Senescent cells accumulate with age in tissues throughout the body, primarily when a cell reaches the Hayflick limit on replication, but also because of damage or stress. When a cell becomes senescent it ceases to replicate and undergoes profound metabolic changes that cause it to secrete a pro-inflammatory, pro-growth set of signals known as the senescence-associated secretory phenotype (SASP). This serves a useful purpose in the context of potentially cancerous cells, attracting the immune system to destroy them, and aids in regeneration from injury. In youth, senescent cells are efficiently destroyed by the immune system, but with advancing age this clearance slows down. A growing imbalance between creation and destruction allows senescent cells to accumulate, and the inflammatory signaling that is useful in the short term becomes increasingly harmful when sustained for the long term.
One of the possible approaches to the treatment of aging is to destroy senescent cells. While appearing to be beneficial in mice, extending life span and reversing age-related dysfunction in many studies, there are some concerns that removing senescent cells could cause harm in some contexts. For example if senescent cells are supporting the structure of a sizable atherosclerotic plaque then clearing them could increase the risk of plaque rupture and a consequent heart attack or stroke. While not yet supported by a sizable body of evidence, this viewpoint has led a number of research teams to search for ways to reduce the SASP rather than destroy senescent cells. If a senescent cell just sat there and did not signal, then its contribution to degenerative aging would be largely eliminated. One might look at the senescent cells in long-lived naked mole-rats, for example, as they exhibit an attenuated SASP and do not appear to contribute to aging in way that senescent cells do in mice.
Thus one sees papers like today's open access research materials, in which researchers dig into the fine details of the mechanisms by which the senescent state triggers inflammatory signaling. Researchers are looking for potential targets for therapies that could interfere in the generation of the SASP without causing meaningful side-effects in the biochemistry of non-senescent cells.
Cellular senescence is a stable form of cell-cycle arrest triggered by stresses such as DNA damage, oncogene activation, and telomere shortening. Senescent cells accumulate with age in many tissues and contribute to chronic inflammation, tissue dysfunction, and age-related pathologies through secretion of pro-inflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs), collectively termed the senescence-associated secretory phenotype (SASP). Persistent DNA damage signaling in senescent cells promotes the formation of cytoplasmic chromatin fragments (CCFs) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which sustains SASP and systemic inflammation. Identifying the molecular drivers that maintain this chronic inflammatory state is essential for understanding and targeting age-related dysfunction.
Cyclin D1 (CCND1), classically defined as a regulator of G1 progression through activation of CDK4/CDK6 and phosphorylation of the retinoblastoma protein (pRB), is paradoxically elevated in senescence despite proliferative arrest. The functional significance of CCND1 upregulation in non-proliferating, senescent cells remain unclear. Moreover, whether CCND1's unconventional accumulation contributes causally to persistent DNA damage signaling, cytoplasmic chromatin stress, or inflammatory gene expression has not been explored.
Here, we investigate the role of CCND1 and its associated kinase CDK6 in sustaining DNA damage, cytosolic chromatin accumulation, and inflammatory signaling in senescence. Using complementary in vitro and in vivo models, we reveal an essential role for the CCND1-CDK6 complex in promoting persistent DNA damage, CCF formation, and cGAS-STING-driven inflammation. Mechanistically, we identify previously unrecognized interactions between CCND1 and chromatin-associated kinesin proteins, such as KIF4A, which has been implicated in chromatin architecture and DNA repair. Finally, we show that genetic ablation of CCND1 in aged hepatocytes or pharmacological inhibition of CDK4/6 significantly attenuates chronic inflammatory signaling and ameliorates age-associated functional decline, suggesting broad therapeutic implications.
View the full article at FightAging
