Dietary and Behavioral Interventions Protect against Age Related Activation of Caspase Cascades in the Canine Brain

Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aβ accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aβ, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON – control environment/control diet, AOX– control environment/antioxidant diet, ENR – enriched environment/control diet, AOX/ENR– enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging

Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/ gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer. Copyright © 2007 American Association for Cancer Research.link_to_subscribed_fulltex

Word generalization by a dog (Canis familiaris): is shape important?

We investigated the presence of a key feature of human word comprehension in a five year old Border Collie: the generalization of a word referring to an object to other objects of the same shape, also known as shape bias. Our first experiment confirmed a solid history of word learning in the dog, thus making it possible for certain object features to have become central in his word comprehension. Using an experimental paradigm originally employed to establish shape bias in children and human adults we taught the dog arbitrary object names (e.g. dax) for novel objects. Two experiments showed that when briefly familiarized with word-object mappings the dog did not generalize object names to object shape but to object size. A fourth experiment showed that when familiarized with a word-object mapping for a longer period of time the dog tended to generalize the word to objects with the same texture. These results show that the dog tested did not display human-like word comprehension, but word generalization and word reference development of a qualitatively different nature compared to humans. We conclude that a shape bias for word generalization in humans is due to the distinct evolutionary history of the human sensory system for object identification and that more research is necessary to confirm qualitative differences in word generalization between humans and dogs

Either taking it easy or feeling too tired: old Cory's shearwaters display reduced activity levels while at sea

It has long been known that birds change their behaviour, reproductive performance and survival as they mature, including in the first few years after recruitment into the breeding population. However, and contrasting with the description of patterns of actuarial and reproductive senescence in later years, there are surprisingly few studies documenting changes in behaviour in old individuals. Such studies are important, as birds provide particularly interesting models for studying the biology of senescence. It has been suggested that, unlike mammals, birds may remain physically fit until an advanced age, yet this has limited empirical support. In this paper, we used activity (immersion) loggers to show that old (>26 years) Cory’s Shearwaters Calonectris diomedea are less active when foraging at sea, spend more time resting on the water and have a smaller number of take-offs and landings during darkness, when compared to experienced mid-aged individuals (13–20 years old). Old individuals also tended to have reduced immune response against an experimental challenge using phytohaemagglutinin. These results are in line with observed reductions in activity levels with age in a wide range of non-avian taxa, and may suggest that old seabirds are physically less fit than younger individuals. Alternatively, old birds might simply be more experienced and their reduction in activity might reflect a strategic regulation of investment in different activities. Our study illustrates the potential for gaining insights into avian aging patterns and processes by looking into the behaviour of model organisms. We therefore encourage more research focusing on behavioural parameters that may reflect variations in physical condition or strategic choices, during both the breeding and non-breeding seasons