Unraveling Organ Specific and Shared Aging Signatures Across Life Span

Abstract

Aging is a gradual, multifactorial process characterized by a progressive decline in physiological function and resilience. This loss of systemic integrity increases vulnerability to disease and ultimately leads to death. While previous studies have explored age-related molecular changes within individual organs, most have focused on transcriptomic profiles and only to a limited extent on the proteome. Moreover, system-level studies that integrate multi-organ and multi-omics data remain scarce, leaving a fragmented view of how aging unfolds across the body. To address this gap, we constructed a comprehensive, multi-organ transcriptomic and proteomic atlas of aging in male C57BL/6J mice. We profiled eight organs - kidney, spleen, liver, lung, heart, testis, skeletal muscle, and brain - across six age groups spanning early adulthood (3-5 months), midlife (8-14 months), and late life (20-26 months). Our analyses revealed both organ-specific and systemic molecular signatures of aging, with distinct temporal patterns. Functional enrichment and network analysis uncovered shared and organ-specific pathways, including those related to immune activation, mitochondrial dysfunction and translational collapse. Moreover, one of the main hallmarks of aging that emerged from our analysis was the upregulation of cellular senescence markers across tissue. Senescent cells accumulate during aging and contribute to tissue dysfunction. Their selective targeting has become an important therapeutic goal. To address the limited knowledge of senescenceassociated surface markers, we performed a broad quantitative analysis of the senescence-associated surfaceome across senescence models in murine and human cells. This work revealed four cell surface proteins with extracellular epitopes identified as promising senescence-associated targets. Overall, by linking multi-organ omics, aging trajectories, and senescence-associated surface remodeling, this thesis provides a framework for understanding how systemic aging patterns and cellular hallmarks intersect, and how these insights may inform future strategies for targeted intervention in aging and age-related disease.