Understanding aging: revealing order out of chaos.

Aging is often described as an extremely complex process affecting all of the vital parameters of an individual. In this article, we review how understanding of aging evolved from the first analyses of population survival to the identification of the molecular mechanisms regulating life span. Abundant evidence implicates mitochondria in aging and we focus on the three main components of the mitochondrial theory of aging: (1) increased reactive oxygen species (ROS) production, (2) mitochondrial DNA (mtDNA) damage accumulation, and (3) progressive respiratory chain dysfunction. Experimental evidence shows a relationship between respiratory chain dysfunction, ROS damage, and aging in most of the model organisms. However, involvement of the mtDNA mutations in the aging process is still debated. We recently created a mutant mouse strain with increased levels of somatic mtDNA mutations causing a progressive respiratory chain deficiency and premature aging. These mice demonstrate the fundamental importance of the accumulation of mtDNA alterations in aging. We present here an integrative model where aging is provoked by a single primary event leading to a variety of effects and secondary causes.