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.
Keywords:
53BP1; Centenarian; Chromatin organisation; Lamins; Prelamin A; Rapamycin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged, 80 and over
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Aging / genetics*
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Aging / metabolism
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Antibiotics, Antineoplastic / pharmacology*
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Cell Nucleus / drug effects
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cellular Senescence / drug effects
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Cellular Senescence / genetics
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Chromatin / drug effects
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Chromatin / genetics
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Chromatin / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects*
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Fibroblasts / metabolism
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Gene Expression Regulation, Developmental
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Humans
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Intracellular Signaling Peptides and Proteins / agonists
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lamin Type A
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Longevity / genetics*
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism
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Nuclear Proteins / agonists
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Oxidative Stress
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Protein Precursors / agonists
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Protein Precursors / genetics*
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Protein Precursors / metabolism
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Signal Transduction
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Sirolimus / pharmacology*
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Tumor Suppressor p53-Binding Protein 1
Substances
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Antibiotics, Antineoplastic
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Chromatin
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Intracellular Signaling Peptides and Proteins
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Lamin Type A
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Membrane Proteins
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Nuclear Proteins
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Protein Precursors
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TP53BP1 protein, human
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Tumor Suppressor p53-Binding Protein 1
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prelamin A
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Metalloendopeptidases
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ZMPSTE24 protein, human
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Sirolimus