Doubled lifespan and patient‐like pathologies in progeria mice fed high‐fat diet

Abstract

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.

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells

“…However, TUDCA did not prolong lifespan in Apoe −/− Lmna G609G/G609G mice with ubiquitous progerin expression. This is in accordance with previous observations that, unlike HGPS patients, these mutant mice apparently die from atherosclerosis‐independent causes, possibly arrhythmias, starvation, and cachexia (Hamczyk et al , ; Kreienkamp et al , ). In contrast to Apoe −/− Lmna G609G/G609G mice, Apoe −/− Lmna LCS/LCS SM22αCre mice most likely die from atherosclerosis‐related causes (Hamczyk et al , ).…”

Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

“…None of currently available drugs was able to counteract adipose tissue loss, either in less severe LMNA ‐linked lipodystrophies (Araujo‐Vilar & Santini, 2019) or in HGPS (Gordon et al, 2018). On the other hand, in Lmna G609G / G609G mice subjected to high fat diet, an impressive life span extension was obtained (Kreienkamp et al, 2019; Kreienkamp & Gonzalo, 2020), suggesting a main role of adipose tissue loss in HGPS pathogenesis. Thus, amelioration of white adipose tissue condition by tocilizumab might contribute to the overall improvement of health status here observed in progeroid mice.…”

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

“…Given this hypoglycemia and bradykinesia which preceded death, our lab began to embark on a more thorough metabolic characterization of these mice [80,81]. Interestingly, Lmna G609G/G609G mice have energy alterations well before their ultimate decline.…”