A suboptimal maternal diet combined with accelerated postnatal growth results in an altered aging profile in the thymus of male rats

Abstract

Reduced fetal nutrition and rapid postnatal growth accelerates the aging phenotype in many organ systems; however, effects on the immune system are unclear. We addressed this by studying the thymus from a rat model of developmental programming. The recuperated group was generated by in utero protein restriction, followed by cross-fostering to control-fed mothers, and were then compared with controls. Fat infiltration and adipocyte size increased with age ( P < 0.001) and in recuperated thymi ( P < 0.05). Cortex/medulla ratio decreased with age ( P < 0.001) and decreased ( P < 0.05) in 12-mo recuperated thymi. Age-associated decreases in thymic-epithelial cell ( P < 0.01) and thymocyte markers ( P < 0.01) were observed in both groups and was decreased ( P < 0.05) in recuperated thymi. These data demonstrate effects of developmental programming upon thymic involution. The recuperated group had longer thymic telomeres than controls ( P < 0.001) at 22 d and at 3 mo, which was associated with increased expression of telomere-length maintenance molecules [telomerase RNA component ( Terc; P < 0.01), P23 ( P = 0.02), and Ku70 and Ku80 ( P < 0.01)]. By 12 mo, recuperated offspring had shorter thymic telomeres than controls had ( P < 0.001) and reduced DNA damage-response markers [( DNA-PKcs, Mre11 ( P < 0.01), Xrcc4 ( P = 0.02), and γ-H2ax ( P < 0.001], suggesting failure of earlier compensatory responses. Our results suggest that low birth weight with rapid postnatal growth results in premature thymic maturation, resulting in accelerated thymic aging. This could lead to increased age-associated vulnerability to infection.-Tarry-Adkins, J. L., Aiken, C. E., Ashmore, T. J., Fernandez-Twinn, D. S., Chen, J.-H., Ozanne, S. E. A suboptimal maternal diet combined with accelerated postnatal growth results in an altered aging profile in the thymus of male rats.

Keywords: developmental programming; immunosenescence; involution.

Figure 1

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon total thymus area (A), thymic cortex to medulla area ratio (B), cortex to total thymus area ratio (C), 3-mo control (D) (representative image), 3-mo recuperated (E) (representative image), 12-mo control (F) (representative image), and 12-mo recuperated (G) (representative image). Results are expressed as means ± sem; n = 8/group. C, control; R, recuperated. *P < 0.05, ***P < 0.001.

Figure 2

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon fibrosis in the thymus of 3- and 12-mo-old, male rats. Fibrosis/thymus area (A), 3-mo control (B) (representative image), 3-mo recuperated (C) (representative image), 12-mo control (D) (representative image), and 12-mo recuperated (E) (representative image) results are shown. Results are expressed as means ± sem; n = 8/group. C, control; R, recuperated . ***P < 0.001.

Figure 3

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the expression of markers of fat accumulation in the thymus of 3- and 12-mo-old, male rats. Total adipose area (A), average adipocyte count (B), average adipocyte area (C), and Lep (D) and Glut4 (E) mRNA expression are shown. Results are expressed as means ± sem. C, control; R, recuperated; n = 8/group. For gene expression data, overall effect of maternal diet (P mat diet) <0.06, and overall effect of age (P age) <0.01. *P < 0.05, ***P < 0.001 for histologic data.

Figure 4

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the expression of TEC and thymocyte markers in 3- and 12 mo-old male rats. A) Geometric mean of markers of TEC lineage. B) Geometric mean of markers of thymocyte lineage. C) Ratio of TEC to thymocyte markers. Results are expressed as means ± sem; n = 8/group. C, control; R, recuperated. Interaction between maternal diet and age (P int) <0.05. Overall effect of maternal diet <0.01. Overall effect of age <0.01. TEC/thymocyte ratio is expressed as a geometric mean.

Figure 5

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the thymic telomere length in 22-d, 3-mo, and 12-mo male rats. 145-48.5kb (A), 48.5-8.6kb (B), 8.6-4.2kb (C), and 4.2-1.3kb (D). Results are expressed as median ± interquartile range and total range, excluding outliers. C, control; R, recuperated; n = 8/group.

Figure 6

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the expression of telomerase complex molecules in the thymus of 3- and 12-mo-old male rats. Tert1 (A), Terc (B), Hsp90 (C), and P23 (D). Results are expressed as means ± sem; n = 8/group. C, control; R, recuperated. P adj-int <0.01; P mat diet <0.03 and 0.01; P age <0.01 and 0.05.

Figure 7

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the expression of shelterin complex proteins in the thymus of 3- and 12-mo-old male rats. Trf1 (A), Trf2 (B), Tin2 (C), Pot1 (D), Ku70 (E), and Ku80 (F). Results are expressed as means ± sem. C, control; R, recuperated; n = 8/group. P int <0.01, 0.02, and 0.05. P mat <0.01; P age <0.01.

Figure 8

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the expression of markers of DNA damage repair in the thymus of 3- and 12-mo-old male rats. DNA-PKcs (A), Mre11 (B), Xrcc4 (C), and γH2ax (D). Results are expressed as means ± sem; n = 8/group. C, control; R, recuperated. Padj-int < 0.01 and 0.03. P mat diet <0.01, 0.01, and 0.02; P age <0.01.

Figure 9

Correlations of thymic telomere length analysis vs. gene expression of γH2ax in 3- and 12-mo-old male rats. A) γH2ax vs. 145–48.5 kb. B) γH2ax vs. 48.5–8.6 kb. C) γH2ax vs. 8.6–4.2 kb. D) γH2ax vs. 4.2–1.3 kb. Results are expressed as means ± sem; n = 8/group. C, control; R, recuperated.

Figure 10

The effect of in utero protein restriction, accelerated postnatal growth, and aging upon the expression of sources of nonmitochondrial ROS and antioxidant-defense capacity in the thymus of 3- and 12-mo-old male rats. Xo (A), MnSOD (B), CuZnSOD (C), ECSOD (D), Catalase (E). Results are expressed as means ± sem; n = 8.group. C, control; R, recuperated. P int <0.01; P age <0.01.