Geroscience at Penn

Brad Johnson, MD, PhD

Dr. Johnson's lab is interested in the biology of human aging and cancer, and focuses particularly on how they are influenced by telomere maintenance and dysfunction. Telomeres are the structures that cap the ends of chromosomes, and this location makes them critical for genome stability as well as particularly susceptible themselves to a variety of insults including oxidative damage, exonucleolytic attack, and inappropriate processing by recombination factors.

One focus of the lab is to investigate mechanisms of telomere maintenance. They have identified roles for the RecQ family DNA helicases in coordinating recombination-dependent mechanisms that maintain telomeres. This family of helicases includes those that are deficient in the Werner and Bloom syndromes, which are diseases characterized by premature aging and elevated rates of cancer. Their findings in mice and yeast have helped establish telomere defects as an important cause of the clinical phenotypes observed in these syndromes. More recently, the lab has also begun exploring roles for chromatin regulatory factors, including SUMO modifiers and regulators of histone acetylation, in telomere maintenance. Their hope is that by better understanding how RecQ helicases and chromatin factors maintain telomeres, new methods for preserving telomere function in normal tissues and for disrupting telomere function in malignancies may be developed.

Learn more about Dr. Johnson’s research here.

Foteini Mourkioti, PhD

Dr. Mourkioti’s lab has a long-term interest in understanding the fundamental aspects of skeletal muscle function in normal, diseased and aging conditions and in the practical aspects of manipulating these functions by using animal models and tissue engineering approaches for treatment intervention. One area of investigation in the lab is to understand how telomeres shorten in premature skeletal muscle diseases.

The lab has identified that telomere attrition of muscle stem cells during muscle regeneration and they recently discovered the molecular link between stem cell functional exhaustion and telomere shortening. DMD. We predict that identification of selective therapies that will sustain muscle stem cell function and will better define the involvement of prolonged activation of stem cells in directing muscle regeneration in aging conditions.

Learn more about Dr. Mourkioti’s research here.

Joe Baur, PhD

Dr. Baur’s lab is interested in the molecular mechanisms that connect nutrient intake to longevity. Although the causes of aging are not known, age-related diseases and degenerative processes can be delayed experimentally in rodents by decreasing energy intake in the absence of malnutrition (caloric restriction, CR). Whether these benefits can be mimicked by modulating the same signaling and metabolic pathways in the absence of CR is an active area of investigation.

A major focus of the lab is on understanding how changes in nicotinamide adenine dinucleotide (NAD) metabolism contribute to aging, obesity, and disease. NAD concentration falls with age and is increased by CR. The Baur lab uses genetic models, isotopic labeling strategies, and metabolomics to probe the pathways by which NAD is synthesized and influences whole-body metabolism. These methods are also employed to study the effects of supplemental NAD precursors and to explore compartmentalization of NAD pools. In mitochondria such compartmentalization may directly influence fuel selection and circadian variations in metabolism.  Another area of interest is the mechanisms by which rapamycin affects metabolism. Rapamycin, an inhibitor of the nutrient-sensing mTOR complexes, is the most robust pharmacological strategy to extend the maximum lifespan of a mammalian species, even when started late in life. However, the underlying mechanisms remain unknown, and side effects including elevation of serum lipids and a diabetes-like syndrome are observed. The Baur lab is currently studying the molecular events that impair lipid and glucose homeostasis and whether the effects of the drug on longevity might be separable from its undesirable side effects.

Learn more about Dr. Baur’s research here.