Of mice and men: WSU team first to mimic our DNA end caps in rodents to study aging on the cellular level

Scientists have long tried to unlock the secrets to helping people live longer at the cellular level, where aging occurs because of the gradual shortening of protective caps called telomeres at the ends of chromosomes.

The caps act like shoelace tips to prevent chromosomes from unraveling. As telomeres get shorter slowly into the senior years, cells can lose the ability to divide for healthy growth. Studying that process in an entire body has been untouchable – until now.

A Washington State University research team is the first to create genetically engineered mice to have more human-like telomeres, led by WSU Pharmacy and Pharmaceutical Sciences Professor Jiyue Zhu. It’s groundbreaking because mice normally have telomeres up to 10 times longer than in humans, and they don’t have telomere-related aging.

The WSU research paper proving the mice-telomere model was published this week in Nature Communications. Long term, the research could help humans live healthier, longer lives.

In humans, each time a cell divides, it loses a little bit of its telomere sequence and “this is one reason we age,” Zhu said. “Cells become old cells and can no longer divide. In some cases, they become very old cells and just sit there, do damage or the cell would just die.”

Called HuT mice for humanized telomeres, these rodents open up different kinds of studies on cellular aging in a mammal body and the various organs.

“What we did was to modify the mouse gene responsible for coding telomerase, the protein that synthesizes telomeres,” Zhu said. “We introduced regulatory sequences of human genes into the mice. While it’s still a mouse gene, we altered how it is controlled. It’s a complex form of genetic engineering.

Zhu said it’s “the first mouse model with truly humanized telomeres.”

“Now, we aim to observe how these mice age.”

Zhu recently received $5 million in grants to study aging in these mice and to research cancer implications. The funding includes grants from the National Institute on Aging, National Institute of General Medical Sciences and the U.S. Department of Defense, with the latter to study how telomere length affects melanoma cancer cells.

Now, Zhu will collaborate with WSU researchers on two early focuses: studying how shorter telomeres impact lifespan and exploring strategies to extend people’s “healthspan,” or life without age-related diseases.

He said the work has implications for developing future drugs and treatments – and perhaps later – anti-aging steps to activate cells to protect telomeres for longer lifespans. Many diseases begin at the cellular level, so development of drugs is often targeted there.

Mice live an average 2½ to 3 years, and the WSU team expects up to three years to gather data.

The group’s hypothesis is that the mice with shorter telomeres will age faster. They’ll do biochemical, metabolic and neural behavior tests to track functioning. The research will mark when aging begins and the rate.

The studies will eye another key part in human telomere regulation: telomerase, a protein complex that acts like a work crew to repair telomeres. Telomerase adds a bit of DNA onto a telomere so it can maintain length or even sometimes elongate.

While telomerase is expressed in higher amounts in certain human cells such as stem cells or in testes and ovaries, telomerase is controlled at a low level in most other cells, Zhu said.

“It’s highly regulated in humans,” he said. “In mice, it’s a different story. Besides having longer telomeres, they also naturally have high levels of telomerase in their adult tissues. In the HuT mice, we modified this so they expressed much lower levels of telomerase enzyme in their tissues, essentially mimicking the human situation.”

In contrast, cancer cells in humans divide rapidly and have high amounts of telomerase to maintain telomere length. One of the WSU research goals is to find ways of reducing this telomerase expression in cancer cells.

“We plan to induce melanoma in these mice and to see whether shorter telomeres make them more resistant to cancer. The hypothesis is that mice with short telomeres will have increased protection against cancer.”

About 10 years ago, he and other researchers focused more on telomere regulation in humans, and how it differed significantly in animals. Lacking the ability to study the process in lab animals, it restricted telomere-aging research to isolated human cells in a petri dish.

“This mice model is very different, in watching a whole organism going through the aging process,” said Zhu, who started working at WSU in 2014. “Mice are very similar to humans in terms of organ structure, genes and genetic makeup.”

Zhu said the WSU team eventually hopes to share the mice worldwide to advance aging and human longevity research. “There are thousands of people studying aging, and we believe that the new mice model creates a tool for all the scientists in the world to study these processes.”