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Is “Cryptic Transcription” the Source of Human Aging?

Anti aging researchers may have discovered the secret of human aging in the life cycle of stem cells.

We are all familiar with the unmistakable signs of aging – weakness, wrinkled skin, lowered resistance to disease, sexual health issues, and so on. However, unraveling what triggers them has been quite a challenge and kind of the “Holy Grail” of anti-aging researchers.

Recently, anti-aging researchers at Baylor College of Medicine and collaborating institutions have discovered that a cellular phenomenon called “cryptic transcription” may be the key that everyone has been searching for.

Cryptic transcription is something that occurs in the life and death cycle of certain cells. However, previously, the phenomenon seemed to only occur only in yeasts and worms and has been linked to aging in these organisms. The Baylor team has discovered that the process also happens at an accelerated rate in mammalian stem cells as they get older.

The team reports in the journal Nature Aging that cryptic transcription occurs because a cellular mechanism that keeps it in check falls apart as cells get old. The findings suggest that strategies that control cryptic transcription could have pro-longevity effects.

“In previous work, we showed that cryptic transcription in yeasts and worms is not only a marker of aging but also a cause,” said corresponding author Dr. Weiwei Dang, assistant professor of molecular and human genetics and the Huffington Center on Aging at Baylor. “Reducing the amount of this aberrant transcription in these organisms prolonged their lifespan.”

Cryptic transcription is a phenomenon that interferes with normal cellular processes. Normal gene transcription is the first step in the production of proteins. It begins in a specific location on the DNA called the promoter. This is where the protein-coding gene begins to be transcribed into RNA, which is eventually translated into protein. Gene transcription is a well-regulated cellular process, but as cells age, they lose their ability to control it.

“Promoters have a specific DNA sequence that identifies the starting point of the transcription process that is usually located preceding the actual protein-coding sequence,” explained Dang. “But promoter look-alike sequences do exist in other locations, including along the actual protein-coding sequence, and they could start transcription and generate shorter transcripts, called cryptic transcripts. Here we investigated whether cryptic transcription increased with age in mammals and potential mechanisms involved in this phenomenon.”

The team worked with mammalian stem cells, which have been shown to play a significant role in aging. They adopted a method to detect cryptic transcription to determine the level of this transcription in mice and human stem cells, and cultured cells. When compared to young stem cells, older ones indeed had increased cryptic transcription. They also looked into other aging cells and found that, in the majority of cells spanning a range of tissues, cryptic transcription was also elevated with age.

“Altogether, our findings indicate that elevated cryptic transcription is a hallmark of mammalian aging,” Dang said.

“It is still not clear how elevated cryptic transcription contributes to aging, but the evidence is accumulating that it is detrimental to mammals as it is for yeast and worms,” Dang said. “Future studies may result in ways of reduce the pro-aging effects of cryptic transcription.”

If, as Dang says, researchers can find ways to reduce or inhibit cryptic transcription, it could open up drugs or other treatment methodologies that could profoundly increase human lifespan and/or healthspan.

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