Michael J. Day, BSc, BVMS(Hons), PhD, DSc, DECVP, FASM, FRCPath, FRCVS
School of Clinical Veterinary Science University of Bristol, Langford, United Kingdom
One of the major advances in companion animal health care is the increasing longevity of our canine and feline patients. This has led to the development of the discipline of geriatric medicine and research into dietary and pharmacological means of prolonging the physical and mental quality of life of the older pet. One part of these investigations relate to changes in the immune system that occur with ageing (immunosenescence) which clearly impact on the health of the geriatric animal. Altered immune defenses may account for increased susceptibility to infectious, inflammatory, autoimmune and neoplastic disease in older animals. There are striking parallels between human and companion animal immunosenescence which makes the dog and cat attractive model systems for studies of human ageing.
In this regard, one particular aspect of canine ageing provides a unique model system for basic research. It has long been recognized that small breed dogs have a significantly longer lifespan than dogs of larger breeds and understanding the genetic basis for this observation may provide clues to the ageing process. The most striking discovery in this area was the recent recognition that a nucleotide polymorphism in the gene encoding the insulin-like growth factor-1 (IGF-1) distinguishes small and large breed dogs. This gene is well known as a determinant of body size in mammalian species and in many species there is a correlation between small body size and longevity. IGF-1 is also associated with ageing with a recognized decline in the concentration of serum IGF-1 in older humans and animals. A recent study has shown that older cats also have significant reduction in IGF-1 concentration.
Immunosenescence in Man
The characteristic features of immunosenescence have been best characterized in man. The immunological changes that occur in older individuals include:
A reduced ability to mount a delayed type hypersensitivity (DTH) response to antigen administered intradermally
Reduced in vitro proliferative responses of blood lymphocytes and reduced production of IL-2 by cells in these cultures
Lower serum IgA concentration
Reduced response to vaccination
Reduced total number of T cells in the blood
No consistent change in the proportion of CD8+ T cells in the blood
Lower naïve and increased memory T cells in the blood
Increased NK cells in the blood
Higher pro-inflammatory cytokine production
Increased expression of Th2 cytokines, suggesting an imbalance in immune function with immune deviation away from a Th1 phenotype
Increased concentrations of serum antibody but possible production of antibody of lower affinity for antigen
Increased autoantibody production
Reduced resistance to infection
Immunosenescence in the Dog
The immunological changes that occur in ageing dogs follow the same general trends described above for man. There is reduction in the ability of blood lymphocytes to proliferate in response to mitogens and an altered balance in the relative proportions of blood lymphocytes, characterized by fewer CD4+ T cells, increased CD8+ T cells and fewer B cells. The ability to produce immunoglobulin is maintained, with a general trend to increased concentration of serum IgG. Similar to man, there is a reduced ability to mount DTH responses to recall antigens.
One of the most comprehensive studies of canine immunosenescence was that performed by HogenEsch et al. in 2004. This project compared immune parameters in 32 young dogs of mean age 3 years and 33 older dogs of mean age 12 years. The older dogs had reduced proliferative responses of blood lymphocytes when stimulated with mitogens. There were alterations in the relative proportions of blood lymphocytes amongst the older dogs, characterized by reduction in the proportion of CD4+ T cells and elevation in CD8+ T cells, with a CD4 to CD8 ratio of 3.0 in young dogs compared with 1.8 in older dogs. The older dogs had fewer CD4 T cells that co-expressed the marker CD45 that is suggested to define naïve T cells, but a greater proportion of CD4+ CD29+ memory T cells. The older animals also had higher concentrations of IgA in the serum and saliva.
Two studies performed by Greeley et al. (1996 and 2001) provided information on other aspects of canine immunosenescence. The in vitro function of natural killer (NK) cells did not alter with age although male dogs had greater NK cell function than females. There was no impairment of the ability of blood neutrophils to phagocytose targets in vitro with age. One of these two studies (1996) demonstrated a gender difference in blood lymphocyte mitogen responsiveness with cells from older male dogs less responsive than those from older females. Finally, there was no impairment in the ability of older dogs to mount a serum antibody response to challenge with a novel antigen (KLH).
In contrast to human studies, a recent investigation in the dog has shown a progressive dominance of IFN-γ producing Th1 CD4+ T cells in the blood with increasing age (Horiuchi et al., 2007).
Immunosenescence in the Cat
A number of investigators have also studied ageing changes in the immune system of the cat. The most comprehensive study compared a range of immune parameters in adult cats aged 2-5 years (n=50) and senior cats aged 10-14 years (n=51). The senior population had lower total white blood cell counts and lower numbers of blood lymphocytes and eosinophils. Consistent with man and dogs, the older cats also had a reduced numbers of CD4+ T cells in the blood but uniquely also had a reduction in CD8+ cells, with an overall reduction in the CD4 to CD8 ratio (adult cats 1.75 compared with 1.35 in senior cats). Senior cats also had a reduced proportion of B cells and CD56+ NK cells. Similar to other species, senior cats had elevation in the serum concentration of IgM and IgA and there was no significant difference in the amount of serum complement or acute phase proteins between the two age groups. The reduction in CD4+ T cells in senior cats is associated with reduced IGF-1 concentration and it is proposed that IGF-1 may be important for maintaining thymic output of these cells in the ageing cat (Campbell et al., 2005).
Nutritional Support of the Ageing Immune System
Given these immunosenescence changes much research has been conducted into whether it is possible to 'boost immunity' in geriatric populations through dietary supplementation. In humans it is recognized that the level of intake of protein and energy can influence a range of immunological parameters including cell-mediated immune function, phagocytic cell function, complement function, secretory IgA production and cytokine production. There is great interest in the concept that caloric restriction may increase life span and help maintain immunological function and recognition that obesity is associated with reduced immune function.
One important area of geriatric medicine relates to vaccination protocols for older animals. There is little knowledge base as to how older animals respond to vaccination and whether they may require a tailored vaccination protocol. It is often anecdotally suggested that geriatric animals may require more frequent revaccination but in fact the evidence suggests that older animals are equally capable of mounting persisting antibody responses. The 2004 study of HogenEsch et al. compared the serological response of young and old dogs to vaccination with rabies and multivalent canine vaccines and demonstrated no significant difference in the ability of older dogs to develop protective antibody titres to rabies, distemper and parvovirus. In fact, the older dogs had higher rabies antibody titres prior to vaccination than the younger animals.
References are available upon request.