Another way to look at the aging trajectory is to model it as a set of molecular transitions that lead to changes in BioAge. Examination of biomarker scores for BioAge-low brains in Figure 4 suggests that upregulation and disruption of Lipa biomarker happens very early in the aging process because most of these samples have the lowest Lipa scores in the cohort. Comparing Inflame with Lipa and BioAge shows that activation of the inflammation biomarker also happens early in the aging process, but not as early as Lipa activation, because there are BioAge-young patients with high Lipa score yet low Inflame. These and other observations can be summarized in the form of a state transition model shown in Figure 7. Aging starts with upregulation of APOE and other lipid metabolic genes together with Notch and TGFβ signaling, signifying the transition from N0 to N1. The following upregulation of the Inflame biomarker is associated with transition from N1 to N2. The brains in these states were diagnosed as normal because the subjects did not yet exhibit any cognitive impairment associated with
