Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques.

Higher systemic levels of the proinflammatory cytokine interleukin-6 (IL-6) were found to be associated with lower gray matter volume and tissue density in old rhesus macaques. This association between IL-6, and these brain indices were attenuated by long-term 30 % calorie restriction (CR). To extend these findings, the current analysis determined if a CR diet in 27 aged rhesus monkeys compared to 17 normally fed controls reduced circulating levels of another proinflammatory cytokine, interleukin-8 (IL-8), and raised levels of anti-inflammatory interleukin-10 (IL-10). Further, these cytokines were regressed onto imaged brain volume and microstructure using voxel-wise regression analyses. CR significantly lowered IL-8 and raised IL-10 levels. Across the two dietary conditions, higher IL-8 predicted smaller gray matter volumes in bilateral hippocampus. Higher IL-10 was associated with more white matter volume in visual areas and tracts. Consuming a CR diet reduced the association between systemic IL-8 and hippocampal volumes. Conversely, CR strengthened associations between IL-10 and microstructural tissue density in the prefrontal cortex and other areas, particularly in a region of dorsal prefrontal cortex, which concurred with our prior findings for IL-6. Consumption of a CR diet lowered proinflammatory and increased anti-inflammatory cytokine concentrations, which lessened the statistical association between systemic inflammation and the age-related alterations in important brain regions, including the hippocampus.

Effects of aging and calorie restriction on white matter in rhesus macaques.

Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage. Oligodendrocytes are particularly susceptible to inflammation and oxidative stress, therefore, we hypothesized that CR would have a beneficial effect on brain white matter and would attenuate age-related decline in this tissue. CR monkeys and controls underwent diffusion tensor imaging (DTI). A beneficial effect of CR indexed by DTI was observed in superior longitudinal fasciculus, fronto-occipital fasciculus, external capsule, and brainstem. Aging effects were observed in several regions, although CR appeared to attenuate age-related alterations in superior longitudinal fasciculus, frontal white matter, external capsule, right parahippocampal white matter, and dorsal occipital bundle. The results, however, were regionally specific and also suggested that CR is not salutary across all white matter. Further evaluation of this unique cohort of elderly primates to mortality will shed light on the ultimate benefits of an adult-onset, moderate CR diet for deferring brain aging.

Age-related changes in neural volume and microstructure associated with interleukin-6 are ameliorated by a calorie-restricted diet in old rhesus monkeys.

Systemic levels of proinflammatory cytokines such as interleukin-6 (IL-6) increase in old age and may contribute to neural atrophy in humans. We investigated IL-6 associations with age in T1-weighted segments and microstructural diffusion indices using MRI in aged rhesus monkeys (Macaca mulatta). Further, we determined if long-term 30% calorie restriction (CR) reduced IL-6 and attenuated its association with lower tissue volume and density. Voxel-based morphometry (VBM) and diffusion-weighted voxelwise analyses were conducted. IL-6 was associated with less global gray and white matter (GM and WM), as well as smaller parietal and temporal GM volumes. Lower fractional anisotropy (FA) was associated with higher IL-6 levels along the corpus callosum and various cortical and subcortical tracts. Higher IL-6 concentrations across subjects were also associated with increased mean diffusivity (MD) throughout many brain regions, particularly in corpus callosum, cingulum, and parietal, frontal, and prefrontal areas. CR monkeys had significantly lower IL-6 and less associated atrophy. An IL-6xCR interaction across modalities also indicated that CR mitigated IL-6 related changes in several brain regions compared to controls. Peripheral IL-6 levels were correlated with atrophy in regions sensitive to aging, and this relationship was decreased by CR.

Quantitative histologic effects on mouse thymus of controlled dietary restriction.

Specific volume fractions (VF) of cellular populations of 6-month-old mouse thymus are altered in animals dietarily restricted since weaning. The VF ratios of cortex:medulla are 2:1 for restricted animals and 1:1 for controls. Thymic cortex of restricted mice exhibits a greater VF of lymphoid cells. Dietary restriction did not alter the VF of medullary lymphoid cells. The VF of non-lymphoid cellular elements tended to decrease throughout the thymus with dietary restriction. No dietary effect on the VF of thymic vascular and connective tissues was observed. VF ratios of cortical lymphoid cells:medullary lymphoid cells show a tendency to increase in restricted mice as does the VF ratio of cortical lymphoid cells:cortical non-lymphoid cells. The VF ratio of thymic medullary lymphoid cells:medullary non-lymphoid cells also increases in restricted mice. VF ratios of cortical non-lymphoid cells:medullary non-lymphoid cells were not altered by diet.

