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Martin S.A.,SMPH | Demuth T.M.,SMPH | Miller K.N.,SMPH | Pugh T.D.,SMPH | And 9 more authors.
Aging Cell | Year: 2016

The hippocampus is critical for cognition and memory formation and is vulnerable to age-related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR, implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region- and age-specific differences in nicotinamide adenine dinucleotide (NAD)-derived metabolic cofactors. Age-related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC-1α, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD(P)H. Levels of hippocampal PGC-1α were lower with CR, as were levels of GSK3β, a key regulator of PGC-1α turnover and activity. Regional distribution and colocalization of PGC-1α and GSK3β in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC-1α and GSK3β was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell-type and regional specificity in the metabolic response to age and delayed aging by CR, and suggest that PGC-1α and GSK3β play a role in implementing the neuroprotective program induced by CR. © 2016 The Anatomical Society and John Wiley & Sons Ltd.


Meyer L.A.,University of Wisconsin - Madison | Johnson M.G.,University of Wisconsin - Madison | Johnson M.G.,Grecc William S Middleton Memorial Veterans Hospital | Cullen D.M.,Creighton University | And 7 more authors.
Bone | Year: 2016

Increased bone formation resulting from mechanical loading is well documented; however, the interactions of the mechanotransduction pathways are less well understood. Endothelin-1, a ubiquitous autocrine/paracrine signaling molecule promotes osteogenesis in metastatic disease. In the present study, it was hypothesized that exposure to big endothelin-(big ET1) and/or mechanical loading would promote osteogenesis in ex vivo trabecular bone cores. In a 2 × 2 factorial trial of daily mechanical loading (-2000 με, 120 cycles daily, "jump" waveform) and big ET1 (25 ng/mL), 48 bovine sternal trabecular bone cores were maintained in bioreactor chambers for 23 days. The bone cores' response to the treatment stimuli was assessed with percent change in core apparent elastic modulus (δEapp), static and dynamic histomorphometry, and prostaglandin E2 (PGE2) secretion. Two-way ANOVA with a post hoc Fisher's LSD test found no significant treatment effects on δEapp (= 0.25 and 0.51 for load and big ET1, respectively). The δEapp in the "no load + big ET1" (CE, 13 ± 12.2%, p = 0.56), "load + no big ET1" (LC, 17 ± 3.9%, p = 0.14) and "load + big ET1" (LE, 19 ± 4.2%, p = 0.13) treatment groups were not statistically different than the control group (CC, 3.3% ± 8.6%). Mineralizing surface (MS/BS), mineral apposition (MAR) and bone formation rates (BFR/BS) were significantly greater in LE than CC (= 0.037, 0.0040 and 0.019, respectively). While the histological bone formation markers in LC trended to be greater than CC (= 0.055, 0.11 and 0.074, respectively) there was no difference between CE and CC (= 0.61, 0.50 and 0.72, respectively). Cores in LE and LC had more than 50% greater MS/BS (= 0.037, p = 0.055 respectively) and MAR (= 0.0040, p = 0.11 respectively) than CC. The BFR/BS was more than two times greater in LE (= 0.019) and LC (= 0.074) than CC. The PGE2 levels were elevated at 8 days post-osteotomy in all groups and the treatment groups remained elevated compared to the CC group on days 15, 19 and 23. The data suggest that combined exposure to big ET1 and mechanical loading results in increased osteogenesis as measured in biomechanical, histomorphometric and biochemical responses. © 2016.

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