Communication: Melatonin, Hyperhomocysteinemia, Thioretinaco Ozonide, Adenosylmethionine and Mitochondrial Dysfunction in Aging and Dementia.

The indoleamine hormone melatonin is synthesized by the pineal gland, controls circadian rhythm, and is dependent upon adenosyl methionine for enzymatic synthesis of melatonin from N-acetyl serotonin. Pineal melatonin secretion declines dramatically with aging and dementia. Elevated plasma homocysteine is a risk factor for atherosclerosis and Alzheimer's disease, and the marked decline in adenosyl methionine with aging leads to dysregulation of methionine metabolism and hyperhomocysteinemia. Thioretinaco ozonide is a disulfonium complex formed from thioretinamide, cobalamin, and ozone, which binds the alpha and gamma-phosphate groups of adenosine triphosphate (ATP) and oxygen in the process of oxidative phosphorylation within mitochondria. Decreased adenosyl methionine concentrations with aging are attributed to the loss of thioretinaco ozonide from mitochondria, impairing adenosyl methionine synthesis from thioretinaco ozonide and ATP. Melatonin is present in mitochondria, where it inhibits the opening of the mitochondrial permeability transition pore, explaining its anti-oxidant and anti-apoptotic effects by reducing oxygen consumption, restoration of membrane potential and reduction of superoxide production. In aging, the enzyme cyclic nucleotide phosphodiesterase is lost from mitochondria by the opening of the permeability transition pore and disruption of the outer mitochondrial membrane, a process that is inhibited by melatonin. Thioretinaco ozonide is progressively lost from dysfunctional mitochondria by disruption of the outer mitochondrial membrane, explaining its depletion during the aging process. Accordingly, the anti-aging effects of diallyl trisulfide and metformin are attributable to inhibition of the opening of the mitochondrial permeability transition pore, preventing loss of thioretinaco ozonide from mitochondria. The hyperhomocysteinemia and suppressed immunity that are observed in atherosclerosis and dementia are attributed to the deficiency of adenosylmethionine caused by increased polyamine synthesis and decreased nitric oxide synthesis by host cells infected with pathogenic microbes. According to this analysis, the critical loss of thioretinaco ozonide from mitochondria through the opening of the permeability transition pore and disruption of the outer mitochondrial membrane by decreased melatonin secretion leads to the impaired oxidative phosphorylation, oxidative stress, calcium influx, apoptosis and mitochondrial dysfunction observed in aging and dementia.