Non-enzymatic molecular damage as a prototypic driver of aging

J Biol Chem. 2017 Apr 14;292(15):6029-6038. doi: 10.1074/jbc.R116.751164. Epub 2017 Mar 6.


The chemical potentialities of metabolites far exceed metabolic requirements. The required potentialities are realized mostly through enzymatic catalysis. The rest are realized spontaneously through organic reactions that (i) occur wherever appropriate reactants come together, (ii) are so typical that many have proper names (e.g. Michael addition, Amadori rearrangement, and Pictet-Spengler reaction), and (iii) often have damaging consequences. There are many more causes of non-enzymatic damage to metabolites than reactive oxygen species and free radical processes (the "usual suspects"). Endogenous damage accumulation in non-renewable macromolecules and spontaneously polymerized material is sufficient to account for aging and differentiates aging from wear-and-tear of inanimate objects by deriving it from metabolism, the essential attribute of life.

Keywords: aging; damage; enzyme; enzyme mechanism; mechanism; metabolism; metabolite; metabolite damage; side reaction; side-product; spontaneous chemistry; substrate specificity.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / metabolism*
  • Animals
  • Humans
  • Oxidation-Reduction
  • Reactive Oxygen Species / metabolism*


  • Reactive Oxygen Species