Can telomere manipulation stop the biological clock?

Wailea, Hawaii - Factors including UV exposure and psychological stress can accelerate the aging process, partly through their influence on telomeres, an expert says. Research is beginning to uncover strategies to counter these forces, however.

Telomeres are critical for protecting the genome, preventing cancers and regulating the aging process, says Barbara A. Gilchrest, M.D., professor and chair emeritus, department of dermatology, Boston University School of Medicine.

Overall, “Aging is nature’s way of protecting organisms from alterations in the genome. Nature doesn’t care if our skin looks awful. It only cares that the genome is protected. When cells divide, there is a tiny but known, constant risk of mistakes being made in replicating the genome. That’s one of the reasons cancer risk increases with age,” says Dr. Gilchrest, who spoke at MauiDerm 2013. “Additionally, sun exposure is known to cause DNA damage.”

Rather than allow cells that are becoming mutated and dysregulated because of accumulated DNA damage to replicate, she says, the aging process shuts these cells down.

“It’s been well documented that with repeated cell division, the cells ultimately will undergo either senescence (the cells simply stops dividing) or apoptosis (cell suicide),” Dr. Gilchrest says.

Along with cumulative DNA damage, she says that over the past decade, research has identified telomere shortening as another major aging mechanism.

“Currently, telomere biology is perhaps the hottest topic in our attempts to understand aging skin and other tissues,” she says.

Looking deeper at DNA

In the DNA replication process, “At the tip of each chromosome reside approximately 10,000 base pairs of telomeric DNA,” all of which repeat the TTAGGG (thymine, adenine, guanine) sequence and form a loop at the end of each chromosome. “The very end of the telomere tucks into the proximal part of the telomere, making a closed loop that essentially hides the TTAGGG sequence within the double-stranded DNA. Thus, the cell never sees this TTAGGG sequence - except when the chromosomes must straighten out in order to be replicated, or at times of major damage, when the telomeric strands may separate because of bulky adducts or to accomadate repair proteins.”

Without telomeres, Dr. Gilchrest says, any cell will die.

“It's also been shown that the telomeres shorten with each round of replication. Therefore, telomeres have been called the biological clock. They tell a cell how old it is, and if it’s time to enter senescence or apoptosis,” she says.

Similarly, “If one experimentally disrupts telomeres and exposes the TTAGGG sequence, the cell responds as if it had experienced DNA damage. It will turn on all of its DNA damage response pathways, which include the p53 protein, also called the Guardian of the Genome.”

The cell responds strongly to environmental insults, Dr. Gilchrest says, because within the TTAGGG sequence, “The thymidines are where UV causes most of its damage. It dimerizes or hooks together adjacent thymidine residues. That explains about 80 percent of the damage that results from sun exposure. Guanine residues are the site of oxidative damage, and chemical carcinogens also target guanines and, less often, adjacent guanine-adenine residues. Therefore, the telomeres are a superb target for DNA damage.”

Response to damage

Research has shown that any DNA-damaging agent that injures cells creates damage throughout the genome, she adds. “But you get far more damage in the telomere. With UV, for example, you get about seven times more damage in the telomere than in the rest of the DNA. To me, it suggests that one of the functions of telomeres is to recognize that damage is occurring, and to help the cells respond appropriately. One appropriate mutation-avoidance response might be aging.”

Moreover, “Telomere lengths have been strongly implicated in human aging,” she says

In people older than 60 years, Dr. Gilchrest says, telomere length correlates with longevity (Cawthon RM, Smith KR, O’Brien E, et al. Lancet. 2003;361(9355):393-395). Conversely, she says, extremely short telomeres characterize rare diseases marked by accelerated aging, such as Werner syndrome and progeria.

Impact of stress

Other factors that contribute to aging include stress. In this regard, a study co-authored by Nobel Prize laureate Elizabeth Blackburn, Ph.D., showed that mothers dealing with the stress of chronically ill children had shorter telomeres and decreased telomerase activity versus mothers with healthy children (Epel ES, Blackburn EH, Lin J, et al. Proc Natl Acad Sci U S A. 2004;101(49):17312-17315). However, physical activity appears to prevent telomere shortening caused by psychological stress (Puterman E, Lin J, Blackburn E, et al. PLoS One. 2010;5(5):e10837).

More recently, a study showed that endogenously reactivating telomerase activity in telomerase-deficient mice extends telomeres, reduces DNA damage signaling and prevents age-associated degeneration of multiple organs (Jaskelioff M, Muller FL, Paik JH, et al. Nature. 2011;469(7328):102-106). Accordingly, study authors write that their results “support the development of regenerative strategies designed to restore telomere integrity.”

No one knows when these insights might generate anti-aging therapies for the skin or other organs, Dr. Gilchrest says, but many efforts are being harnessed toward this goal.

“For now,” she says, “we must still rely on minimizing environmental DNA damage from sun exposure, cigarette smoke, air pollution and other carcinogens.”

Disclosures: Dr. Gilchrest reports no relevant financial interests.