title: Dietary and behavioral interventions protect against age related activation of caspase cascades in the canine brain.
abstract: 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.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, United States of America. ssnigdha@uci.edu
authors.forename: Shikha
authors.initials: S
authors.lastname: Snigdha
authors.forename: Nicole
authors.initials: N
authors.lastname: Berchtold
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.forename: Tommy
authors.initials: T
authors.lastname: Saing
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002417:Cattle; D002518:Ceramides / Q000378:metabolism; D019587:Dietary Supplements; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D010805:Physical Conditioning, Animal / Q000502:physiology*; D039961:Semaphorins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002518:Ceramides; D039961:Semaphorins; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases