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The trace elements zinc and manganese are essential for human health, especially due to their enzymatic and protein stabilizing functions. If these elements are ingested in amounts exceeding the requirements, regulatory processes for maintaining their physiological concentrations (homeostasis) can be disturbed. Those homeostatic dysregulations can cause severe health effects including the emergence of neurodegenerative disorders such as Parkinson’s disease (PD). The concentrations of essential trace elements also change during the aging process. However, the relations of cause and consequence between increased manganese and zinc uptake and its influence on the aging process and the emergence of the aging-associated PD are still rarely understood. This doctoral thesis therefore aimed to investigate the influence of a nutritive zinc and/or manganese oversupply on the metal homeostasis during the aging process. For that, the model organism Caenorhabditis elegans (C. elegans) was applied. This nematode suits well as an aging and PD model due to properties such as its short life cycle and its completely sequenced, genetically amenable genome. Different protocols for the propagation of zinc- and/or manganese-supplemented young, middle-aged and aged C. elegans were established. Therefore, wildtypes, as well as genetically modified worm strains modeling inheritable forms of parkinsonism were applied. To identify homeostatic and neurological alterations, the nematodes were investigated with different methods including the analysis of total metal contents via inductively-coupled plasma tandem mass spectrometry, a specific probe-based method for quantifying labile zinc, survival assays, gene expression analysis as well as fluorescence microscopy for the identification and quantification of dopaminergic neurodegeneration.. During aging, the levels of iron, as well as zinc and manganese increased.. Furthermore, the simultaneous oversupply with zinc and manganese increased the total zinc and manganese contents to a higher extend than the single metal supplementation. In this relation the C. elegans metallothionein 1 (MTL-1) was identified as an important regulator of metal homeostasis. The total zinc content and the concentration of labile zinc were age-dependently, but differently regulated. This elucidates the importance of distinguishing these parameters as two independent biomarkers for the zinc status. Not the metal oversupply, but aging increased the levels of dopaminergic neurodegeneration. Additionally, nearly all these results yielded differences in the aging-dependent regulation of trace element homeostasis between wildtypes and PD models. This confirms that an increased zinc and manganese intake can influence the aging process as well as parkinsonism by altering homeostasis although the underlying mechanisms need to be clarified in further studies.
Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.
Aging in speech production is a multidimensional process. Biological, cognitive, social, and communicative factors can change over time, stay relatively stable, or may even compensate for each other. In this longitudinal work, we focus on stability and change at the laryngeal and supralaryngeal levels in the discourse particle euh produced by 10 older French-speaking females at two times, 10 years apart. Recognizing the multiple discourse roles of euh, we divided out occurrences according to utterance position. We quantified the frequency of euh, and evaluated acoustic changes in formants, fundamental frequency, and voice quality across time and utterance position. Results showed that euh frequency was stable with age. The only acoustic measure that revealed an age effect was harmonics-to-noise ratio, showing less noise at older ages. Other measures mostly varied with utterance position, sometimes in interaction with age. Some voice quality changes could reflect laryngeal adjustments that provide for airflow conservation utterance-finally. The data suggest that aging effects may be evident in some prosodic positions (e.g., utterance-final position), but not others (utterance-initial position). Thus, it is essential to consider the interactions among these factors in future work and not assume that vocal aging is evident throughout the signal.
Life and death of stationary linear response in anomalous continuous time random walk dynamics
(2014)
Linear theory of stationary response in systems at thermal equilibrium requires to find equilibrium correlation function of unperturbed responding system. Studies of the response of the systems exhibiting anomalously slow dynamics are often based on the continuous time random walk description (CTRW) with divergent mean waiting times. The bulk of the literature on anomalous response contains linear response functions like one by Cole-Cole calculated from such a CTRW theory and applied to systems at thermal equilibrium. Here we show within a fairly simple and general model that for the systems with divergent mean waiting times the stationary response at thermal equilibrium is absent, in accordance with some recent studies. The absence of such stationary response (or dying to zero non-stationary response in aging experiments) would confirm CTRW with divergent mean waiting times as underlying physical relaxation mechanism, but reject it otherwise. We show that the absence of stationary response is closely related to the breaking of ergodicity of the corresponding dynamical variable. As an important new result, we derive a generalized Cole-Cole response within ergodic CTRW dynamics with finite waiting time. Moreover, we provide a physically reasonable explanation of the origin and wide presence of 1/f noise in condensed matter for ergodic dynamics close to normal, rather than strongly deviating.
Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis.
