Abstract
Chromatin structure is essential for gene regulation and genome stability, as neurons must preserve their 3D genome organization throughout life. This structure gradually deteriorates with aging and is further disrupted in neurodegenerative diseases. To investigate whether aging and neurodegeneration share early chromatin changes or diverge, we perform Hi-C on cortical neurons from adult, aged, and brain-specific SIRT6-knockout (S6-KO) mice and compare them to the previously published Hi-C data sets from a CK-p25 Alzheimer's disease model stratified by γH2AX levels. All models show early features such as weakened interactions between chromosomes in expanded nuclei, A- to B-compartment shifts, and loss of architectural loops. However, aged neurons retain TAD prominence, short-range interactions, and enhancer–promoter loops, whereas pathological models showed reduced TAD prominence, shorter loops, and disorganized A–B mixing. These changes correlate with increased DNA damage. Our findings suggest that aging represents a “primed” state, in which chromatin regulation begins to erode, but further stressors like DNA damage are associated with progression toward neurodegenerative breakdown.