Our bodies are made up of trillions of cells, and millions of them die every day. As such, we’re constantly producing millions of new cells to replace the old ones. It has been suggested that as we age, cells lose functionality over time; they divide more slowly for example or pick up mutations and damage. Reporting in the Journal of Biological Chemistry, researchers have now gained more insight into the aging process by investigating cell senescence, in which cells stop generating new cells. This process is seen in several disease states, such as heart disease and osteoporosis.
"Senescent cells are effectively the opposite of stem cells, which have an unlimited potential for self-renewal or division," explained the lead author of the new study, graduate candidate Alireza Delfarah of the University of Southern California's Viterbi School of Engineering . "Senescent cells can never divide again. It's an irreversible state of cell cycle arrest."
This study may help generate new treatments for age-related decline. "To drink from the fountain of youth, you have to figure out where the fountain of youth is, and understand what the fountain of youth is doing," said Assistant Professor of Chemical Engineering and Materials Science Nick Graham. “We're doing the opposite; we're trying to study the reasons cells age, so that we might be able to design treatments for better aging."
Our DNA is made up of four nucleotide bases. When cells divide, the entire genome has to be replicated so that each cell will get a complete copy of it, requiring a lot of those nucleotides. In this work, the researchers found that senescent cells stop generating nucleotides. The scientists halted nucleotide production in young cells and found that the young cells became senescent - they aged.
"This means that the production of nucleotides is essential to keep cells young," Delfarah said. "It also means that if we could prevent cells from losing nucleotide synthesis, the cells might age more slowly."
The researchers traced nutrient consumption in young cells that were growing robustly, and discovered that senescent cells often possess two nuclei, but do not create DNA. Senescnece is sometimes considered a shield against cancer, noted Graham. When cells sense that they’ve picked up damage, they can enter a senescent state so that they stop creating new, damaged cells that can contribute to disease.
"Sometimes people talk about senescence as a double-edged sword, that it protects against cancer, and that's a good thing. But then it also promotes aging and diseases like diabetes, cardiac dysfunction or atherosclerosis and general tissue dysfunction," Graham explained.
Graham is not trying to prevent senescence; it could encourage the growth of cancer. "But then on the other hand, we would like to find a way to remove senescent cells to promote healthy aging and better function," he added.
Senolytic drugs aim to eliminate aging cells. In mouse model trials, aging is improved with senolytics, said Graham. "They can take a mouse that's aging and diminishing in function, treat it with senolytic drugs to eliminate the senescent cells, and the mouse is rejuvenated. If anything, it's these senolytic drugs that are the fountain of youth," Graham said.
A good senolytic drug has to selectively target the unique features of senescent cells, he noted. "That's where we're coming in - studying senescent cell metabolism and trying to figure out how the senescent cells are unique, so that you could design targeted therapeutics around these metabolic pathways," Graham said.