Working memory load-dependent brain response predicts behavioral training gains in older adults
(2014)
In the domain of working memory (WM), a sigmoid-shaped relationship between WM load and brain activation patterns has been demonstrated in younger adults. It has been suggested that age-related alterations of this pattern are associated with changes in neural efficiency and capacity. At the same time, WM training studies have shown that some older adults are able to increase their WM performance through training. In this study, functional magnetic resonance imaging during an n-back WM task at different WM load levels was applied to compare blood oxygen level-dependent (BOLD) responses between younger and older participants and to predict gains in WM performance after a subsequent 12-session WM training procedure in older adults. We show that increased neural efficiency and capacity, as reflected by more "youth-like" brain response patterns in regions of interest of the frontoparietal WM network, were associated with better behavioral training outcome beyond the effects of age, sex, education, gray matter volume, and baseline WM performance. Furthermore, at low difficulty levels, decreases in BOLD response were found after WM training. Results indicate that both neural efficiency (i. e., decreased activation at comparable performance levels) and capacity (i. e., increasing activation with increasing WM load) of a WM-related network predict plasticity of the WM system, whereas WM training may specifically increase neural efficiency in older adults.
Working memory (WM) performance declines with age. However, several studies have shown that WM training may lead to performance increases not only in the trained task, but also in untrained cognitive transfer tasks. It has been suggested that transfer effects occur if training task and transfer task share specific processing components that are supposedly processed in the same brain areas. In the current study, we investigated whether single-task WM training and training-related alterations in neural activity might support performance in a dual-task setting, thus assessing transfer effects to higher-order control processes in the context of dual-task coordination. A sample of older adults (age 60–72) was assigned to either a training or control group. The training group participated in 12 sessions of an adaptive n-back training. At pre and post-measurement, a multimodal dual-task was performed in all participants to assess transfer effects. This task consisted of two simultaneous delayed match to sample WM tasks using two different stimulus modalities (visual and auditory) that were performed either in isolation (single-task) or in conjunction (dual-task). A subgroup also participated in functional magnetic resonance imaging (fMRI) during the performance of the n-back task before and after training. While no transfer to single-task performance was found, dual-task costs in both the visual modality (p < 0.05) and the auditory modality (p < 0.05) decreased at post-measurement in the training but not in the control group. In the fMRI subgroup of the training participants, neural activity changes in left dorsolateral prefrontal cortex (DLPFC) during one-back predicted post-training auditory dual-task costs, while neural activity changes in right DLPFC during three-back predicted visual dual-task costs. Results might indicate an improvement in central executive processing that could facilitate both WM and dual-task coordination.
Older adults with amnestic mild cognitive impairment (aMCI) who in addition to their memory deficits also suffer from frontal-executive dysfunctions have a higher risk of developing dementia later in their lives than older adults with aMCI without executive deficits and older adults with non-amnestic MCI (naMCI). Handgrip strength (HGS) is also correlated with the risk of cognitive decline in the elderly. Hence, the current study aimed to investigate the associations between HGS and executive functioning in individuals with aMCI, naMCI and healthy controls. Older, right-handed adults with amnestic MCI (aMCI), non-amnestic MCI (naMCI), and healthy controls (HC) conducted a handgrip strength measurement via a handheld dynamometer. Executive functions were assessed with the Trail Making Test (TMT A&B). Normalized handgrip strength (nHGS, normalized to Body Mass Index (BMI)) was calculated and its associations with executive functions (operationalized through z-scores of TMT B/A ratio) were investigated through partial correlation analyses (i.e., accounting for age, sex, and severity of depressive symptoms). A positive and low-to-moderate correlation between right nHGS (rp (22) = 0.364; p = 0.063) and left nHGS (rp (22) = 0.420; p = 0.037) and executive functioning in older adults with aMCI but not in naMCI or HC was observed. Our results suggest that higher levels of nHGS are linked to better executive functioning in aMCI but not naMCI and HC. This relationship is perhaps driven by alterations in the integrity of the hippocampal-prefrontal network occurring in older adults with aMCI. Further research is needed to provide empirical evidence for this assumption.
Repetitive, monotonic, and effortful voluntary muscle contractions performed for just a few weeks, i.e., resistance training, can substantially increase maximal voluntary force in the practiced task and can also increase gross motor performance. The increase in motor performance is often accompanied by neuroplastic adaptations in the central nervous system. While historical data assigned functional relevance to such adaptations induced by resistance training, this claim has not yet been systematically and critically examined in the context of motor performance across the lifespan in health and disease. A review of muscle activation, brain and peripheral nerve stimulation, and imaging data revealed that increases in motor performance and neuroplasticity tend to be uncoupled, making a mechanistic link between neuroplasticity and motor performance inconclusive. We recommend new approaches, including causal mediation analytical and hypothesis-driven models to substantiate the functional relevance of resistance training-induced neuroplasticity in the improvements of gross motor function across the lifespan in health and disease.
Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice.