Readers' Rating:

Rate this article

Over the past few decades, canine life span has continued to increase, due in part to improved veterinary care, vaccination programs, and nutritional status. It is estimated that one third to one half of today’s pet dogs and cats are considered to be ‘senior’ (>7 years of age) (Lund et al., 1999).

Similar to humans, geriatric dogs have an increased incidence of medical complications and complex diseases. One age-related disease receiving considerable attention in recent years is that of cognitive dysfunction. Canine Cognitive Dysfunction Syndrome (CDS) has been proposed to describe the progressive neurodegenerative disorder of senior dogs (Ruehl et al., 1995).

Dogs with CDS may display several abnormal behaviors including spatial disorientation and/or confusion, altered learning and memory, activity changes (purposeless, repetitive, or decreased), altered social relationships, altered sleep-wake cycles, increased anxiety or restlessness, altered appetite and/or self-hygiene, and decreased perception and/or responsiveness (Landsberg and Araujo, 2005). Although the age of onset may be 11 years or greater before clinical signs become apparent to owners, recent findings suggest that cognitive decline can be detected as early as 6 years of age in a laboratory environment (Araujo, 2004).

General physiologic changes associated with aging tissues include progressive organ degeneration (lack of reserve), tissue hypoxia, decreased enzyme systems, behavioral changes, dryness of mucosal tissues, cellular membrane alterations, and decreased immune surveillance (Fortney, 2001). Many of these age-related changes are thought to contribute to the development of disease.

With age, numerous anatomic changes occur within brain tissue, including decreased brain mass, increased ventricular size, meningeal calcification, demyelination, glial changes (increased size and number of astrocytes), increased lipofuscin concentration, increased number of apoptic bodies, neuroaxonal degeneration, and a decreased number of neurons (Su et al., 1998; Borras et al., 1999).

Functional changes such as decreased catecholamine neurotransmitters, increased monoamine oxidase B activity, and decreased cholinergic activity also occur with age (Milgram et al., 1993; Gerlach et al., 1994).

ß-amyloid deposition is virtually undetectable in young dogs, but can be extensive in the elderly (Cummings et al., 1996). As in humans, ß-amyloid deposition in dogs is strongly associated with cognitive dysfunction (increased error rate in discriminatory, reversal and spatial learning tests) (Head et al., 1998). In addition to ß-amyloid, several other proteins are linked with the pathology of neurodegenerative diseases including normal tau protein, synaptic proteins, amyloid precursor protein (APP), and apolipoprotein E (APOE). Although strong correlations exist between these proteins and cognitive dysfunction, few mechanisms by which they contribute to disease have been demonstrated.

Oxidative stress is known to contribute to genomic instability and cellular senescence, and thus, is one of the most popular theories of aging (Finkel and Holbrook, 2000).

Reactive oxygen species such as superoxide anion, hydrogen peroxide, and hydroxyl radicals are generated by metabolism and cause molecular damage to proteins, lipids, and nucleic acids. Because mitochondria are the major site of free radical production, they are often the primary target for oxidative damage and subsequent dysfunction. Researchers have demonstrated that as mitochondria age, they become less efficient and produce a greater amount of free radicals and less energy compared with younger mitochondria (Shigenaga et al., 1994).

Postmitotic cells are thought to be the most susceptible to oxidative damage because of their inability to replace themselves. Therefore, organs such as the brain, heart, and skeletal muscle may be the most vulnerable to oxidative damage. Anderson et al. (2000) demonstrated a correlation between DNA damage, much of which is caused by oxidative damage, and amyloid ß-peptide (Aß) deposition in brain tissue of aged dogs.

In vitro, Aß has been shown to trigger degeneration of cultured neurons through activation of an apoptotic pathway (Loo et al., 1993). Although apoptotic cell number and ß-amyloid plaques have not been significantly correlated in all experiments, the correlation between apoptotic cell number and dementia index was significant in the study reported by Kiatipattanasakul et al. (1996). Thus, while it appears that both DNA damage and ßamyloid deposition are associated with cognitive dysfunction, it is unclear whether these events act in concert or are independent of one another.


Current dietary intervention strategies

Due to the evidence of oxidative damage and its effect on aging tissues, many dietary strategies to combat brain aging involve the body’s natural antioxidant defense systems, altering enzymes such as superoxide dismutase, catalase, and glutathione peroxidase or supplementing free radical scavengers such as vitamins A, C, and E. For example, an antioxidant-rich diet supplemented with vitamins E and C, ß-carotene, selenium, DL- α-lipoic acid, L-carnitine, and various other flavonoids and carotenoids contained in spinach flakes, tomato pomace, grape pomace, carrot granules, and citrus pulp, has been reported to improve cognitive performance in aged dogs (Siwak et al., 2005).

