Biomarkers May Hone Anti-aging Therapies

Vanderbilt University Medical Center investigators have identified new molecular indicators — or “biomarkers” — of aging in the skin that could be used to evaluate anti-aging therapies. Their findings are reported in this month's Journal of Investigative Dermatology.

“There's a lot of interest in the pharmaceutical and cosmetic industries in developing products that will minimize or reduce certain signs of aging,” said James Sligh Jr., M.D., Ph.D., assistant professor of Medicine and Cell & Developmental Biology. “The quantifiable biomarkers we've characterized could be useful for monitoring laboratory-simulated aging as well as potential drugs or therapies that alter the aging process.”

The new biomarkers are changes to the DNA of cellular organelles called mitochondria. Mitochondria, which have their own DNA that is distinct from the DNA in the cell's nucleus, serve as the “power plants” of the cell. They manufacture energy in the form of the molecule ATP. Energy generation includes, as a byproduct, the production of reactive oxygen species, which can damage the DNA present in mitochondria, Sligh said.

Some theories of cellular aging — why and how cells age — center on mitochondria and decreased energetic capacity resulting from mitochondrial DNA mutations, Sligh explained. In addition, mutations in mitochondrial DNA have been associated with tumor development.

“We initiated this project with the idea that perhaps there was a specific mitochondrial DNA deletion signature that would be associated with tumor development in the skin,” Sligh said.

The investigators searched for mitochondrial DNA deletion mutations in skin samples from patients having non-melanoma skin cancer removed in the Vanderbilt Mohs Clinic. Mohs micrographic surgery is a treatment for skin cancer, particularly the most common forms: basal and squamous cell carcinomas.

Sligh and colleagues were surprised to find a panel of mitochondrial DNA deletions in the tumor-free skin that was adjacent to the tumors, but not in the tumors themselves. The tumor samples were more likely to have full-length mitochondrial DNA, with point mutations rather than significant deletions, Sligh said.

The mitochondrial DNA mutations in the tumor-free skin correlated with the aging process, Sligh said. The newly identified deletion mutations will now go into “Mitomap,” a database of all known human mitochondrial genome changes.

“Unraveling the molecular clues as to why aging cells function differently than young cells requires that we have molecular markers that we can track,” Sligh said. “It won't be long before other investigators who have other human tissue specimens — brain, lung, heart, for example — look for these changes and report back.

“It will be interesting to see if the mitochondrial DNA mutations we've found are markers of aging in other tissues or if they are specific to tissues exposed to ultraviolet light.”

Either way, the newly identified biomarkers will provide another tool for studying mitochondrial damage that contributes to aging and cancer, and for screening compounds that prevent or reverse the process, Sligh said.

Alex Eshaghian, an MSTP student, and former VU medical student Ruth Ann Vleugels, M.D., are the lead authors of the Journal of Investigative Dermatology paper. Other contributors include Jeffrey Canter, M.D., Michel McDonald, M.D., and Thomas Stasko, M.D. The research was supported by the VA Medical Research Service, Vanderbilt Skin Diseases Research Center, Ellison Medical Foundation and American Cancer Society.