Assessing mechanisms and evidence of a causal role for cellular senescence and somatic mutations in aging (IMAGE)
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Figure 1. The DNA damage cascade and its effects on aging from the molecular to the systemic level. In the nucleus of the cell, DNA damage triggers protective mechanisms, initiating DNA damage signaling and coordinating DNA repair. The primary outcome of DNA damage signaling can be the induction of cellular senescence, whereas failed or inaccurate DNA repair can lead to DNA mutations. When a mutation occurs in oncogenes or tumor suppressor genes, it can trigger oncogene-induced senescence, representing an intersection between these two events. At the tissue level, mutations may generate consequential effects, including transcriptional noise, genetic mosaicism, and immune and stem cell dysfunction. Cellular senescence too can impact the stem and immune compartments and have a broader effect due to the senescence-associated secretory phenotype (SASP), which propagates in an autocrine and paracrine fashion, inducing tissue remodeling and potentially exacerbating immune dysfunction. At the systemic level, an aberrant microenvironment, immune response, and regenerative capacity can contribute to age-related functional decline, and it has been speculated the same potential for transcriptional noise and clone formation. In the figure, cellular senescence with its associated mechanisms of aging is depicted in light blue, SASP in blue, and somatic mutations in red; solid arrows indicate links that are more strongly supported by experimental evidence, while dotted arrows represent more speculative links.
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Copyright: © 2026 Trastus and d’Adda di Fagagna. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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