Ageing as developmental decay: insights from p16INK4a

• The p16INK4a cell cycle regulator is a biomarker of ageing.
• p16INK4a plays a key role in cellular senescence and stem cell dynamics.
• p16INK4a is regulated by pathways that drive early development.
• We hypothesize that ageing could result from developmental decay.

The p16INK4a cell cycle regulator is one of the best ageing biomarkers because it is suppressed in early embryogenesis and progressively induced during ageing. p16INK4a plays a crucial role in key cell fate decisions which contribute to ageing, such as cellular senescence and stem cell dynamics. Detailed examination of the pathways regulating p16INK4a expression has revealed an overlap with those regulating early development. We present the hypothesis that ageing might be primarily driven by gradual functional decay of developmental pathways. To support this, we summarise the role of p16INK4a in ageing and our current knowledge on p16INK4a regulation. The developmental decay hypothesis implies that the much-evidenced damage associated with all aspects of ageing might be secondary to such decay.