Stressing the cell cycle in senescence and aging

• Persistent DNA damage triggers a senescence-associated secretory program.
• p16INK4a is a biomarker for senescence and aging but its levels do not predict longevity.
• In senescence, RB represses a specific subset of E2F target genes involved in DNA replication.
• The irreversibility of senescence involves RB-dependent epigenetic events.

Senescence represents a permanent exit from the cell cycle and its role in curtailing the proliferation of damaged and potentially oncogenic cells has relevance both as a front-line defense against cancer and as an underlying cause of aging. The retinoblastoma protein (RB) and p53 tumor suppressors are central to the process and the growth arrest is primarily implemented by the cyclin-dependent kinase (CDK) inhibitors, p16INK4a and p21CIP1. In contrast to terminal differentiation, senescence is a general response to a diverse range of cellular stresses and is typically accompanied by a characteristic set of phenotypic changes. Of particular note is a secretory program whose autocrine and paracrine effects can advertize the presence of senescent cells within a tissue and promote their clearance by the immune system. In this short review, we will highlight recent advances in understanding the relationship between senescence and aging and the distinction between senescence and terminal differentiation, from a cell cycle perspective.

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