The Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences

doi: 10.1093/gerona/glu276pmid: N/A

doi: 10.1093/gerona/glu275pmid: N/A

doi: 10.1093/gerona/glu273pmid: N/A

doi: 10.1093/gerona/glu272pmid: N/A

doi: 10.1093/gerona/glu271pmid: N/A

doi: 10.1093/gerona/glu274pmid: N/A

Li, Weiquan; Miller, Richard A.

doi: 10.1093/gerona/glu040pmid: 24691093

Work in yeast has shown that longevity extension induced by nutrient deprivation, altered ribosomal function, or diminished target of rapamycin action requires the activity of GCN4. We hypothesized that increased activity of ATF4, the mammalian equivalent of yeast GCN4, might be characteristic of mutations that extend mouse life span. Fibroblasts from the skin of two such mutants (Snell dwarf and PAPP-A knockout) were found to have higher levels of ATF4 protein and expression of several ATF4 target genes in responses to amino acid withdrawal, cadmium, hydrogen peroxide, and tunicamycin. ATF4 pathways were also elevated in liver of both kinds of long-lived mutant mice. Thus, a connection between ATF4 pathways and longevity may have deep evolutionary roots, and further studies of ATF4 mechanisms may provide insights into the links between cellular stress resistance, protein translation control, and aging.

Ferrando-Martínez, Sara; Ruiz-Mateos, Ezequiel; Dudakov, Jarrod A.; Velardi, Enrico; Grillari, Johannes; Kreil, David P.; Muñoz-Fernandez, Mª Ángeles; van den Brink, Marcel R. M.; Leal, Manuel

doi: 10.1093/gerona/glu030pmid:

Duivenvoorde, Loes P. M.; van Schothorst, Evert M.; Swarts, Hans J. M.; Keijer, Jaap

doi: 10.1093/gerona/glu027pmid: 24615069

Indirect calorimetry (InCa) can potentially be used to noninvasively assess metabolic and age-related flexibility. To assess the use of InCa for this purpose, we tested the sensitivity and response stability over time of three InCa-based treatments in old versus adult mice. Diurnal patterns of respiratory exchange ratio were followed for 24 hours under standard conditions (Treatment 1), but the results were not stable between test periods. As a challenge, fasted mice received glucose to test switch-effectiveness from fat to glucose oxidation (Treatment 2). No differences between groups were observed, although old mice showed higher adiposity and lower white adipose tissue (WAT) mitochondrial density, indicative of age-impaired metabolic health. Lastly, adaptation to a challenge of oxygen restriction (OxR, 14.5% O2) was assessed as a novel approach (Treatment 3). This treatment stably detected significant differences: old mice did not maintain reduced oxygen consumption under OxR during both test periods, whereas adult mice did. Further biochemical and gene expression analyses showed that OxR affected glucose and lactate homeostasis in liver and WAT of adult mice, supporting the observed differences in oxygen consumption. In conclusion, InCa analysis of the response to OxR in mice is a sensitive and reproducible treatment to noninvasively measure age-impaired metabolic health.

Passaro, Angela; Dalla Nora, Edoardo; Morieri, Mario L.; Soavi, Cecilia; Sanz, Juana M.; Zurlo, Amedeo; Fellin, Renato; Zuliani, Giovanni

doi: 10.1093/gerona/glu028pmid: 24621946

The mechanisms linking diabetes and cognitive impairment/dementia, two common conditions of elderly people, are not completely known. Brain-derived neurotrophic factor (BDNF) has antidiabetic properties, and reduced circulating BDNF was associated with dementia. We investigated the relationship between plasma BDNF levels, dementia, and diabetes in a sample of 164 community-dwelling elderly individuals, including 50 participants with vascular dementia, 44 with late onset Alzheimer’s disease, 23 with cerebrovascular disease not dementia, and 47 controls (C). Presence/absence of diabetes was registered; new diagnoses of diabetes were made by the American Diabetes Association criteria. BDNF plasma levels were measured by ELISA. Both diagnosis of dementia and diabetes were associated with lower BDNF plasma values compared with the respective controls; moreover, dementia and diabetes correlated with BDNF plasma levels, independent of possible confounders. A progressive reductions of BDNF plasma levels from C (383.9±204.6 pg/mL), to cerebrovascular disease not dementia (377.1 ± 130.2), to vascular dementia (313.3 ± 114.8), to late onset Alzheimer’s disease (264.7 ± 147.7) was observed, (late onset Alzheimer’s disease vs C, p: .03; late onset Alzheimer’s disease vs cerebrovascular disease not dementia, p: .002). Demented patients affected by diabetes had the lowest BDNF mean levels (264.9 pg/mL) among individuals enrolled in this sample, suggesting the existence of a “synergistic” effect of dementia and diabetes on BDNF levels.