Mitochondria and PGC-1α in Aging and Age-Associated Diseases

Aging is the most significant risk factor for a range of degenerative disease such as cardiovascular, neurodegenerative and metabolic disorders. While the cause of aging and its associated diseases is multifactorial, mitochondrial dysfunction has been implicated in the aging process and the onset and progression of age-associated disorders. Recent studies indicate that maintenance of mitochondrial function is beneficial in the prevention or delay of age-associated diseases. A central molecule seems to be the peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), which is the key regulator of mitochondrial biogenesis. Besides regulating mitochondrial function, PGC-1α targets several other cellular processes and thereby influences cell fate on multiple levels. This paper discusses how mitochondrial function and PGC-1α are affected in age-associated diseases and how modulation of PGC-1α might offer a therapeutic potential for age-related pathology. 1. Introduction In the last 20 years, mitochondrial dysfunction has been recognized as an important contributor to an array of human pathologies [1–3]. Mitochondrial dysfunction is particularly associated with the onset and progression of many age-related disorders such as neurodegenerative and cardiovascular diseases as well as metabolic disorders and age-related muscle wasting. In most cases it is not clear if the mitochondrial dysfunction is causative of the disease or if it is a secondary effect of the disease. Also, it is not understood if mitochondrial dysfunction is an aggravating factor in disease progression. Recent work suggests that maintenance of mitochondrial function is beneficial in at least some age-related diseases [4]. The peroxisome proliferator-activated receptor (PPAR) γ coactivator α (PGC-1α) integrates regulation of mitochondrial function into the modulation of different, tissue-specific metabolic pathways and thereby links mitochondrial function to important cellular signaling pathways that ultimately control cell survival [5, 6]. The following review discusses how mitochondrial dysfunction is associated with age-related diseases and what impact PGC-1α and its targets have in these diseases and their prevention. 2. Mitochondrial Function, ROS, and Aging 2.1. Mitochondrial Function and OXPHOS Mitochondria play a central role in the cell metabolism: besides being key player in apoptosis, mitochondria house major cellular metabolic pathways. The fatty acid oxidation and citric acid cycle convert nutrients absorbed from ingested food to electron donors to NADH and FADH. These