Multilevel Nutrition Interventions for Obesity Prevention Among Children With Intellectual and Developmental Disabilities: A Systematic Review.

Cellular senescence is a hallmark of aging tissue and is characterized by persistent cell cycle arrest, cell and nuclear enlargement, and a pro-inflammatory secretory profile [, ]. The accumulation of senescent cells has been implicated in driving many devastating diseases such as idiopathic pulmonary fibrosis [, ]. In parallel, there are various compositional and mechanical changes to the extracellular matrix (ECM) with age and disease, such as elevated collagen content leading to increased stiffness [–]. However, the role of these changing mechanics in senescence induction is not well understood. Counter to the expected response to elevated stiffness, a decline in activity of Yes-associated protein (YAP) and closely-related signaling partner TAZ (Transcriptional coactivator with PDZ-binding motif), master regulators of mechanotransduction, has been well documented with senescence [–]. YAP/TAZ signaling has been reported as the gatekeeper of cellular senescence in stromal cells through the preservation of nuclear envelope integrity []. Additionally, others have reported that changes in YAP activity are responsible for the morphological changes and secretory profile of senescent cells []. However, these studies relied on genetic manipulation of YAP/TAZ rather than mechanically mediated changes in YAP/TAZ activity. Thus, the interaction between stiffness-mediated YAP/TAZ activation and senescence-induced YAP/TAZ decline is yet to be elucidated. Previous studies investigating the role of stiffness on senescence phenotype showed mixed results. Various studies reported that substrates with stiffnesses of 15 kPa and above enhanced the senescent phenotype of stromal cells [–]. Further, one study showed that 16 kPa hydrogels were sufficient on their own to induce senescence in vascular smooth muscle cells []. Conversely, other studies reported that soft substrates, ranging from 0.5 to 6 kPa, either enhanced or induced the senescent phenotype in stromal cells [, ]. Yet, even within these studies there are variable findings. One study found that passage two primary rat cardiac fibroblasts showed increased levels of senescence on 6 kPa hydrogels, while passage five cells showed equally high levels of senescence on 6 or 40 kPa substrates, and freshly isolated cells show no senescence on either hydrogel []. Another study showed that transferring cells from 0.5 kPa substrates to 25 kPa substrates elevated levels of p16 and p21, two canonical markers of cellular senescence, arguing that these biomarkers are mechanically regulated []. Taken together, these studies highlight the need for clarity into the role of stiffness in senescence regulation, especially in the context of substrates that mimic tissue mechanics.