Centenarian lamins: rapamycin targets in longevity

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.

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

“…To test this hypothesis, we induced oxidative stress in HGPS fibroblasts and age‐ and passage‐matched controls (Table 1) and analyzed samples under basal conditions, during DNA damage response (DDR) or after 48 hr of DNA damage recovery (Figure 1a). Following 4‐hr exposure to H 2 O 2 , we did not observe lamin A/C modulation, neither in control nor in HGPS cells (Supporting Information Figure S1a,b), while prelamin A was significantly increased and its levels were decreased after stress recovery (Supporting Information Figure S1a–c), as previously reported (Lattanzi et al, 2014). Of note, also progerin, the truncated prelamin A form accumulated in HGPS cells tended to increase during DDR (Supporting Information Figure S1a–d).…”

“…Prelamin A, the precursor of lamin A, is transiently accumulated during oxidative or replicative stress (Lattanzi et al, 2014; Liu, Drozdov, Shroff, Beltran, & Shanahan, 2013). Moreover, proteins involved in repair of stress‐induced DNA damage are recruited by lamins to damaged sites or inside the nuclear compartment (Gibbs‐Seymour, Markiewicz, Bekker‐Jensen, Mailand, & Hutchison, 2015; Gonzalez‐Suarez et al, 2011; Lattanzi et al, 2014).…”

“…Prelamin A, the precursor of lamin A, is transiently accumulated during oxidative or replicative stress (Lattanzi et al, 2014; Liu, Drozdov, Shroff, Beltran, & Shanahan, 2013). Moreover, proteins involved in repair of stress‐induced DNA damage are recruited by lamins to damaged sites or inside the nuclear compartment (Gibbs‐Seymour, Markiewicz, Bekker‐Jensen, Mailand, & Hutchison, 2015; Gonzalez‐Suarez et al, 2011; Lattanzi et al, 2014). Consistent with these functions, lamin A/C has been implicated in mechanisms related to physiological (Lattanzi et al, 2014) and pathological aging (Evangelisti, Cenni, & Lattanzi, 2016), above all in progeroid laminopathies (Camozzi et al, 2014).…”

“…Moreover, proteins involved in repair of stress‐induced DNA damage are recruited by lamins to damaged sites or inside the nuclear compartment (Gibbs‐Seymour, Markiewicz, Bekker‐Jensen, Mailand, & Hutchison, 2015; Gonzalez‐Suarez et al, 2011; Lattanzi et al, 2014). Consistent with these functions, lamin A/C has been implicated in mechanisms related to physiological (Lattanzi et al, 2014) and pathological aging (Evangelisti, Cenni, & Lattanzi, 2016), above all in progeroid laminopathies (Camozzi et al, 2014). Here, we analyzed cells from patients affected by HGPS, a premature aging syndrome linked to LMNA mutations, and observed an altered modulation of CDKN1A , encoding p21, in HGPS under oxidative stress.…”

“…Moreover, lamin A/C has been demonstrated to bind gene promoters or neighboring domains and this binding has been linked to distinct transcriptional outcomes (Lee, Welton, Smith, & Kennedy, 2009; Lund & Collas, 2013; Mattout et al, 2011). Finally, a clear link has been established between stress‐induced chromatin remodeling, including acetylation or methylation of HDAC2 substrates H3 histone lysine 9 (H3K9) and H4 histone lysine 16 (H4K16), and lamin A/C posttranslational modifications (Ghosh et al, 2015; Lattanzi et al, 2007, 2014 ; Liu et al, 2013; Mattioli et al, 2008). Based on the whole evaluation of those reported data, we wondered if HDAC2 could mediate lamin A/C‐dependent effects on p21 expression during DDR.…”