Non-enzymatic molecular damage as a prototypic driver of aging

Abstract

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 ( 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.

Discovery of a widespread prokaryotic 5-oxoprolinase that was hiding in plain sight

“…Although OP had long been known as a damage product of glutamine, glutamate, and ␥-glutamyl phosphate (9 -11), the discovery of eukaryote-type OPase in the context of the ␥-glutamyl cycle probably favored the general view, mentioned above, that OP comes mainly from this cycle (1,45). If so, it illustrates how a "metabolic pathway-centric" view of metabolism (46,47) can divert attention away from metabolite damage and the mechanisms that counter it, in this case enabling three very common damage-control genes to "hide in plain sight" in the genomes of two iconic model bacteria as these genomes were sequenced in 1997 (48,49).…”

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

“…Genomic instability, telomere attrition, transcriptional and translational errors, and metabolites alterations are the primary hallmarks of the aging process [54][55][56][57][58][59][60]. The accumulation of irreparable macromolecular damage due to metabolically or environmentally generated free radicals, spontaneous errors in biochemical reactions, and the biologically programmed decline in the endocrine and immune system functions have been proposed as the main drivers of aging [61][62][63][64]. In addition, external factors, such as diet, physical activity, environment, and interaction with commensal and pathogenic microbiomes, can influence aging in various model organisms, including humans [65][66][67][68][69].…”

Essential Physiological Differences Characterize Short- and Long-Lived Strains of Drosophila melanogaster

“…TOR activation will inhibit autophagy and protein turnover and accelerate the accumulation of damage (38,55). The damage theory is the currently most supported explanation for aging (2,40) Figure 1A) but this is a result of small changes in gene expression: median log2fold change values were 0.4043 for upregulated and -0.4289 for downregulated genes ( Figure 1B). Four independent biological samples provide enough statistical power to make statistically significant inferences about differences in gene expression, we chose not to use an arbitrary cut-off for log2fold change to filter differentially regulated genes.…”

“…Our previous (39) and current results suggest a key role for TOR in explaining differences in lifespan between wild type flies in different environmental conditions. Accumulation of damage is the most supported hypothesis to explain ageing (40). However, there is an alternative model that proposes extended activation of pro-growth pathways (e.g.…”