Hutchinson-Gilford progeria syndrome (HGPS), a lethal rare genetic disorder, is characterized by premature aging. HGPS is most commonly caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein termed progerin. We have showed that Neuropeptide Y (NPY) increases autophagy in the hypothalamus (1), a brain area recently identified as a central regulator of whole-body aging (2). In addition, we also observed that NPY mediates caloric restriction-induced autophagy (1). Some previous studies suggested that could play a role as an ageing regulator (3). Taking all this into account, the aim of the present study was to investigate if NPY could be a relevant strategy to delay the premature aging phenotype of HGPS.
Primary cultures of dermal fibroblasts derived from HGPS patients, that express NPY Y1, Y2 and Y5 receptors, were used as progeria cell model. Cells were exposed to NPY and several cellular aging hallmarks were evaluated: progerin accumulation; autophagy impairment; nuclear abnormalities; DNA damage; decreased cell proliferation; cellular senescence.
In HGPS fibroblasts, NPY (100nM) increased autophagic flux and decreased progerin levels and the number of dysmorphic nuclei, a hallmark of HGPS cells, and gammaH2AX, a marker of DNA damage. NPY increased HGPS cells proliferative capacity (increase of the number of Ki-67-positive cells). Moreover, NPY decreased the number of senescence associated-beta-galactosidase positive cells, indicating that NPY slowed down the progression of cellular senescence.
Altogether, these results show that NPY rescues several hallmarks of cellular aging of HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS. This study also suggest that NPY could be a potential therapeutic strategy not only for HGPS but also for normal aging or age-related diseases.
(1)Aveleira et al.PNAS 2015: 112:E1642-51; (2)Zhang et al.Nature 2013: 497(7448) 211-6. (3) Botelho and Cavadas, Trends Neurosci. 2015:38:701-11.
FUNDING: Progeria Research Foundation (USA), European Regional Development Fund (ERDF), through Centro 2020 Regional Operational Programme: CENTRO-01-0145-FEDER-000012-HealthyAging2020, COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and FCT(POCI-01-0145-FEDER-007440,UID/NEU/04539/2013;IF/00825/2015; SFRH/BD/51965/2012;SFRH/BD/120023/2016).
