Date Published: December 12, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Ray Kreienkamp, Cyrielle Billon, Gonzalo Bedia‐Diaz, Carolyn J. Albert, Zacharie Toth, Andrew A. Butler, Sara McBride‐Gagyi, David A. Ford, Angel Baldan, Thomas P. Burris, Susana Gonzalo.
Hutchinson‐Gilford Progeria Syndrome (HGPS) is a devastating premature aging disease. Mouse models have been instrumental for understanding HGPS mechanisms and for testing therapies, which to date have had only marginal benefits in mice and patients. Barriers to developing effective therapies include the unknown etiology of progeria mice early death, seemingly unrelated to the reported atherosclerosis contributing to HGPS patient mortality, and mice not recapitulating the severity of human disease. Here, we show that progeria mice die from starvation and cachexia. Switching progeria mice approaching death from regular diet to high‐fat diet (HFD) rescues early lethality and ameliorates morbidity. Critically, feeding the mice only HFD delays aging and nearly doubles lifespan, which is the greatest lifespan extension recorded in progeria mice. The extended lifespan allows for progeria mice to develop degenerative aging pathologies of a severity that emulates the human disease. We propose that starvation and cachexia greatly influence progeria phenotypes and that nutritional/nutraceutical strategies might help modulate disease progression. Importantly, progeria mice on HFD provide a more clinically relevant animal model to study mechanisms of HGPS pathology and to test therapies.
Hutchinson‐Gilford Progeria Syndrome (HGPS) is caused by LMNA gene mutation and expression of a mutant lamin A protein called progerin, which disrupts nuclear architecture and genome stability and function, promoting cellular senescence (Collins, 2016; Gonzalo & Kreienkamp, 2015; Prokocimer, Barkan, & Gruenbaum, 2013). At the organismal level, progerin unleashes a trove of devastating aging pathologies including alopecia, bone and joint abnormalities, lipodystrophy, cardiovascular disease (CVD), and atherosclerosis (Gonzalo, Kreienkamp, & Askjaer, 2016; Ullrich & Gordon, 2015). The progerin‐expressing LmnaG609G/G609G mouse (herein G609G) carries the equivalent human mutation in homozygosis and has been widely used for studying the mechanistic bases underlying progeria, as well as the outcomes of various therapeutic avenues (Osorio et al., 2011). Cellular phenotypes include nuclear morphological abnormalities, increased genomic instability, deregulated gene expression, and premature senescence (Gonzalo et al., 2016; Ullrich & Gordon, 2015). G609G mice develop some progeroid features such as growth impairment, lipodystrophy, bone abnormalities, and cardiovascular alterations (Osorio et al., 2011; Villa‐Bellosta et al., 2013). However, these mice die at a very young age (~100 days) of unknown etiology and do not mimic the severity of disease of HGPS patients.
Our study demonstrates the importance of caloric intake to the development of various phenotypes in G609G mice. The finding that HFD results in the largest extension of life recorded to date in an HGPS mouse model suggests that a nutritional/nutraceutical approach could provide a powerful tool for modulating disease course in both mice and humans. Interestingly, the Progeria Research Foundation recommends feeding high calorie foods to HGPS patients:Children with Progeria actually eat enough calories to grow, but the basic disease process in Progeria does not allow them to grow normally. Some parents also report that the children tend to take in smaller, more frequent meals. Therefore, the goal is to give them nutritious and high calorie foods and supplements.