Dietary fat and cholesterol inclusion levels and fatty acid form may also impair cognitive development and accelerate brain aging. It has been reported that both the generation and clearance of Aß are regulated by cholesterol, which modulates the processing of both APP and Aß. Elevated cholesterol level increases Aß in cellular and most animal models and is a risk factor for Alzheimer’s disease (Jarvik et al., 1995). Dietary fat intake has also been associated with psychosocial and cognitive function in young children.

Although total fat and saturated fat intake were unrelated to performance on achievement and intelligence tests, cholesterol and polyunsaturated fatty acid intakes were inversely and directly related to performance, respectively (Zhang et al., 2005). Supplementation of a Ginkgo biloba extract is believed to improve cognitive function in Alzheimer’s disease patients, possibly by inhibiting ß-amyloid production by lowering free cholesterol levels as demonstrated in aged rats (Yao et al., 2004).

A specific group of lipids, the omega-3 fatty acids, have been tested for their beneficial effects on brain health. Whalley et al. (2004) reported improved cognition in elderly humans consuming food supplements containing omega-3 fatty acids and having greater erythrocyte omega-3 fatty acid concentrations.

Docosahexaenoic acid (DHA; 22:6n-3), a product of the omega-3 pathway, appears to play an important role in neuronal development and cognitive function. Kelley (2005) reported that a diet containing elevated concentrations of omega-3 fatty acids (including DHA) resulted in greater erythrocyte DHA concentrations in pregnant bitches throughout gestation, greater erythrocyte DHA concentrations in offspring, and increased trainability of offspring, substantiating the importance of this fatty acid in the neurologic development of dogs.


Using genomic biology to study brain health

Although numerous anatomic changes to brain tissue have been associated with aging, very few exact mechanisms responsible for these changes and their effect on cognitive function have been identified. Besides the inaccessibility to brain tissue, limiting factors include the complexity of brain function, the numerous genetic and environmental factors contributing to brain health, and the time and costs associated with executing these experiments. In addition to improved imaging technologies that enable researchers to scan brain tissue in vivo, recent advances in genomic biology have greatly expanded research opportunities. Applying genomic tools and concepts to companion animal research should greatly enhance our understanding of the aging process and its impact on brain health.

Efforts put forth by the National Institutes of Health (NIH) have resulted in genome sequencing of numerous animal models, including the dog and cat. Based on sequence data generated by recent canine sequencing projects (Kirkness et al., 2003; Lindblad- Toh et al., 2005), a canine SNP (single nucleotide polymorphism) map is also being developed (www.genome.gov/12511476).

Canine genome sequence data enable genomescanning experiments to be performed. These experiments may be critical in the study of canine aging by identifying genetic loci or gene clusters contributing to age-related diseases. Human experiments have already identified associations between genetic polymorphisms present in the APOE gene and brain health.

A recent study identified the APOE e4 allele as a strong risk factor for increased amyloid deposition and cognitive impairment in humans (Bennett et al., 2005). Human studies have also identified correlations between interleukin-1 (IL-1) variants having increased levels of inflammatory mediators and increased severity of several chronic diseases, including Alzheimer’s disease (Griffin et al., 2000; Grimaldi et al., 2000). SNP assessment in dogs may identify genetic profiles associated with age-related disease incidence including those associated with brain health.

In addition to the availability of canine genome sequence data, tools used to measure mRNA and protein concentrations continue to be developed and improved. Current techniques not only have a much lower detection limit than previous methods, but are more accurate and can be automated. Moreover, ‘high-throughput’ techniques such as DNA microarrays enable the measurement of thousands of mRNA transcripts simultaneously, providing researchers with a holistic view of a cell, tissue, or organism.

Microarray analysis is a popular strategy used to identify genes and biologic pathways associated with complex diseases that are otherwise poorly understood. Genes significantly up- or down-regulated in the diseased state can then be studied in more detail in subsequent experiments.

DNA microarrays have been used to study aged brain tissue of mice (Lee et al., 2000; Jiang et al., 2001; Weindruch et al., 2002), humans (Lu et al., 2004), and dogs (Swanson et al., 2006). In general, aging seems to result in a gene expression profile indicative of an inflammatory response, oxidative stress, and reduced neurotrophic support (Lee et al., 2000; Lu et al., 2004). Moreover, in aged mice, genes associated with protein turnover and growth and trophic factors were downregulated (Lee et al., 2000).

