It is the purpose of this report to identify possible metabolic deficiencies that might serve as biochemical markers of aging. It is proposed that the multiplicity of physical and physiological changes associated with aging could be most readily explained by alterations in the regulation and/or the activities of enzymes that occupy central positions in metabolism. Specifically, a search for metabolic markers of aging might include efforts to determine if there are age-related changes in the following enzymes or enzyme systems: (a) allosteric enzymes that catalyze reactions in highly branched metabolic pathways; (b) enzymes that catalyze opposing reactions between metabolites that are common intermediates in biosynthetic and biodegradative pathways (reactions which in the absence of final control would lead to futile substrate cycling); (c) enzymes that catalyze bimolecular reactions in which one member of a coenzyme pair is a cosubstrate (e.g., reactions involving NAD+ or NADH); (d) enzymes that are regulated by phosphorylation/dephosphorylation cycles; and (e) G-protein-dependent enzyme systems. It is also emphasized that changes in the concentrations and ratios of coenzyme substrate pairs (e.g., [NAD]/[NADH], [CoA]/[acyl CoA]) and the energy charge ratio [ATP] + 0.5 [ADP]/[ATP] + [ADP] + [AMP] may signal deviations from normal metabolism and therefore might be reliable markers of aging. In addition, because of their critical roles in metabolism, changes in the concentration of GTP, GDP and the second messengers, c-AMP, c-GMP should be monitored. Finally, it is noted that the accumulation of the altered forms of some enzymes which occurs during aging reflects imbalance between posttranslational modification of the enzymes and the degradation of the altered enzyme forms. The biological mechanisms involved and the genetic implications are discussed.