Figure 2. Multifactorial Events in Mammalian Aging.

Oxidative stress is generated when reactive oxygen and nitrogen species (RONS) production exceeds protection from antioxidant defenses, and can lead to damaged proteins and mtDNA mutations. Replication errors are an additional source of mtDNA mutations. mtDNA mutations can result in reduction or loss of respiratory complex function and a pool of aberrant mitochondrial proteins. In certain situations (e.g., homoplasmic inherited mtDNA base-substitution mutations), specific mtDNA mutations could lead to increased oxidative stress, but this is not a feature of mice bearing random accumulations of mtDNA mutations. Activation of apoptosis could occur through mechanisms that sense energetic deficits or by signaling via rare misfolded proteins that might be capable of interacting with apoptotic regulators such as Bax or Bak. Prolonged activation of apoptotic cell death would gradually deplete tissues of both differentiated and possibily regenerative stem cells, leading to eventual tissue dysfunction and aging-related phenotypes. Additionally, chronic energetic deficiency in itself may contribute to altered tissue functioning with age. Inset: Polg^D257A mitochondrial mutator mouse (right) showing hair graying, alopecia, and kyphosis compared to a healthy age-matched control mouse.

ETS, electron transport system; RONS, reactive oxygen and nitrogen species