Salk research delves into reversing the aging process, cell by cell

A rapt audience hung on to every word that Dr. Jan Karlseder spoke during his lecture, “Keep Tabs on Your Telomeres: The Role of Chromosome Ends in Aging and Disease.”

Karlseder is an award-winning professor of molecular and cellular biology at the Salk Institute of Biological Studies, holding the Donald and Darlene Shiley Chair. He spoke June 8 at the Del Mar Powerhouse, sponsored by the Del Mar Foundation and filmed by Del Mar TV.

He received his Ph.D. from the Institute for Molecular Biology in Austria and completed post-doctorate degrees at the Center for Applied Genetics (Austria) and Rockefeller University.

Karlseder’s laboratory studies the functions of the telomeres at the end of linear chromosomes. His evening presentation, enhanced with graphic images, gave a clear understanding of how telomeres affect aging.

Every mammalian cell has a nucleus that contains chromosomes with DNA. Through colorful magnified images of stained cells, Karlseder showed that the tips of chromosomes — telomeres — get shorter with age, a major driver of cellular aging. “We are trying to understand why this happens, and our purpose is to extend the health span,” he explained.

Health span is the period of life, until about 40 or 50 years old, when a person is not suffering from disease. “Our goal is to push that out to age 75 so that everybody may live healthily to that point, which will make a huge impact on life and also on the financial status of services like Social Security,” said Karlseder.

With cellular aging come age-associated diseases like Alzheimer’s, diabetes, hypertension, arthritis, cancer and more, which are problems for human well-being as well as being a financial burden, with 80 percent of health care dollars being spent in the last five to 10 years of life, said Karlseder.

“The big question my lab is asking is, ‘What controls aging cells, what is the clock that measures it and what is the connection between this clock and age-onset diseases?’”

Cells divide only a certain number of times, then they expire. Controlling this process are telomeres — segments of DNA — located at the end of chromosomes.

Every time a cell divides, the telomere gets smaller until it is too short to function. Unable to protect the end of the chromosome, genetic material is eaten away, which correlates to aging.

Karlseder gave three examples of research from his lab to illustrate the importance of examining the aging cell.

First, researchers looked at genome instability. Examining cells from people with Werner’s syndrome — a disease that causes accelerated aging — it was evident that some of the chromosomes did not have telomeres, some were missing and some were disorganized.

In the lab, using tissue cultures from Werner’s syndrome patients, this genome instability was suppressed by activating the enzyme telomerase, and the cells grew normally.

“This is relevant because everything that happens in these people also happens to us, just not as accelerated,” Karlseder explained.

Second, researchers examined the hereditary material held in the DNA, which must be well-organized to fit inside the cell. This is accomplished by proteins called histones that wrap around the DNA molecules in a specific way.

“We looked at old cells to see if the same amount of histones were present as in a young cell, and it was clear that fewer histones were visible in the old cell,” said Karlseder.

An experiment was devised to take an old cell and force it to have the same amount of histones as a young cell. Consequently, it became indistinguishable from the young cell.

“Here we can reverse the effect of aging without making the cell immortal. This is precisely the idea of elevating the health span ... at least in tissue culture, this is possible,” said Karlseder.

Third, researchers aimed to answer the basic question, “What is aging?”

“If I asked 10 people in this room what is aging to them, I’ll get 10 different answers,” said Karlseder, “The same is true for scientists.”

But all agree that age-associated diseases are a major factor in the aging process, he said.

Karlseder’s lab looked at the commonalities between the different age-associated diseases and discovered that stress played a major role.

A recent observation showed that in a young cell, telomeres establish chromosomal territories. “We found out there is a very short window of time during the cellular division cycle where the telomeres establish a territory by going to the nuclei envelope,” Karlseder explained.

Stress is created when these telomeres are not able to organize in the nuclei envelope in the old cell, suggesting the reason for the synergy of age-associated diseases.

“It doesn’t really matter what the responsive genes are; if you can’t organize how they interact with each other, suddenly everything goes wrong, as they cannot organize the genome correctly,” said Karlseder. “This again shows how these tiny telomeres influence the whole cell.”

This finding means that the telomeres of an old cell could be engineered to enter the nuclei and thus suppress these diseases.

Theoretically, telomeres regulate the life span of cells and how chromosomes organize and might well be responsible for the onset of disease. “This is something that we are trying to figure out and how we can extend the human health span without causing cancer,” Karlseder said.

Visit www.salk.edu to find out more about the Salk Institute of Biological Studies. Visit http://www.delmarfoundation.org/ for future talks sponsored by the Del Mar Foundation

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