Summary: Long-lived species evolved efficient mechanisms of genome and epigenome maintenance, which can be adapted to extend human lifespan and healthspan. Furthermore, genomic instability has been implicated in Alzheimer's Disease (AD) and Related Dementias (ADRD). Investigating long-lived species provides us with an unparallelled opportunity to discover novel longevity adaptations perfected over millions of years of evolution. In the current period of support, we made several discoveries that shed light onto the mechanisms responsible for more efficient genome and epigenome maintenance in long-lived mammals. We demonstrated that DNA double-strand break (DSB) repair strongly correlates with species maximum lifespan. We showed that SIRT6 is responsible for the major part of this correlation. We demonstrated that a SIRT6 variant with enhanced mono- ADP-ribosylation activity is enriched in human centenarians. We demonstrated that somatic mutation rates inversely correlate with maximum lifespan of species. We found that transposable elements become derepressed with age and contribute to inflammation and epigenetic drift. Finally, we developed transcriptomic signatures of short- and long-lived species and demonstrated DNA DSB repair genes are more highly expressed in long-lived species, while inflammation and cytoplasmic DNA sensing pathways are dampened in long-lived species. We discovered that the longest-lived mammal, the bowhead whale, has extremely efficient and accurate DNA DSB repair, mediated by high levels of cold-induced RNA binding protein (CIRBP). Our unpublished data demonstrates that several bat species have highly efficient DNA DSB repair mediated by yet unknown mechanisms. We also obtained preliminary data that long-lived species have a more stable epigenome when subjected to DNA damage and identified combinatorial histone modifications (PTMs) that correlate with longevity. These findings put us in an excellent position to identify the fundamental mechanisms of longevity and develop antiaging interventions based on targeting these newly identified pathways. Our aims are: (1) Understand epigenetic determinants of longevity. We will identify genes controlled by longevity-associated PTMs, identify reader and writer enzymes and test whether these PTMs can be manipulated to extend lifespan; (2) Understand the mechanisms of genome and epigenome stability in long-lived species; we will identify proteins that promote more efficient DNA repair in long-lived species and identify DNA and RNA modifications associated with longer lifespan using state-of-the-art mass spectrometry approaches; (3) Test whether interventions targeting longevity adaptations, i.e. SIRT6, CIRBP and cytoplasmic DNA sensing pathways improve genome and epigenome stability, delay AD onset, and increase lifespan in mice. We will collaborate with Project 2 to test the relationship between genome stability and AD, with Project 3 to measure mutation rates and with Project 4 to t...