title: Lamins are rapamycin targets that impact human longevity: a study in centenarians.
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 and organism 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.
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna IOR, 40136 Bologna, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
authors.forename: Michela
authors.initials: M
authors.lastname: Ortolani
authors.forename: Marta
authors.initials: M
authors.lastname: Columbaro
authors.forename: Sabino
authors.initials: S
authors.lastname: Prencipe
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Catia
authors.initials: C
authors.lastname: Lanzarini
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Cenni
authors.forename: Paolo
authors.initials: P
authors.lastname: Garagnani
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Storci
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafè
authors.forename: Cristina
authors.initials: C
authors.lastname: Capanni
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D034904:Lamin Type A; D008136:Longevity / Q000235:genetics*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D011498:Protein Precursors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C090764:prelamin A; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human; D020123:Sirolimus
keywords: 53BP1; Centenarian; Chromatin organisation; Lamins; Prelamin A; Rapamycin