Silencing without clearing: pharmacological modulation of the SASP in aging and disease

Abstract

The global rise in life expectancy has led to an increasing prevalence of age-related diseases, including neurodegenerative disorders, cancer, type 2 diabetes mellitus, and cardiovascular conditions, placing substantial societal and economic burdens on healthcare systems worldwide. A key mechanism underlying both aging and these pathologies is cellular senescence (CS), now recognized as one of the 12 hallmarks of aging. Senescent cells exert their effects largely through the senescence-associated secretory phenotype (SASP), a complex pro-inflammatory secretome that disrupts tissue homeostasis in neighbouring cells and actively promotes disease progression. This review first describes the biology of CS and the SASP in the context of aging and age-related pathologies, with emphasis on key regulatory pathways. We then provide a comprehensive overview of current senomorphic agents, i.e., compounds that modulate the SASP without eliminating senescent cells, covering their mechanisms of action, the signaling pathways they target, and the translational challenges they face. A particular focus is placed on the context-dependent dual role of the SASP. While its proinflammatory components drive tissue damage in chronic disease, SASP factors also contribute to wound healing, immune surveillance, and embryonic development. This duality has important implications for therapeutic design. Although senomorphics hold genuine promise as anti-aging interventions, substantial gaps remain between preclinical observations and clinical applicability. Future research must clarify the functions of individual SASP components, identify robust senescence biomarkers, and develop selective compounds with defined dose-response relationships and acceptable safety profiles.