Richard D. Kealy

Diet restriction and ageing in the dog: major observations over two decades

This report reviews decade two of the lifetime diet restriction study of the dog. Labrador retrievers (n 48) were paired at age 6 weeks by sex and weight within each of seven litters, and assigned randomly within the pair to control-feeding (CF) or 25 % diet restriction (DR). Feeding began at age 8 weeks. The same diet was fed to all dogs; only the quantity differed. Major lifetime observations included 1.8 years longer median lifespan among diet-restricted dogs, with delayed onset of late life diseases, especially osteoarthritis. Long-term DR did not negatively affect skeletal maturation, structure or metabolism. Among all dogs, high static fat mass and declining lean body mass predicted death, most strongly at 1 year prior. Fat mass above 25 % was associated with increasing insulin resistance, which independently predicted lifespan and chronic diseases. Metabolizable energy requirement/lean body mass most accurately explained energy metabolism due to diet restriction; diet-restricted dogs required 17 % less energy to maintain each lean kilogram. Metabonomics-based urine metabolite trajectories reflected DR-related differences, suggesting that signals from gut microbiota may be involved in the DR longevity and health responses. Independent of feeding group, increased hazard of earlier death was associated with lower lymphoproliferative responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen; lower total lymphocytes, T-cells, CD4 and CD8 cells; lower CD8 percentages and higher B-cell percentages. When diet group was taken into account, PWM responses and cell counts and percentages remained predictive of earlier death.

The influence of age on the canine immune system

Immune function was assessed in a group of 47 Labrador Retrievers, ranging in age from 0.8 to 11.5 years, in order to establish baseline data on canine immunosenescence. Natural killer cell activity, lymphocyte subset distributions, antibody production, and mitogen-induced lymphoproliferative responses, all of which have been demonstrated to undergo age-related changes in humans and mice, were chosen as indicators of immune function. Dogs were categorized by age as young (mean 2.4 years), middle-aged (mean 5.8 years), and old (mean 9.1 years). Natural killer cell activity was not affected significantly by age. Lymphocyte subset analysis revealed a significant age-related increase in the percentage of cells staining with a pan T-cell reagent, accompanied by a corresponding increase in the percentage of CD8 cells from youth to middle age. An age-related decrease in the percentage of B-cells was observed concomitant with the increases in T-cell percentages. A gender-related difference in pan T-cell distribution was also observed, with females having a higher percentage than males. Lymphoproliferative responses of both young and middle-aged dogs to the mitogens concanavalin A, phytohemagglutinin, pokeweed mitogen, and staphylococcal enterotoxin B were significantly higher than those of old dogs. In general, the mitogen responses of male dogs were affected more dramatically by age than those of females. A significant age-related decline in in vivo antibody responses to the protein antigen, keyhole limpet hemocyanin, was not observed, although the mean titers of the young dogs were higher than those of the old.

The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs.

While aging studies employing a cross-sectional design have been informative in documenting many age-related alterations in immune function between different age cohorts within a population, longitudinal studies are invaluable for verifying changes at the level of the individual and for defining the precise periods of life during which particular changes occur. In the present study, a battery of immunological parameters were evaluated in a group of Labrador Retrievers as part of a comprehensive longitudinal aging study. Twenty-three dogs (14 females, 9 males; from 4 to 11 years of age) were evaluated annually for total WBC counts, lymphocyte subset distributions, natural killer cell activity and neutrophil phagocytic activity, and biannually for lymphoproliferative activity. An age-related decline in absolute numbers of lymphocytes, T-cells, CD4-cells and CD8-cells was observed in both genders. The distribution of lymphocyte subsets shifted with age, most dramatically in the females; percentages of B-cells declined while those of T-cells increased. Changes in percentages of CD4- and CD8-cells over the 8-year period were not dramatic; in females, percentages of CD8-cells increased significantly in early- to mid-life and then stabilized. Lymphoproliferative responses to mitogens declined over time in both genders. Males demonstrated higher levels of NK cytolytic activity than females; a marginal decline in activity with age was observed. No significant age-related changes in the phagocytic capacity of PMN were observed. These longitudinal findings help to discriminate between those immune parameters which change most dramatically in early-life versus those which either change more dramatically later in life or change gradually over the entire span of life. In addition they identify significant gender differences in several parameters and corroborate our previously published cross-sectional aging data in the same species.

