IN-DEPTH: GERIATRIC MEDICINE/METABOLICS
study group is too young. Less intuitively, a study population that is too old may cause age-related immune defects to be missed because the selected population may have survived to extreme old age as the result of exceptional immune function.5 It is likely that biomarkers of aging differ with the pro- gression of animals from old to very old age. Cer- tainly, risk of specific diseases, frailty, or other impairments vary along the spectrum of aging. Finally, it is also important that the control popula- tion be a suitable age. For example, adult animals are needed in the control population if the goal of the study is to compare the immune function changes that develop in old age, whereas the control group would include younger animals if the goal was to assess the whole spectrum of age-associated im- mune changes.
3. Age-Associated Changes in Immune Function
Cell Populations Age-associated alterations in lymphocyte subset populations have been documented in several spe- cies including people, dogs, and rodents.6–9 Aro- bust decrease in naive T-cells, thought to be the result of thymic involution, is a consistent finding in aged people and rodents.10–13 In addition, it has been suggested the loss of naive T-cells may be the result of lifelong infection by viruses, especially herpes viruses such as cytomegalovirus or other chronic antigenic stimulants.14,15 Because of a lack of available antibodies that differentiate equine memory cells from naive cells, changes in naive T- cell populations have not been directly examined in aging in the horse. Other findings in human leukocyte populations include alterations in total lymphocytes, CD4, CD8, and B-cells. The CD4:CD8 ratio, an indicator of whether lymphocyte populations favor an inflamma- tory or immunosuppressive bias, has been reported to be altered in human geriatric populations.16–18 Several studies have investigated lymphocyte popu- lations in aged horses and ponies.19–22 Total lym- phocyte populations decrease in aged horses.19–21 Other observations include a decrease in the total number of CD4, CD8, and B-cells21 and an increase in the percentage of CD4 lymphocytes in aged horses.22 In ponies, a decrease in total monocyte and eosinophil counts has been reported.20 The CD4:CD8 ratio was found to be increased in aged horses,21 suggesting that a proinflammatory state occurs in old horses as in people.
Cytokine and Acute-Phase Protein Profiles in the Aged Horse
Serum cytokine profiles in the aged human typically are those of a pro-inflammatory phenotype.23,24 Aged horses show similar cytokine profiles with in- creased gene expression of tumor necrosis factor (TNF)-, interleukin (IL)-6, IL-1, IL-8, interferon (IFN)-, IL-15, and IL-1822,25 and increased proin-
flammatory: anti-inflammatory cytokine ratios in- cluding IL6:IL10 and TNF-:IL10 ratios.25 Serum cytokine concentration of TNF- was increased in aged horses in one study22 but not another.25 Sev- eral confounding factors might affect serum TNF- concentration including concurrent illness, inflam- mation, or season of sample collection. The role of other serum cytokines in aging of horses has not been extensively examined because of the limited availability of valid assays. The effect of age on serum acute phase protein concentrations is not yet known, although assays validated for use in horse are now available for the measurement of serum amyloid A and C-reactive protein.
PBMC Cytokine Response to Stimulation
Several studies have evaluated the impact of aging on the responsiveness of equine peripheral blood mononuclear cells (PBMC) after immune stimula- tion. Inflammatory response after stimulation of whole blood or PBMC from healthy aged people re- sults in a greater release of proinflammatory cyto- kines than that observed in adults.26,27Similar studies have revealed an increase in TNF- and IFN- production from PBMC after stimulation in aged horses.22,25
Lymphocyte Function
One of the most consistent findings in immunose- nescence is a decrease in the ability of lymphocytes to proliferate. Studies in rodents and people have shown impaired lymphocyte proliferation may in- volve a decrease in serum IL-2 concentration or IL-2 receptor expression.11,28,29 However, a decrease in lymphocyte proliferation has also been reported independent of these two factors, suggesting defects in intracellular signaling may also occur with ag- ing.30 Horses also have an age-associated decrease in lymphocyte proliferation20,22,31 that is not respon- sive to IL-2 supplementation and not associated with a change in lymphocyte IL-2 receptor expres- sion.20 This suggests that, similar to what has been reported in people, the age-associated defect in lymphocyte division in horses may be caused by alterations in intracellular signaling.
Neutrophil Function
Although immunosenescence affects primarily adaptive immunity, changes in innate immunity oc- cur as well. Innate immunity includes the response of neutrophils and macrophages as a first-line de- fense against pathogens. Age-associated changes in neutrophil function that have been reported in people and rodents include decreases in phagocyto- sis, oxidative burst, chemokinesis, and chemotaxis. Neutrophil numbers appear to be maintained.32–35 In healthy aged horses, neutrophil adhesion, oxida- tive burst, and phagocytosis were all found to be unchanged, whereas chemotaxis was increased, com- pared with that observed in healthy adult horses.36 In contrast, preliminary data suggest that horses
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