Decoding Aging: A New Understanding from Gene Transcription to Cellular Decline

Abstract：A groundbreaking study from the Max Planck Institute, published in Nature in 2023, has proposed a novel explanation for aging centered around increased gene transcription speed. Researchers found that as organisms age, the rate at which genetic information is copied from DNA to RNA accelerates, leading to disruptions in cellular processes such as RNA splicing and error correction. This acceleration results in higher error rates and cellular dysfunction. By genetically slowing transcription in fruit flies and nematodes, the researchers successfully extended lifespan by 10-20%, suggesting a causal link between faster transcription and aging. They further identified chromatin loosening and a decline in histone H3 proteins as key contributors to this acceleration. Restoring histone levels slowed transcription and delayed aging. While promising, the study raises new questions about the mechanisms driving chromatin changes and whether transcription speed can be safely controlled for anti-aging therapies. This discovery opens new possibilities for targeted interventions aimed at extending healthy lifespan by modulating gene transcription rates.

Aging is not only a profound philosophical and scientific question but also a major focus in the biomedical industry.

The reasoning is clear: with rising life expectancy, most major human diseases show a strong correlation with age. For instance, the incidence of cancer at age 20 is about 25 per 100,000, but it escalates dramatically to 1% in individuals over 60. Similarly, Alzheimer’s disease, which affects less than 1% of those under 60, rises to nearly 50% in people around 90.

In an aging society, identifying the emerging medical needs and developing targeted treatments has become a top priority for the biomedical industry. Conversely, most current medical strategies focus on treating diseases individually—targeting specific conditions with specific treatments. However, if we could slow or even reverse systemic aging itself, we might be able to address multiple health issues simultaneously at their root.

Over the past two to three decades, significant progress has been made in understanding aging. For example, researchers have clarified how exercise can help delay aging, while drugs such as metformin and rapamycin are undergoing serious clinical trials for their potential anti-aging effects. Stem cell technology has also been explored as a possible tool for rejuvenation. However, given the complexity of aging, it is difficult to imagine a single intervention capable of completely halting the process.

Scientists have proposed numerous models to explain why and how aging occurs. These theories include:

• The Telomere Hypothesis: Aging results from the shortening of protective DNA sequences (telomeres) at the ends of chromosomes during cell division.

• The Free Radical Hypothesis: Aging arises from mitochondrial dysfunction leading to an excess of reactive oxygen species (ROS), which damage cells.

• The Epigenetic Hypothesis: Aging is linked to frequent breaks and repairs in DNA, causing abnormal epigenetic modifications.

In April 2023, a groundbreaking study from the Max Planck Institute published in Nature introduced a novel model of aging. It suggested that increased transcription speed—the rate at which genetic information is copied from DNA to RNA—could be a fundamental driver of aging and that slowing this process might extend lifespan.

The Role of Transcription in Aging

DNA serves as the blueprint of genetic information, while proteins execute most biological functions in living organisms. The process of protein production involves two steps:

1. Transcription: RNA polymerase copies DNA into RNA.

2. Translation: Ribosomes read the RNA to assemble proteins.

Given the central role of proteins in nearly all biological processes, the researchers hypothesized that changes in transcription and translation might influence the aging process. They focused on whether aging altered the speed of transcription within cells.

To investigate, the scientists examined the transcription rate in aging cells, specifically focusing on introns—non-coding regions of genes that are transcribed but later removed from the final RNA. If transcription speed increased while the rate of intron removal remained constant, the proportion of intron-containing RNA would decrease in older cells.

This clever methodology allowed the researchers to indirectly measure transcription speed. Their findings were striking: across multiple species—including humans, rats, mice, fruit flies, and nematodes—as well as in cultured cell lines, aging was consistently associated with faster transcription rates.

Caloric Restriction and Longevity Mutations

Interestingly, the researchers observed that transcription speed increased less significantly in animals subjected to caloric restriction—an intervention long known to extend lifespan. Similarly, animals with specific longevity-associated gene mutations also showed a reduction in transcription acceleration during aging.

Notably, the increase in transcription speed was widespread, affecting most genes rather than being limited to a few specific ones. This pattern suggested a systemic biological shift rather than a localized genetic defect.

Is Faster Transcription Causing Aging?

While accelerated transcription correlated with aging, the researchers needed to determine if it was merely a byproduct or an actual driver of cellular decline. To test this, they genetically modified fruit flies and nematodes to slow down their transcription rates by targeting RNA polymerase II, the enzyme responsible for transcription.

The results were profound: genetically slowing transcription extended the lifespan of these organisms by 10-20%, indicating a causal link between transcription speed and aging.

Why Does Faster Transcription Cause Harm?

The next critical question was why increased transcription speed would be detrimental. The answer seems to lie in the delicate balance between transcription and other cellular processes like RNA splicing and error correction.

Transcription is not a simple copying process—it involves complex steps, including splicing introns and correcting errors. When transcription speeds up but these downstream processes do not, errors accumulate. The researchers found that older cells showed:

• Increased RNA sequence errors.

• Reduced accuracy in intron removal.

• Higher rates of abnormal circular RNA formation, which can disrupt protein synthesis.

These disruptions could impair protein production, compromising cell function and accelerating biological decline.

Why Does Transcription Accelerate with Aging?

The researchers hypothesized that structural changes in chromatin—the tightly packed form of DNA—might be the cause. Normally, DNA is wrapped around histone proteins to form a compact structure that controls gene accessibility and transcription rates.

In aging cells, this packaging appears to loosen, making genes more accessible and allowing transcription to speed up.

Further supporting this, the researchers found that histone H3 protein levels decreased significantly in aging cells. When they artificially increased H3 protein levels in both aging fruit flies and cell cultures, transcription speed slowed, and cellular aging was delayed.

Key Takeaways from the Study:

• Aging correlates with increased gene transcription speed across species.

• Faster transcription may disrupt cellular balance, leading to functional decline.

• Genetically slowing transcription can extend lifespan in model organisms.

• Loss of chromatin structure and histone proteins may be a primary cause of accelerated transcription during aging.

Unanswered Questions and Future Directions

While this study provides compelling insights, it also raises several unresolved questions:

1. Why Does Chromatin Degrade with Age?

   
   

   Is it due to cellular wear and tear, or could it be an actively regulated process?

2. Can Transcription Speed Be Safely Controlled?

   
   

   Could future therapies slow transcription in a controlled manner without harmful side effects?

3. Could Histone Therapy Be Viable?

   
   

   Since histone depletion is linked to increased transcription speed, could histone-modulating drugs offer a safe anti-aging strategy?

Conclusion: A New Lens on Aging Research

This groundbreaking study suggests that faster gene transcription may play a central role in the aging process, shifting the focus of anti-aging research toward controlling transcription rates. If further validated, this model could open new avenues for therapeutic interventions aimed at delaying age-related decline and extending healthy lifespan.