Researchers discover new cause of cell aging

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Researchers discover new cause of cell aging

Findings have huge implications for cancer and age-related health conditions

New research from the USC Viterbi School of Engineering could be essential to our understanding of how the aging process works. These discoveries could pave the way for better cancer treatments and revolutionary new drugs that could greatly improve human health in the twilight of life.

The book, written by Nick Graham, Assistant Professor of Chemical and Materials Engineering, and his team in collaboration with Scott Fraser, Senior Professor of Biological and Biomedical Engineering, and Pin Wang, Zohrab A. Kaprielian Fellow in Engineering, was recently published in the Journal of Biological Chemistry.

"To drink from the fountain of youth, you have to know where the fountain of youth is and understand what it does," Graham said. "We are doing the opposite; we are trying to study the reasons why cells age, so that we can design treatments for better aging."

What causes cell aging?

To achieve this, principal author Alireza Delfarah, a graduate student at Graham's laboratory, focused on senescence, a natural process by which cells stop creating new cells. This process is one of the main causes of age-related decline, which manifests itself in diseases such as arthritis, osteoporosis and heart disease.

"Senescent cells are actually the opposite of stem cells, which have unlimited potential for self-renewal or division," Delfarah said. "Senescent cells can never divide again. It is a state of irreversible cell cycle failure."

The research team discovered that aging senescent cells have stopped producing a class of chemicals called nucleotides, which are the building blocks of DNA. When they took young cells and forced them to stop producing nucleotides, they became senile, or elderly.

"This means that nucleotide production is essential to keep cells young," says Delfarah. "It also means that if we could prevent cells from losing nucleotide synthesis, cells could age more slowly."

Graham's team examined young cells that were proliferating strongly and gave them molecules labelled with stable carbon isotopes to determine how the nutrients consumed by a cell were transformed into different biochemical pathways.

Scott Fraser and his laboratory worked with the research team to develop 3D images of the results. The images unexpectedly revealed that senescent cells often have two nuclei and do not synthesize DNA.

Until now, senescence has mainly been studied in cells called fibroblasts, the most common cells that make up the connective tissue of animals. Graham's team focuses instead on how senescence occurs in epithelial cells, the cells that line the surfaces of organs and structures of the body and the type of cells in which most cancers occur.

Graham said that senescence is more widely known as the body's protective barrier against cancer: When cells suffer damage that could be at risk of developing cancer, they enter senescence and stop proliferating so that the cancer does not develop and spread.

"Sometimes people talk about senescence as a double-edged sword that protects against cancer, and that's a good thing," Graham said. "But it also promotes aging and diseases such as diabetes, cardiac dysfunction or atherosclerosis and general tissue dysfunction," he said.

Graham said the goal was not to completely prevent senescence, as it could release cancer cells.

"But on the other hand, we would like to find a way to eliminate senescent cells to promote healthy aging and better functioning," he says.

Graham said the team's research has applications in the emerging field of senolytics, the development of drugs that could eliminate aging cells. He said that clinical trials in humans are still in the early stages, but studies in mice have shown that by eliminating senescent cells, mice age better and have a more productive life span.

"They can take an aging mouse with declining function, treat it with senolytic drugs to eliminate senescent cells, and the mouse is rejuvenated. Rather, it is these senolytic drugs that are the fountain of youth," Graham said.

He added that in order to design effective senolytic drugs, it is important to identify what is unique in senescent cells, so that the drugs do not affect normal and non-senentary cells.

"This is where we come in, by studying the metabolism of senescent cells and trying to understand how senescent cells are unique, so that we can design targeted treatments around these metabolic pathways," explains Dr. Graham.