In aged humans, genes playing a role in synaptic function and plasticity that underlie learning and memory were among those most significantly downregulated in brain tissue (Lu et al., 2004). Jiang et al. (2001) also noted that proteases that play an essential role in regulating neuropeptide metabolism, APP processing, and neuronal apoptosis were upregulated in aged brain, suggesting a major role in brain aging.

We observed similar results in aged dog brain tissues, with genes associated with inflammatory response and oxidative stress having increased expression. Interestingly, two peptides shown to increase cognitive performance, somatostatin and neuropeptide Y, had decreased expression levels in aged dogs (Swanson et al., 2006).

Although DNA microarrays have had a major positive effect on biologic research, they do have limitations. Besides the semi-quantitative nature of microarrays that requires validation by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), a low correlation between protein and mRNA concentration is observed for some genes.

These discrepancies may be due to a number of factors, including the level at which a gene is regulated (e.g., transcription vs. translation) and the occurrence of posttranslational modifications. Thus, a great need for techniques able to identify and quantify proteins exists.

Experiments using proteomic analysis to evaluate aged brain tissues in rodent models have recently been reported (Poon et al., 2005). These preliminary experiments substantiate the oxidative damage theory of aging, because increased concentrations of oxidized proteins were detected in many of these aged tissues. More such efforts are necessary to complement the mRNA datasets being generated, measure post-translational modifications of newly synthesized proteins, and detect the amount and type of protein damage in tissues of aged animals.

References

Anderson, A.J., W.W. Ruehl, L.K. Fleischmann, K. Stenstrom, T.L. Entriken and B.J. Cummings. 2000. DNA damage and apoptosis in the aged canine brain: Relationship to Aß deposition in the absence of neuritic pathology. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 24:787-799.

Araujo, J.A. 2004. Age-dependent learning and memory decline in dogs: Assessment and effectiveness of various interventions. Presented at the 141st American Veterinary Medical Association Conference, Schaumberg, IL.

Bennett, D.A., J.A. Schneider, R.S. Wilson, J.L. Bienias, E. Berry-Kravis and S.E. Arnold. 2005. Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J. Neurol. Neurosurg. Psychiatry 76:1194-1199.

Borras, D., I. Ferrer and M. Pumarola. 1999. Age related changes in the brain of the dog. Vet. Pathol. 36:202-211.

Cummings, B.J., E. Head, A.J. Afagh, N.W. Milgram and C.W. Cotman. 1996. ß-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol. Learning Memory 66:11-23.

Finkel, T. and N. Holbrook. 2000. Oxidants, oxidative stress and the biology of aging. Nature 408:239-247.

Fortney, W.D. 2001. Clinical perspectives and issues related to senior companion animals. Proceedings from a Pre-Congress Symposium: World Small Animal Veterinary Association, World Congress 2001. The Iams Company, Dayton, OH, USA.

Gerlach, M., P. Riederer and M.B.H. Youdim. 1994. Effects of disease and aging on monoamine oxidases A and B. In: Monoamine Oxidase Inhibitors in Neurological Diseases (A. Lieberman, C.W. Olanow and M.B.H. Youdim, eds). Marcel Dekker, New York, NY, USA, pp. 21-30.

Griffin W.S., J.A. Nicoll, L.M. Grimaldi, J.G. Sheng and R.E. Mrak. 2000. The pervasiveness of interleukin-1 in Alzheimer pathogenesis: A role for specific polymorphisms in disease risk. Exp. Gerontol. 35:481-487.

Grimaldi L.M., V.M. Casadei, C. Ferri, F. Veglia, F. Licastro, G. Annoni, I. Biunno, G. De Bellis, S. Sorbi, C. Mariani, N. Canal, W.S. Griffin and M. Franceschi. 2000. Association of early-onset Alzheimer’s disease with an interleukin-1 alpha gene polymorphism. Ann. Neurol. 47:361-365.

Head, E., H. Callahan, B.A. Muggenburg, C.W. Cotman and N.W. Milgram. 1998. Visualdiscrimination learning ability and beta-amyloid accumulation in the dog. Neurobiol. Aging 19:415-425.

Jarvik, G.P., E.M. Wijsman, W.A. Kukull, G.D. Schellenberg, C. Yu and E.B. Larson. 1995. Interactions of apolipoprotein E genotype, total cholesterol level, age and sex in prediction of Alzheimer’s disease: a case-control study. Neurol. 45:1092-1096.

Jiang, C.H., J.Z. Tsien, P.G. Schultz and Y. Hu. 2001. The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc. Natl. Acad. Sci. 98:1930-1934.

