Review: Chemical Pathology of Homocysteine VI. Aging, Cellular Senescence, and Mitochondrial Dysfunction

Ann Clin Lab Sci. 2018 Sep;48(5):677-687.


Following the discovery that caloric restriction extends the lifespan of many species of animals, the free radical theory of aging attributes the occurrence of oxidized nucleic acids, proteins, and lipids to reactive oxygen radical species originating from the metabolism of foods and the diminished efficacy of oxidative metabolism. Because of the decline of many critical neuro-hormones in aging, the neuroendocrine theory of aging attributes these changes to reduced feedback control of hormone production by the hypothalamus. Several rare genetic diseases attribute accelerated aging to changes in deoxyribonucleic acid (DNA) repair, depletion of the coenzyme nicotinamide adenine dinucleotide (NAD+), and altered methionine and homocysteine metabolism. The theory of oxidative phosphorylation attributes mitochondrial adenosine triphosphate (ATP) synthesis to the active site, thioretinaco ozonide oxygen NAD+ phosphate, which couples polymerization of NAD+ and phosphate to ATP produced by reduction of oxygen by electrons derived from foods. Loss of the thioretinaco ozonide oxygen ATP complex from the opening of the mitochondrial permeability transition pore (mPTP) is proposed to explain the abnormalities of oxidative metabolism occurring in cellular aging and carcinogenesis, thereby uniting the free radical and neuroendocrine theories of aging. Cellular senescence is associated with shortening of telomeres and decreased activity of telomerase, and exposure of cultured endothelial cells to homocysteine causes cellular senescence, shortened telomeres, and increased acidic β-galactosidase, a marker of cellular senescence. The decrease in telomerase with aging is related to decreased nitric oxide production by nitric oxide synthase. The pathogenic microbes occurring in atherosclerotic plaques and in cerebral plaques in dementia inhibit nitric oxide synthesis by up-regulation of polyamine biosynthesis from adenosyl methionine and putrescene, causing the hyperhomocysteinemia and suppressed immunity that is observed in atherosclerosis and dementia. Progressive mitochondrial dysfunction occurs in aging because of loss of the thioretinaco ozonide oxygen ATP complex from mitochondrial membranes by opening of the mitochondrial permeability transition pore. Melatonin, a neuro-hormone, and cycloastragenol, a telomerase activator, both prevent mitochondrial dysfunction by inhibition of mPTP pore opening. The carcinogenic effects of radiofrequency radiation and mycotoxins are attributed to loss of thioretinaco ozonide from opening of the mPTP and decomposition of the active site of oxidative phosphorylation. The anti-aging effects of retinoids, the decreased concentration of cerebral cobalamin coenzymes in aging, and the diminished concentration of NAD+ from sirtuin activation, as observed in aging, all support the concept of loss of the thioretinaco ozonide oxygen ATP active site from mitochondria as the cause of decreased oxidative phosphorylation and mitochondrial dysfunction in aging.

Keywords: adenosyl methionine; aging; asymmetric dimethylarginine; carcinogenesis; cellular senescence; cobalamin; dementia; endothelial progenitor cells; homocysteine; melatonin; mitochondrial dysfunction; mitochondrial membrane potential; mitochondrial permeability transition pore; mycotoxin; nicotinamide adenine dinucleotide; nitric oxide; oxidative phosphorylation; radiofrequency radiation; retinoic acid; sirtuin; telomere; thioretinaco ozonide; thioretinamide.

Publication types

  • Review

MeSH terms

  • Aging / physiology*
  • Animals
  • Atherosclerosis / metabolism
  • Calcium / metabolism
  • Cellular Senescence / physiology*
  • Dementia / metabolism
  • Homocysteine / metabolism*
  • Humans
  • Mitochondria / physiology*
  • Mitochondrial Membrane Transport Proteins / physiology
  • Mitochondrial Permeability Transition Pore
  • NAD / metabolism
  • Nitric Oxide / biosynthesis
  • Oxidative Phosphorylation
  • Telomere


  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Homocysteine
  • NAD
  • Nitric Oxide
  • Calcium