John J. Lehman, M.D.
Project Overview:
With aging, the ability of key organs in the body to generate energy through intracellular structures known as mitochondria declines. Dysfunction of these mitochondria also contributes to the generation of broadly toxic reactive intermediates, known as reactive oxygen species (ROS). Peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) was identified in recent years as a master regulator of mitochondrial function in many highly energy-dependent tissues, including heart, muscle, brain, and liver. PGC-1α accomplishes its role by serving as a transcriptional coactivator, boosting the expression of genes encoding proteins central to both mitochondrial energy-transducing capacity and protection from ROS-mediated cellular damage. In addition to being induced with fasting and with caloric restriction (an age-retarding and lifespan-extending intervention), PGC-1a is induced in skeletal muscle with exercise, with PGC-1a capable of driving the formation in skeletal muscle of slow-twitch fibers with high mitochondrial content. The ability of PGC-1a to suppress reactive oxygen species and promote mitochondrial capacity has been linked with the suppression of neurodegeneration in an animal model of the chronic neurologic disorder Huntington’s disease. Recent exciting data in rodents also implicates activation of PGC-1a by the sirtuin SIRT1 in resveratrol-mediated improvement of health and survival of mice on a high-calorie diet. Given that SIRT1 and resveratrol have been shown to contribute to lifespan extension, their interaction with PGC-1α suggests that PGC-1α may contribute to the mechanism of their beneficial effects on aging. This proposal seeks to define the role for PGC-1a as a critical regulatory molecule in the control of longevity and mitochondrial energy metabolism in skeletal muscle and heart using mice genetically deficient in PGC-1a (PGC-1a-/- mice), with comparison to calorie restricted human skeletal muscle. These studies will attempt to link PGC-1a, a master regulator of energy metabolism, with the mitochondrial changes of aging and calorie restriction, thus possibly defining a novel therapy for age-associated disorders.
Indeed, the central goal of this project is to define whether PGC-1α is essential to maintenance of health with advancing age, and whether PGC-1α is a necessary effector of the age-retarding benefits of caloric restriction. In an effort to understand the molecular events and specific gene targets that altered PGC-1α activity influences in the setting of aging and caloric restriction, gene expression profiling will be performed for heart and skeletal muscle from young and aged PGC-1α+/+ and PGC-1a-/- mice on both standard and calorie restricted diets, with comparison to data from skeletal muscle of control and calorie restricted humans. Integrating into the data analysis evaluation of altered gene expression between control and calorie restricted human subjects will be possible as part of a collaboration with Luigi Fontana (described in the enclosed letter), in the context of ongoing calorie restriction studies performed by Dr. Fontana and my mentor Dr. John Holloszy. In addition to looking at changes in the expression of key individual genes, gene set enrichment analysis will allow definition of specific biologic pathways differentially regulated in the setting of aging and caloric restriction, while evaluating the influence of PGC-1α deficiency on these gene expression changes. Altered gene expression profiles obtained by this computational approach will be correlated with longevity and functional decline, as evidenced by mitochondrial defects, cardiac diastolic dysfunction (heart relaxation/filling impairment), and reduced exercise performance. The unbiased gene expression analysis may also identify novel PGC-1α-dependent and PGC-1α-independent transcriptional regulators capable of influencing age-associated degeneration. Ultimately, changes in expression of PGC-1α and its target genes central to mitochondrial capacity may be identified not only as biomarkers of senescence but also as factors directly influencing the rate of aging. Pharmacologic targeting of PGC-1α or its key regulatory partners may promote appropriate long-term energy metabolic balance while mimicking the beneficial metabolic remodeling of chronic caloric restriction. Insights into the mechanisms of calorie restriction may allow development of drug therapy that could boost the effects of a more modest degree of calorie restriction – one that a broader proportion of the population could successfully follow as part of a healthy diet and lifestyle regimen.
Progress Report:
These studies attempt to link PGC-1α, a master regulator of energy metabolism, with mitochondrial decline with aging, thus possibly defining a novel therapy for age-associated disorders.
Specific Aim 1: To characterize the inability of aging PGC-1α-/- heart to benefit from calorie restriction through gene expression profiling, and to correlate these changes with specific defects in mitochondrial function.
Specific Aim 2: To define a mechanism whereby PGC-1α participates in the favorable metabolic remodeling of skeletal muscle with calorie restriction. The ability of calorie restriction (CR) to maintain a “more youthful” thinner ventricular wall was lost in the absence of PGC-1α in 20 month old mice.
