By Faisal Khan | 2 June 2023
Aging is indeed a complex process influenced by various factors, including genetic, environmental, and lifestyle factors. But Scientists have made significant progress in unraveling the biology of aging in recent years. They have identified several key factors & processes involved in the aging process, such as telomere shortening, genomic instability, epigenetic modifications, cellular senescence, mitochondrial dysfunction & hormonal changes. Each of these pieces contributes to the overall puzzle of aging.
With age, cells express genes faster but with less accuracy. This research shows causation, uses many organisms to show high evolutionary conservation, and tests a well-characterized intervention (dietary restriction). Awesome work. https://t.co/enpgFqHYhI
— Dr. Brandon Berry 🔋 (@mitobrandon) April 14, 2023
Understanding these individual pieces enables scientists to create a more complete picture of the aging process. It also helps identify potential targets for intervention. For example, researchers have explored strategies to extend telomeres, repair DNA damage, modulate epigenetic marks, eliminate senescent cells, improve mitochondrial function & regulate hormonal imbalances. These interventions hold promise for developing therapies that can slow down the aging process and reduce age-related symptoms and diseases.
On top of the many breakthroughs that we have seen in decoding the aging process, researchers have discovered a crucial piece of the aging puzzle in a novel study. By investigating five species spanning the evolutionary scale, including worms, flies, mice, rats, and humans, the team has successfully identified a pivotal molecular process that drives cellular function throughout the body and undergoes degradation as individuals age.
In a groundbreaking revelation, the novel study has shed light on the role of transcription — the initial step in converting genetic material into proteins, in the aging process. This process involves the transformation of DNA into RNA, which acts as a messenger, conveying information to different parts of the cell for protein synthesis. It opens up new avenues of how and why we age but researchers warn, we are still distant from human testing.
While scientists have long suspected that transcription might be affected by aging, the study has provided evidence that contradicts this notion — albeit with an intriguing twist. Surprisingly, in all five species examined, the transcription process actually accelerated as the organisms aged. However, this accelerated pace came at the cost of increased error rates, resembling the challenge of typing faster while blindfolded.
“Together, the data presented here reveal a molecular mechanism contributing to aging and serve as a means for assessing the fidelity of the cellular machinery during aging and disease.”
~ Study Team
Fortunately, a potential solution has been identified. By employing two interventions known to prolong the lifespan, the research team successfully decelerated the transcription process in multiple species, including mice. Additionally, genetic mutations that reversed the error-prone transcription also extended the lifespan of worms and fruit flies, while enhancing the division and growth capabilities of human cells.
Overcoming a significant obstacle in the study of aging hallmarks, researchers have addressed the challenge of species specificity by conducting a comprehensive investigation involving five different species. Employing RNA sequencing, the team examined the speed of an enzyme called Pol II as it transcribed DNA in cells derived from worms, fruit flies, mice, rats, and humans across various age groups.
Human samples encompassed individuals aged between 21 and 70 years, including two “immortal” cell lines maintained in culture. To obtain a more extensive perspective, the researchers analyzed samples from multiple organs, such as the brain, liver, kidneys, and blood. The findings yielded surprising results. While each species exhibited its unique Pol II “speed signature,” the overall trend remained consistent — Pol II accelerated its transcription rate with age across all species and tissues examined.
The specific genes or tissues involved appeared to be less relevant, as this age-related alteration encompassed approximately 200 different genes across multiple species. Rather than a localized effect, the increased speed of Pol II emerged as a universal marker of aging. However, the heightened speed also brought about errors. Precise splicing, which involves editing pre-RNAs, necessitates an optimal speed of Pol II.
Augmenting the transcription rate elevated the risk of erroneous translations, which, as previous studies have indicated, are associated with advanced age and reduced lifespan, as explained by the authors. To investigate potential interventions for slowing down aging, the research team conducted an experiment involving two widely recognized approaches — inhibiting insulin signaling and implementing caloric restriction.
In worms, fruit flies, and mice, disrupting the insulin-sensing pathway at a genetic level resulted in a deceleration of Pol II’s transcription speed. Additionally, subjecting mice to a restricted diet during early adulthood and middle age (but not during old age) also had a similar effect of slowing down Pol II. Another experiment focused on addressing the fundamental question — Does the acceleration of Pol II contribute to the aging process?
Brilliant video showing what aging is.
If only we could reverse it…pic.twitter.com/cBq9dmUzlY
— João Pedro de Magalhães (@jpsenescence) May 29, 2023
To explore this, the team observed a group of genetically modified worms and fruit flies that carried mutations leading to reduced Pol II speed. In comparison to non-mutant organisms, both of these engineered strains exhibited extended lifespans ranging from 10 to 20%. However, when the researchers employed the CRISPR-Cas9 gene-editing technique to reverse the Pol II mutations in the worms, their lifespans shortened & aligned with those of the wild-type counterparts.
This observation suggests that Pol II indeed plays a causative role in the aging process, as explained by the authors. Delving deeper into the intricacies of the transcription machinery, the research team made a significant discovery. To provide some context, DNA is structured as nucleosomes, often described as bacon-asparagus bundles from a scientific standpoint. Comparing human umbilical vein cells and lung cells, the team observed that as cells undergo aging, these nucleosome bundles gradually unwind and disintegrate.
Consequently, this facilitates the movement of Pol II along the DNA strand, leading to an acceleration of transcription speed. To further validate their hypothesis, the researchers genetically introduced two types of histone proteins, which constitute the asparagus component of the nucleosome bundles, into human cells cultured in Petri dishes. This intervention effectively increased the formation of nucleosomes, creating additional obstacles that slowed down Pol II.
"CRISPR-Cas9 has its shortcomings. Because it relies on the cell’s self-healing mechanism to rejoin the broken strains, it may result in off-target effects, such as chromosomal rearrangements or large DNA deletions, which may cause safety concerns." https://t.co/zsUtUCSYi3
— Dion Klitzke (@DionKlitzke) May 31, 2023
Remarkably, the strategy worked. Cells with augmented histone proteins exhibited a reduced likelihood of transitioning into senescent cells. In fruit flies, a well-established model organism in longevity research, the genetic modification resulted in a notable increase in lifespan. Although these findings are still in their early stages, they bring exciting prospects for the development of a new class of anti-aging drugs.
Notably, Pol II has already been extensively studied in the field of cancer therapy, with multiple medications tested and approved. This offers the potential for repurposing these drugs for longevity research, opening up promising avenues for future exploration. Complete research was published in the Journal of Nature.
Reprinted with permission from the author.
Faisal Khan is a prolific Canada-based tech blogger and influencer. He is the founder and editor of the Technicity publication which focuses on technical, scientific and financial knowledge sharing. Follow him on Twitter @fklivestolearn.
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