d-galactose: a model of accelerated ageing sufficiently sensitive to reflect preventative efficacy of an antioxidant treatment

摘要

Considering that the phenomenon of accelerated ageing contributes to early onset of various chronic diseases, modelling of the relevant dysregulated systems or responses is vital for research aimed at identification of potential therapeutic targets. Here, we aimed to establish a model capable of simulating the redox and inflammatory changes of accelerated ageing-specifically, the aim was early phase accelerated ageing, which would allow therapeutic intervention in a preventative approach prior to clinical disease manifestation. A secondary aim was to evaluate the sensitivity of the model to reflect preventative treatment efficacy. Dailyd-galactose injections (250 mg/kg body mass/day) for 8 weeks in 9-week-old male Wistar rats induced a model of early accelerated ageing (decreased plasma FRAP; P < 0.05 and altered inflammatory signalling) and an aged profile in lymph node ultrastructure, but did not yet result in telomere shortening. Preventative daily oral antioxidant administration (grape seed-derived polyphenol, 100 mg/kg body mass) prevented tissue ageing, beneficially modulated the inflammatory response, including neutrophil chemokinetic capacity, and tended to increase absolute telomere length. Data suggests that using a mild model ofd-galactose administration than those employed to induce neurodegeneration, simulated the point where oxidative stress starts to overwhelm the endogenous antioxidant response and where a pro-inflammatory phenotype switch manifests. Furthermore, despite the expected small effect size, the model was sufficiently sensitive to reflect benefits of preventative antioxidant treatment in the context of ageing. This model presents a practical model for use in drug discovery, particularly in the context of preventative medicine aimed at limiting oxidative stress-associated ageing. Since this starting point of accelerated ageing as illustrated by current data, is not expected to reflect major ageing-associated changes yet, we recommend that future preventative drug discovery studies employ a longitudinal study design in order to clearly demonstrate the delay of this starting point by preventative strategies.