Lamins are rapamycin targets that impact human longevity: A study in centenarians

Giovanna Lattanzi, Michela Ortolani, Marta Columbaro, Sabino Prencipe, Elisabetta Mattioli, Catia Lanzarini, Nadir M. Maraldi, Vittoria Cenni, Paolo Garagnani, Stefano Salvioli, Gianluca Storci, Massimiliano Bonafè, Cristina Capanni, Claudio Franceschi

Research output: Contribution to journalArticle

Abstract

The dynamic organisation of the cell nucleus is profoundly modified during growth, development and senescence as a result of changes in chromatin arrangement and gene transcription. A plethora of data suggests that the nuclear lamina is a key player in chromatin dynamics and argues in favour of a major involvement of prelamin A in fundamental mechanisms regulating cellular senescence andorganism ageing. As the best model to analyse the role of prelamin A in normal ageing, we used cells from centenarian subjects. We show that prelamin A is accumulated in fibroblasts from centenarians owing to downregulation of its specific endoprotease ZMPSTE24, whereas other nuclear envelope constituents are mostly unaffected and cells do not enter senescence. Accumulation of prelamin A in nuclei of cells from centenarians elicits loss of heterochromatin, as well as recruitment of the inactive form of 53BP1, associated with rapid response to oxidative stress. These effects, including the prelamin-A-mediated increase of nuclear 53BP1, can be reproduced by rapamycin treatment of cells from younger individuals. These data identify prelamin A and 53BP1 as new targets of rapamycin that are associated with human longevity. We propose that the reported mechanisms safeguard healthy ageing in humans through adaptation of the nuclear environment to stress stimuli.

Original languageEnglish
Pages (from-to)147-157
Number of pages11
JournalJournal of Cell Science
Volume127
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Keywords

  • 53BP1
  • Centenarian
  • Chromatin organisation
  • Lamins
  • Prelamin a
  • Rapamycin

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Lattanzi, G., Ortolani, M., Columbaro, M., Prencipe, S., Mattioli, E., Lanzarini, C., Maraldi, N. M., Cenni, V., Garagnani, P., Salvioli, S., Storci, G., Bonafè, M., Capanni, C., & Franceschi, C. (2014). Lamins are rapamycin targets that impact human longevity: A study in centenarians. Journal of Cell Science, 127(1), 147-157. https://doi.org/10.1242/jcs.133983