title: On methionine restriction, suppression of mitochondrial dysfunction and aging.
abstract: Rats and mice, when subjected to methionine restriction (MetR), may live longer with beneficial changes to their mitochondria. Most explanations of these observations have centered on MetR somehow suppressing the effects of oxygen free radicals. It is suggested here that MetR's effects on protein metabolism should also be considered when attempting to explain its apparent anti-aging actions. Methionine is the initiating amino acid in mRNA translation. It is proposed that MetR decreases the protein biosynthesis rate due to methionine limitation, which correspondingly decreases generation of ribosomal-mediated error proteins, which then lowers the total abnormal protein load that cellular proteases and chaperone proteins (mitochondrial and cytoplasmic) must deal with. This will increase protease availability for elimination of proteins damaged postsynthetically and help delay abnormal protein accumulation, the major molecular symptom of aging. The slowed rate of protein synthesis may also alter protein folding, which could also alter polypeptide susceptibility to oxidative attack. MetR will also increase lysosomal proteolysis, including autophagy of dysfunctional mitochondria, and promote mitogenesis. MetR may decrease synthesis of S-adenosyl-methionine (SAM), which could decrease spontaneous O(6)-methylguanine formation in DNA. However decreased SAM may compromise repair of protein isoaspartate residues by protein-isoaspartate methyltransferase (PIMT). Changes in SAM levels may also affect gene silencing. All the above may help explain, at least in part, the beneficial effects of MetR.
authors.affiliation: Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Bart's and the London Queen Mary's School of Medicine and Dentistry, London, UK. alanandjill@lineone.net
authors.forename: Alan R
authors.initials: AR
authors.lastname: Hipkiss
mesh_terms: D000375:Aging / Q000378:metabolism*; D018753:Diet, Protein-Restricted; D006801:Humans; D008715:Methionine / Q000008:administration & dosage* / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species
chemical_list: D011506:Proteins; D017382:Reactive Oxygen Species; D008715:Methionine