Proteomic profiling of aging brains identifies key proteins by which cognitively healthy centenarians defy their age by decades

Abstract Some individuals reach extreme ages without any signs of cognitive decline. Here, we show that based on key proteins, cognitively healthy centenarians have a biologically younger brain. We compared the brain proteomic signatures of 58 self-reported cognitively healthy centenarians with 61 non-demented individuals and 91 AD patients. The abundance of 472 proteins strongly associated with AD Braak stages of which 64 were differentially regulated in centenarians. With increasing Braak stages, the abundance of toxic peptides of MAPT increased in AD patients, while these remained low in centenarians. Furthermore, the abundance of 174 proteins strongly changed with age, of which 108 were differentially regulated in centenarians. In fact, in brains from centenarians the abundances of essential proteins were representative of brains from individuals who were a median 18- and up to 28-years ‘younger’. The proteins involved represent diverse cellular processes, and suggest that maintained protein homeostasis is central in maintaining brain-health.