Centenarian lamins: rapamycin targets in longevity

Nuclear lamins regulate several processes in the cell and have been implicated in the ageing process. Lamin A and its precursor prelamin A are known to be involved in premature‐ageing diseases and represent candidate proteins for the regulation of physiological ageing. On page 147, Giovanna Lattanzi, Claudio Franceschi and colleagues address the role of lamins, and predominantly prelamin A, in chromatin dynamics associated with normal ageing. Using skin fibroblasts from individuals aged 95–105 years, the authors show that the endoprotease ZMPSTE24, which is specific to prelamin A, is downregulated in these fibroblasts, resulting in accumulation of prelamin A; this accumulation triggers recruitment of the inactive form of the DNA damage response protein 53BP1 to the nucleus, an event that accelerates DNA repair processes in fibroblasts from centenarians that are subjected to stress. The authors next examine the effect of rapamycin in fibroblasts from younger individuals. Rapamycin is a drug that can extend lifespan in mice and worms, affects the stability of prelamin A, and triggers nuclear import and activation of 53BP1. Rapamycin treatment was shown to mimic the effects observed in the nuclei of centenarian fibroblasts, including prelamin A accumulation and recruitment of 53BP1. The authors have therefore identified new targets of rapamycin that are associated with human longevity: prelamin A and 53BP1. They propose that the accumulation of non‐toxic levels of prelamin A in fibroblasts from centenarians improves the cellular response to stress by favouring a low‐energy DNA repair mechanism, 53BP1‐mediated non‐homologous end joining, and thereby safeguards healthy ageing in humans.