Article thumbnail

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

By Shikha Snigdha, Nicole Berchtold, Giuseppe Astarita, Tommy Saing, Daniele Piomelli and Carl W. Cotman


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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2011). Abeta(1–42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta.
  2. (2009). Aerobic exercise effects on cognitive and neural plasticity in older adults.
  3. (2010). BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog. Neurobiol Aging.
  4. (2005). BDNF protects neurons following injury by modulation of caspase activity. Neurocrit Care 3: 71–76. Lifestyle Changes Can Attenuate Caspase Activation PLoS
  5. (1996). Betaamyloid accumulation correlates with cognitive dysfunction in the aged canine.
  6. (2002). Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.
  7. (2010). Caspase-3 Activation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization.
  8. (2011). Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease.
  9. (2003). Ceramide accumulation precedes caspase-3 activation during apoptosis of A549 human lung adenocarcinoma cells.
  10. (2001). Ceramide in apoptosis signaling: relationship with oxidative stress.
  11. (2002). Ceramide in apoptosis: an overview and current perspectives.
  12. (2000). Ceramide path in human lung cell death.
  13. (2005). Chronic antioxidant and mitochondrial cofactor administration improves discrimination learning in aged but not young dogs.
  14. (1994). Cognitive functions and aging in the dog: acquisition of nonspatial visual tasks.
  15. (2002). Dietary enrichment counteracts age-associated cognitive dysfunction in canines.
  16. (2009). Effects of age, dietary, and behavioral enrichment on brain mitochondria in a canine model of human aging.
  17. (2007). Exercise builds brain health: key roles of growth factor cascades and inflammation.
  18. (2011). Exercise training increases size of hippocampus and improves memory.
  19. (2010). Functional alterations in memory networks in early Alzheimer’s disease.
  20. (2008). In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons.
  21. (2004). Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease.
  22. (1999). Involvement of sphingomyelinases in TNF signaling pathways.
  23. (2005). Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study.
  24. (2009). Lipidomic analysis of biological samples by liquid chromatography coupled to mass spectrometry.
  25. (2010). Lyketsos CG
  26. (2010). Maturation of the olfactory sensory neurons by Apaf-1/caspase-9-mediated caspase activity.
  27. (2009). Mitochondria, cognitive impairment, and Alzheimer’s disease.
  28. (2006). Neural plasticity in the ageing brain.
  29. (2011). Neurobiology of the aging dog. Age (Dordr).
  30. (2007). Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function.
  31. (1996). Overexpression of Alzheimer’s PHF core tau fragments: implications for the tau truncation hypothesis.
  32. (2010). Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss.
  33. (2008). Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: relevance to Alzheimer’s disease.
  34. (1998). Signaling in and regulation of ionizing radiation-induced apoptosis in endothelial cells. Recent Prog Horm Res 53: 85–92; discussion 93.
  35. (2002). Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis.
  36. (2010). Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines.
  37. (1998). Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis.
  38. (2008). The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches.
  39. (2004). The pathophysiology of mitochondrial cell death.
  40. (2010). Ventricular maps in 804 ADNI subjects: correlations with CSF biomarkers and clinical decline.
  41. (1998). Visual-discrimination learning ability and beta-amyloid accumulation in the dog.