A longitudinal study of the influence of lifetime food restriction on development of osteoarthritis in the canine elbow.

OBJECTIVE To report the effects of age and lifetime calorie restriction on development and progression of osteoarthritis (OA) in elbow joints of Labrador retrievers. STUDY DESIGN Longitudinal cohort study. ANIMALS Labrador retriever dogs (n=48). METHODS Puppies from 7 litters were allotted to 2 groups of 24 dogs each. Diet-restricted (DR) dogs received 25% fewer calories than control-fed (CF) pair mates. Elbow radiographs were taken at 6 and 8 years of age and end of life (EOL). Gross and histopathologic evaluations for OA occurred at EOL. RESULTS There was no statistical difference in radiographic OA frequency between groups at any of the time points. Radiographic OA severity was greater for CF dogs at 6 years only (P<.05). There was no significant difference between feeding groups for histopathologic prevalence or severity of OA. Similarly, there were no differences in gross OA lesions between the groups (P>.05). Fragmented medial coronoid process, un-united anconeal process, and osteochondrosis were not present in any elbow. CONCLUSION No differences in prevalence or severity of radiographic and histopathologic elbow OA were found between feeding groups. Diet restriction resulted in a 1.8-year extension in median lifespan but no additional incremental worsening of elbow disease. Evaluation at time points <6 years may have revealed larger differences in OA prevalence and severity between the dietary groups. CLINICAL RELEVANCE These findings support calorie restriction as a clinical tool to slow progression of elbow OA.

The Effects of Lifetime Food Restriction on the Development of Osteoarthritis in the Canine Shoulder

OBJECTIVE To report effects of age and lifetime food restriction on development and progression of shoulder joint osteoarthritis (OA) in Labrador retriever dogs. STUDY DESIGN Longitudinal life-span, cohort study. ANIMALS Labrador retriever dogs (n=48). METHODS Littermates were paired (gender, weight) to make 24 pairs of genetically similar dogs. Each diet-restricted (DR) pair-mate was fed daily 75% of the same diet consumed by its control-fed (CF) pair-mate for life. Shoulders were evaluated radiographically at years 6, 8, and end of life (EOL). At EOL shoulders were evaluated grossly and by histopathology for OA. RESULTS Radiographic evidence of shoulder OA was identified in 78% of dogs. Severity of radiographic shoulder OA at 6 (P<.03) and 8 years (P<.02) was significantly lower among DR dogs compared with CF dogs. Pooled gross evaluation results revealed 40 of 46 dogs had cartilage erosion on the caudal aspect of the humeral head. By EOL, 91% of dogs had histopathologic changes consistent with OA. CONCLUSION There was a high overall prevalence of radiographic, gross, and histologic OA among dogs. Substantial disparity was found between radiographic evidence of OA (at EOL) and characteristic changes visible by gross and histologic examination. CLINICAL RELEVANCE Radiographic evaluation correlates poorly with severity of shoulder joint pathology. The benefits of DR on shoulder OA are consistent with the demonstrated effect of DR in delaying species- and strain-specific diseases of aging.

Influence of lifetime food restriction on physiological variables in Labrador retriever dogs.

Effects of lifetime food restriction on erythrocytes and numerous clinical chemistry, thyroid, parathyroid, and acid-base variables are reported from a paired-feeding study of 25% diet restriction in dogs. The 48 dogs were paired by gender and weaning weight within litter, and 1 dog in each pair was fed 25% less than its pair mate, from age 8 weeks until death. Erythrocyte and serum biochemistry profiles were evaluated by annual sampling intervals and longitudinally. Erythrocyte variables were slightly higher among control-fed dogs, a possible reflection of the need to support both higher body fat mass and lean mass that uses energy less efficiently. Among serum biochemistry variables, glucose and triglyceride were lower among diet-restricted dogs, while creatinine was slightly higher in the absence of renal disease or failure, over the life spans of the dogs. Glucose outcomes reflect improved glucose tolerance that has been demonstrated with diet restriction protocols in several species, while triglyceride data may reflect the difference in total body fat cells between feeding groups. Creatinine outcomes may reflect lean mass responses to diet restriction or more efficient function of the intracellular proteasome. Serum triiodothyronine levels were lower among diet-restricted dogs. Other clinical chemistry and thyroid variables, parathyroid variables, and acid-base variables were not strongly influenced by diet restriction but revealed age-related effects.