Kelley, R. 2005. Improving puppy trainability through nutrition. In: Proceedings from Symposium: Federation of Animal Science Societies FASS 2005 Joint Annual Meeting. The Iams Company, Dayton, OH, USA, pp. 11-15.

Kiatipattanasakul, W., S.-I. Nakamura, M.M. Hossain, H. Nakayama, T. Uchino, S. Shumiya, N. Goto and K. Doi. 1996. Apoptosis in the aged dog brain. Acta Neuropathol. 92:242- 248.

Kirkness E.F., V. Bafna, A.L. Halpern, S. Levy, K. Remington, D.B. Rusch, A.L. Delcher, M. Pop, W. Wang, C.M. Fraser and J.C. Venter. 2003. The dog genome: Survey sequencing and comparative analysis. Science 301:1898-1903.

Landsberg, G. and J.A. Araujo. 2005. Behavior problems in geriatric pets. Vet. Clin. Small Anim. 35:675-698.

Lee, C.-K., R. Weindruch and T.A. Prolla. 2000. Gene-expression profile of the aging brain in mice. Nature Genet. 25:294-297.

Lindblad-Toh, K., et al,. 2005. Genome sequence, comparative analysis and haplotypes structure of the domestic dog. Nature 438:803-819.

Loo, D.T., A. Copani, C.J. Pike, E.R. Whittemore, A.J. Walencewicz and C.W. Cotman. 1993. Apoptosis is induced by ß-amyloid in cultured central nervous system neurons. Proc. Natl. Acad. Sci. 90:7951-7955.

Lund, E.M., P.J. Armstrong, C.A. Kirk, L.M. Kolar and J.S. Klausner. 1999. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J. Am. Vet. Med. Assoc. 214:1336-1341.

Lu, T., Y. Pan, S.-Y. Kao, C. Li, I. Kohane, J. Chan and B.A. Yankner. 2004. Gene regulation and DNA damage in the aging human brain. Nature 429:883-891.

Milgram, N.W., G.O. Ivy, E. Head, M.P. Murphy, P.H. Wu, W.W. Ruehl, P.H. Yu, D.A. Durden, B.A. Davis, I.A. Paterson and A.A. Boulton. 1993. The effect of L-deprenyl on behavior, cognitive function and biogenic amines in the dog. Neurochem. Res. 18:1211- 1219.

Poon, H.F., R.A. Vaishnav, T.V. Getchell, M.L. Getchell and D.A. Butterfield. 2005. Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice. Neurobiol. Aging (in press).

Ruehl, W.W., D.S. Bruyette, A. DePaoli, C.W. Cotman, E. Head, N.W. Milgram and B. Cummings. 1995. Canine cognitive dysfunction as a model for human age-related cognitive decline, dementia and Alzheimer’s disease: clinical presentation, cognitive testing, pathology and response to L-deprenyl therapy. Prog. Brain Res. 106:217-225.

Shigenaga, M.K., T.M. Hagen and B.N. Ames. 1994. Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. 91:10771-10778.

Siwak, C.T., P.D. Tapp, E. Head, S.C. Zicker, H.L. Murphey, B.A. Muggenburg, C.J. Ikeda-Douglas, C.W. Cotman a nd N.W. Milgram. 2005. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 29:461-469.

Su, M.Y., E. Head, W.M. Brooks, Z. Wang, B.A. Muggenburg, G.E. Adam, R. Sutherland, C.W. Cotman and O. Nalcioglu. 1998. Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol. Aging 19:479-

Swanson, K.S., C.J. Apanavicius, B.M. Vester and N.A. Kirby. 2006. Impact of age on gene expression profiles of canine brain tissue. 2006 Animal Sciences Meeting (submitted).

Weindruch, R., T. Kayo, C.-K. Lee and T.A. Prolla. 2002. Gene expression profiling of aging using DNA microarrays. Mech. Aging Dev. 123:177-193.

Whalley, L.J., H.C. Fox, K.W. Wahle, J.M. Starr and I.J. Deary. 2004. Cognitive aging, childhood intelligence and the use of food supplements: possible involvement of n-3 fatty acids. Am. J. Clin. Nutr. 80:1650-1657.

Yao, Z.-X., Z. Han, K. Drieu and V. Papadopoulos. 2004. Ginkgo biloba extract (Egb 761) inhibits ß-amyloid production by lowering free cholesterol levels. J. Nutr. Biochem. 15:749- 756.

Zhang, J., J.R. Hebert and M.F. Muldoon. 2005. Dietary fat intake is associated with psychosocial and cognitive functioning of school-aged children in the United States. J. Nutr. 135:1967-1973.

Readers' Rating:

Rate this article