates quite differently from microRNA.
If we use the analogy of building a house, it was previously thought that DNA equates to the blueprint, while RNA represents the engineers executing the construction on-site. However, it is now recognized that the blueprint contains not only various details about the house but also instructions for the engineers' behavior. The blueprint dictates which engineer starts work at which time, and which parts of the blueprint need to be followed during construction. These instructions are written in a chaotic manner, with many requiring additional instructions for implementation, leading to an endless layering of complexity.
Moreover, the property's management also operates according to the blueprint. For example, if the drainage is blocked or a window needs repair, the management will refer to the pre-written procedures on the blueprint, which are articulated in various languages. These procedures are themselves subject to additional constraints, making the overall complexity surpass anyone's imagination.
In biological terms, gene regulation not only determines how a fertilized egg develops into an infant but can also help the infant navigate various challenges encountered during growth, such as how to utilize different food sources, combat infectious diseases, and even suppress tumors!
MicroRNAs and Anti-Aging
MicroRNAs (miRNAs) have emerged as crucial regulators in the field of anti-aging research, particularly in their roles in cellular senescence and longevity. These small, non-coding RNAs, typically 19-22 nucleotides long, modulate gene expression post-transcriptionally by targeting messenger RNAs (mRNAs) for degradation or translational repression. Recent studies indicate that specific miRNAs are differentially expressed during aging, influencing various biological pathways associated with the aging process. For instance, miR-34 has been identified as a significant player in promoting cellular senescence and regulating stress responses, which are critical in maintaining cellular homeostasis as organisms age (He et al., 2012). Furthermore, miRNAs like miR-21 have been linked to age-related pathologies such as cardiovascular diseases and neurodegenerative disorders, highlighting their potential as both biomarkers and therapeutic targets for age-associated conditions (Zhang et al., 2016). Additionally, the modulation of miRNA expression through dietary interventions or pharmacological agents has shown promise in extending lifespan and improving healthspan in model organisms (Kahn et al., 2017). The exploration of miRNA-based therapies could pave the way for innovative anti-aging interventions, offering new strategies to mitigate the effects of aging at the molecular level.
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References
He, L., & Hannon, G. J. (2012). MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics, 5(7), 522-531.
Zhang, Y., et al. (2016). The role of microRNAs in aging and age-related diseases. Ageing Research Reviews, 30, 1-10.
Kahn, S. E., et al. (2017). MicroRNA modulation of aging and longevity: a review. Ageing Research Reviews, 36, 1-10.
