Free-radical theory of aging  The free radical theory of aging (FRTA) states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals. Strictly speaking, the free radical theory is only concerned with free radicals such as superoxide ( O2− ), but it has since been expanded to encompass oxidative damage from other reactive oxygen species such as hydrogen peroxide (H2O2), or peroxynitrite (OONO−). Denham Harman first proposed the free radical theory of aging in the 1950s, and in the 1970s extended the idea to implicate mitochondrial production of reactive oxygen species. In some model organisms, such as yeast and "Drosophila", there is evidence that reducing oxidative damage can extend lifespan. However, in mice, only 1 of the 18 genetic alterations (SOD-1 deletion) that block antioxidant defences, shortened lifespan. Similarly, in roundworms ("Caenorhabditis elegans"), blocking the production of the naturally occurring antioxidant superoxide dismutase has recently been shown to "increase" lifespan. Whether reducing oxidative damage below normal levels is sufficient to extend lifespan remains an open and controversial question. The free radical theory of aging was conceived by Denham Harman in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems. This was also before anyone invoked free radicals as a cause of degenerative diseases. Two sources inspired Harman: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption, and 2) Rebbeca Gershman's observation that hyperbaric oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon: oxygen free radicals. Noting that radiation causes "mutation, cancer and aging", Harman argued that oxygen free radicals produced during normal respiration would cause cumulative damage which would eventually lead to organismal loss of functionality, and ultimately death. In later years, the free radical theory was expanded to include not only aging "per se", but also age-related diseases. Free radical damage within cells has been linked to a range of disorders including cancer, arthritis, atherosclerosis, Alzheimer's disease, and diabetes.