Mammalian species differ up to 100-fold in their aging rates and maximum lifespans. Long-lived mammals appear to possess traits that extend lifespan and healthspan. Genomic analyses have not revealed a single pro-longevity function that would account for all longevity effects. In contrast, it appears that pro-longevity mechanisms may be complex traits afforded by connections between metabolism and protein functions that are impossible to predict by genomic approaches alone. Thus, metabolomics and proteomics studies will be required to understand the mechanisms of longevity. Several examples are reviewed that demonstrate the naked mole rat (NMR) shows unique proteomic signatures that contribute to longevity by overcoming several hallmarks of aging. SIRT6 is also discussed as an example of a protein that evolves enhanced enzymatic function in long-lived species. Finally, it is shown that several longevity-related proteins such as Cip1/p21, FOXO3, TOP2A, AKT1, RICTOR, INSR, and SIRT6 harbor posttranslational modification (PTM) sites that preferentially appear in either short- or long-lived species and provide examples of crosstalk between PTM sites. Prospects of enhancing lifespan and healthspan of humans by altering metabolism and proteoforms with drugs that mimic changes observed in long-lived species are discussed.
Keywords: SIRT6; aging; long-lived mammals; naked mole rats; proteomics.
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