A biphasic model of lifespan in nematode Caenorhabditis elegans worm.

Ageing research focuses on identifying lifespan modifiers and understanding and appropriately interpreting their effects. One of the most relevant quantities being studied is the shape of the survival curve that can reveal crucial information on the mechanism of action. Here, we introduce a bilogistic model to describe the shape of the lifespan curves of Caenorhabditis elegans populations. Using the corrected Akaike information criterion and the RMSE as goodness-of-fit tests, we show that the bilogistic model provides a better fit to the experimental data from nematode worms than other mathematical models and can identify and confirm biphasic lifespan data. Our parametric model offers a method to interpret replicate experiments data in terms of the shape parameters of the lifespan curve and enables robust statistical analysis of intra- and inter-group variance. We apply the model to novel lifespan data from C. elegans and Drosophila melanogaster and provide a rational statistical analysis of lifespan modifiers such as temperature and daf-16/FOXO mutation.

Amyloid-ß precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation.

INTRODUCTION: Presenilin-1 (PSEN1) gene mutations are the most common cause of familial Alzheimer's disease (fAD) and are known to interfere with activity of the membrane imbedded γ-secretase complex. PSEN1 mutations have been shown to shift Amyloid-ß precursor protein (AßPP) processing toward amyloid-ß (Aß) 1-42 production. However, less is known about whether PSEN1 mutations may alter the activity of enzymes such as ADAM10, involved with non-amyloidogenic AßPP processing, and markers of oxidative stress. MATERIALS AND METHODS: Control and PSEN1 mutation (L286V and R278I) Human Neural Stem Cells were spontaneously differentiated into neuron and astrocyte co-cultures. Cell lysates and culture media were collected and stored at -80 °C until further analysis. ADAM10 protein expression, the ratio of AßPP forms and Aß1-42/40 were assessed. In addition, cellular redox status was quantified. RESULTS: The ratio of AßPP isoforms (130:110kDa) was significantly reduced in neuron and astrocyte co-cultures carrying PSEN1 gene mutations compared to control, and mature ADAM10 expression was lower in these cells. sAßPP-α was also significantly reduced in L286V mutation, but not in the R278I mutation cells. Both Aß1-40 and Aß1-42 were increased in conditioned cell media from L286V cells, however, this was not matched in R278I cells. The Aß1-42:40 ratio was significantly elevated in R278I cells. Markers of protein carbonylation and lipid peroxidation were altered in both l286V and R278I mutations. Antioxidant status was significantly lower in R278I cells compared to control cells. CONCLUSIONS: This data provides evidence that the PSEN1 mutations L286V and R278I significantly alter protein expression associated with AßPP processing and cellular redox status. In addition, this study highlights the potential for iPSC-derived neuron and astrocyte co-cultures to be used as an early human model of fAD.