Accelerated ageing: from mechanism to therapy through animal models

Abstract

Ageing research benefits from the study of accelerated ageing syndromes such as HutchinsonGilford progeria syndrome (HGPS), characterized by the early appearance of symptoms normally associated with advanced age. Most HGPS cases are caused by a mutation in the gene LMNA, which leads to the synthesis of a truncated precursor of lamin A known as progerin that lacks the target sequence for the metallopotease FACE-1/ZMPSTE24 and remains constitutively farnesylated. The use of Face-1/Zmpste24-deficient mice allowed us to demonstrate that accumulation of farnesylated prelamin A causes severe abnormalities of the nuclear envelope, hyper-activation of p53 signalling, cellular senescence, stem cell dysfunction and the development of a progeroid phenotype. The reduction of prenylated prelamin A levels in genetically modified mice leads to a complete reversal of the progeroid phenotype, suggesting that inhibition of protein farnesylation could represent a therapeutic option for the treatment of progeria. However, we found that both prelamin A and its truncated form progerin can undergo either farnesylation or geranylgeranylation, revealing the need of targeting both activities for an efficient treatment of HGPS. Using Face-1/Zmpste24-deficient mice as model, we found that a combination of statins and aminobisphosphonates inhibits both types of modifications of prelamin A and progerin, improves the ageing-like symptoms of these mice and extends substantially their longevity, opening a new therapeutic possibility for human progeroid syndromes associated with nuclear-envelope defects. We discuss here the use of this and other animal models to investigate the molecular mechanisms underlying accelerated ageing and to test strategies for its treatment.

Suitability of the clonal marbled crayfish for biogerontological research: a review and perspective, with remarks on some further crustaceans

“…Such experiments, supplemented by observations from wild populations, pursue the following goals: (1) to compile a catalogue of ageing phenomena for the animal kingdom, (2) to compare ageing and longevity among and within animal clades, (3) to investigate the biological processes of ageing in detail, and (4) to learn how to achieve healthy old age and improved longevity in humans. The mouse Mus musculus, the rat Rattus norvegicus and the rhesus monkey Macaca mulatta are the most popular models of biogerontology due to their close phylogenetic relationship to humans and their long history as laboratory animals (Conn 2006;Enns et al 2008;Bizon and Woods 2009;Masoro 2009a;Osorio et al 2009). Among the invertebrates, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster are the most intensely studied ageing models, mainly because of short life cycles and well investigated development and genetics (Johnson 2008;Kennedy 2008;Austad 2009;Partridge 2009).…”

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

“…Thus, mutations in the gene encoding lamin A (an essential component of the nuclear envelope) or in Zmpste24 (encoding a metalloproteinase involved in the maturation of lamin A) are responsible for several devastating human progeroid syndromes, including Hutchinson-Gilford progeria, atypical Werner syndrome, restrictive dermopathy, and mandibuloacral dysplasia (3)(4)(5)(6)(7). The elucidation of the molecular mechanisms underlying these diseases has been facilitated by the generation and analysis of Lmna-and Zmpste24-deficient mice, which exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy human progeroid syndromes (8)(9)(10)(11)(12).…”

NF-κB signaling as a driver of ageing

“…The vast majority of progeroid syndromes are a consequence of inefficient DNA repair mechanisms or defective nuclear envelope assembly, which ultimately lead to DNA damage accumulation and chromosome instability (Ramirez et al, 2007;Carrero et al, 2016). The study of progeroid syndromes requires proper experimental models to investigate different alterations and test candidate drugs (Osorio et al, 2009). In the case of NF-κB activation, several laboratories have focused on the role of this signaling pathway in the development of accelerated ageing, using different animal models of progeria and providing essential information about NF-κB function.…”