Ageing is associated with increased hypercoagulability, due to a slow rise of several coagulation factors, factor VIII, fibrinogen and thrombin-antithrombin complexes, markers of fibrinolysis and progressively defective Protein C activation, yet compatible with life at very high age. Mice, naturally aged up to 24 months, likewise show a progressive elevation of coagulation factors, triggering enhanced thrombogenicity during acute injury-induced thrombus formation. To overcome the still gradual natural ageing in mice, several mouse models of premature ageing were characterized, in an effort to allow for more rapid ageing-induced manifestations of natural thrombogenicity.
Thus, the Klotho gene, encoding a type-I membrane protein, related to beta-glucosidases underlies degenerative processes, including arteriosclerosis and osteoporosis, observed in chronic renal failure. Mutations within this protein are associated with ageing and bone loss. Defective Klotho gene expression in the mouse accelerates degeneration of multiple age-sensitive traits, whereas its overexpression extends murine life span. The multidomain protein kinases Bub1 and BubR1 are central components of the mitotic checkpoint for spindle assembly (SAC) and self-monitor the eukaryotic cell cycle. Despite their amino acid sequence conservation and similar domain organization, BUB1 and BUBR1 perform different functions in the SAC. Various p53 mutant mice with a BubR1 insufficiency display early onset of ageing-associated phenotypes, whereas the BubR1H/H mouse is characterized by simultaneous vascular defects. Progerin mouse models show phenotypes ranging from being largely restricted to the vascular system to models with a broader progeria-like phenotype (severe growth retardation, fragile bones, alopecia, skin defects and reduced viability).
The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus, but the most widespread mouse model of premature ageing consists of a circadian clock gene mutant mouse, the brain and muscle arnt like protein-1 (Bmal1). Mice deficient in this circadian transcription factor have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Bmal1-/- mice have reduced lifespan (maximum around 50 weeks) and display symptoms of premature ageing, including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. Their early ageing phenotype correlates with increased levels of reactive oxygen species in some but not all tissues. These findings and data on CLOCK/BMAL1-dependent control of stress responses were evoked to explain the early onset of age-related pathologies in the absence of Bmal1. Their reduced lifespan is still long enough to enable intervention studies on heart function, renal integrity, tissue degeneration and thrombogenicity, including diet feeding and fat composition studies, analysis of the progressive prothrombotic state and anti-oxidant intervention studies for longevity assessment.
Combined though, all these studies raise cautiousness, because no single mouse model can phenocopy human ageing perfectly: even when murine alopecia signals premature ageing, p16INK-4A measurements via qPCR do not always rise, as such is the case during natural mouse ageing and some organs deteriorate more slowly than others (e.g. vascular media and smooth muscle cells), coupled to different exposure/sensitivity to oxidative stress or environmental factors. Also, the major advantage of most accelerated ageing models, i.e. their rapid onset of ageing may insufficiently favor several risk factors, i.e. age-related thrombogenicity factors developing chronically, gradullay deteriorating with ageing. The fragile Bmal1-/- mouse model represents a well-studied compromise, its defects in different organs being well-documented, with a life-span, long enough to allow intervention studies.
Disclosures
No relevant conflicts of interest to declare.
Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models