Modification of mitochondrial respiration by aging and dietary restriction.

Effects of aging and of dietary restriction on mitochondrial recovery and respiratory capacities have been assessed in mice. Old mice (23-26 months) did not differ from adult mice (9-12 months) in amounts of protein recovered in mitochondrial fractions of liver, brain and spleen, but did show a decline in specific activity of cytochrome c oxidase (cyt. c ox.) in liver and spleen. Age effects on in vitro respiration by mitochondria occurred in liver and spleen. In liver, only one substrate (beta-hydroxybutyrate) of four tested was respired at a different rate by old than by young mitochondria. Depression of state 3 respiration and 2,4-dinitrophenol (DNP)-uncoupled rates was observed for this substrate; however, this effect depended on expressing respiration on the basis of mitochondrial protein and was less overt if data were expressed per unit of cyt. c ox. activity. Old spleen mitochondria exhibited a grosser defect, showing a 40% decrease in the respiratory control index (RCI) for (succinate + rotenone)- supported respiration (the only substrate tested) due to a possible increase in state 4 rates. Effects of dietary restriction were assessed in liver and brain of 3-7-month-old mice underfed since weaning. Dietary restriction reduced recovery of total liver mitochondrial protein and liver cyt. c ox. specific activity. Liver mitochondria from restricted mice generally showed increased state 3 rates with no differences from controls in state 4 rates for respiration supported by glutamate or pyruvate + malate, resulting in an increased RCI for these substrates. DNP-uncoupled rates were also raised by dietary restriction. Unlike effects observed in old versus young mice, these differences obtained whether the data were expressed on the basis of mitochondrial protein or on cyt. c ox. activity. Electron microscopy of liver mitochondrial preparations revealed more non-mitochondrial contaminants in old mice and larger mitochondria in dietarily restricted mice. These findings are compatible with reports of age-dependent losses of liver mitochondria and suggest that dietary restriction may retard this loss.

Influence of controlled dietary restriction on immunologic function and aging.

The underfeeding regimens tested in rodents for life span prolongation and/or immunologic effects result in a complex blend of protein and energy restriction while offering at least adequate amounts of all other essential nutrients. Underfeeding started at weaning and continued throughout life represents the only proved way of slowing the rate of aging in homeotherms. Mounting evidence indicates that underfeeding initiated later in life may also influence life span favorably. Old mice after lifelong restriction, or moderately aged mice (16.5 months) after 4.5 months of restriction, display "younger" immune systems than do age-matched, normally fed controls, as judged by response to mitogens, the mixed lymphocyte reaction, and other determinants. The immunologic effects of underfeeding, when measured quite early in life, are strain-dependent in the mouse. Diets designed to restrict the intake per week of energy (but not protein) produce the same effects on immune response capacity in very young mice as do energy restricted, protein unbalanced regimens. Underfeeding early in life drastically dampens thymic growth and alters the timing of involution. Early restriction also produces a profound lowering of body temperature in young (C57BL/10Sn x C3H/HeDiSn)F1 females. On the other hand, temperature lowering was not observed in males of this hybrid fed normally for the first year of life and restricted for 3 months prior to measurement. The mechanisms behind these various effects of controlled dietary restriction (i.e., undernutrition without malnutrition) are poorly understood at present.

Age-dependent micronuclear deterioration in Tetrahymena pyriformis, syngen 1.

In the ciliate Tetrahymena pyriformis, syngen 1, senescence is marked both by mitotic and meiotic cytogenetic irregularities of the micronucleus (germinal nucleus) and by an increased frequency of cell death. Full vigor can be restored through the age-dependent process of genomic exclusion, which in prematurely senscent clones C, A III and A V results in the replacement of defective micronuclei but not in the development of new macronuclei (somatic nuclei). After a period of normal behavior, which lasts about 40 fissions in C and 100 fissions in A III and A V, the new micronucleus placed in the same cytoplasm as the old macronucleus again becomes defective and the rejevenated clone again shows signs of senescence. The origin of these defective micronuclei is traced to action of the old macronucleus. It is suggested that the time of course of aging is regulated through the accumulation of unrepaired damage to the micronuclear genetic material.