Sirtuin 6 (SIRT6) is a deacylase and mono‐ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double‐strand break repair, and more robustly kill cancer cells compared with wild‐type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

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.

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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. Pro-longevity mechanisms are complex traits afforded by connections between metabolism and protein functions that are unlikely to be predicted by genomic approaches alone. Thus, metabolomics and proteomics studies are required to understand the mechanisms of longevity. Sirtuin 6 will be presented as an example of a protein that evolved enhanced enzymatic function in long-lived species and also demonstrates enhanced activity and unique alleles in human centenarians. Proteome analysis reveal several longevity related proteins such as Cip1/p21, FOXO3, TOP2A, AKT1, RICTOR, INSR and SIRT6 harboring PTM sites that preferentially appear in either short- or long-lived species. The prospects of enhancing life expectancy and healthspan of humans by altering metabolism and proteoforms with drugs that mimic changes observed in long-lived species will be discussed.

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