Cells become senescent constantly throughout the body and throughout the life. These are largely somatic cells reaching the Hayflick limit on replication, but cells can also become senescent in response to excessive stress or damage. A senescent cell ceases to replicate and begins to secrete pro-growth, pro-inflammatory signals. Most senescent cells are destroyed by immune cells that are attracted by this signaling. It serves as a useful mechanism to draw the attention of the immune system to regions of damage and dysfunction in tissue. It helps to prevent cancer, for example, and assists in regeneration from injury.
With age, however, the immune system becomes less able to clear senescent cells. Senescent cells linger, their numbers growing. The inflammatory secretions of senescent cells become disruptive to tissue structure and function when sustained over time. This is an important mechanism of degenerative aging, and a number of companies are presently developing senolytic therapies intended to selectively destroy senescent cells. Animal studies show that clearing senescent cells produces some degree of rapid reversal for many aspects of aging and age-related disease.
One of the more interesting features of senescent cells is that they grow in size quite dramatically, relative to their non-senescent counterparts. Researchers have used this feature to sort circulating senescent cells for analysis. As noted by the authors of today's open access paper, this isn't just a side-effect. The growth in size is essential for the energetic signaling produced by senescent cells. Interestingly, one can find ways to sabotage this enlargement of cells on entering the senescent state, and doing so dramatically reduces the harmful senescent cell signaling.
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype
Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU.
Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.
View the full article at FightAging
