In young healthy adults, characteristic obstacle avoidance reflexes (stumble corrective) were elicited with electrical stimulation during walking that were dependent on the anatomical location of cutaneous afferents stimulated (sole versus dorsum of the foot). We previously demonstrated an age-related erosion of these stumble corrective responses when the perturbation was applied to the dorsum of the foot. However, it is unknown whether similar age-related reflex erosion is present with stimulation to the sole of the foot. The purpose of this study was to identify age-dependent differences in stumbling reactions to electrically evoked stimulation of the tibial nerve at the ankle during walking in healthy young (19-39) and older adult (70 years and older) groups. Electromyograms (EMG) of the tibialis anterior (TA), soleus (SOL), medial gastrocnemius (MG), biceps femoris (BF) and vastus lateralis (VL) were recorded along with gait kinematics including angular displacement and velocity at the ankle and knee joint as well as toe clearance relative to the walking surface. The main finding of this study was the significant erosion of the kinematic and EMG stumbling reactions seen in the older adults compared to the young. Specifically, during mid-swing phase, there was reduced peak toe clearance and significantly smaller amplitudes in ankle dorsiflexion and knee flexion angular displacement as well as absent responses in TA and MG in older adults compared to the young. Further, these degraded responses were superimposed on altered mid-swing phase kinematics during unstimulated walking in the older adults showing reduced toe clearance, knee flexion and increased ankle dorsiflexion compared to the young. This combination of degraded reflexes and altered unstimulated kinematics resulted in significantly reduced toe clearance in the older adults and could suggest that these adults are in the prodromal stage of fall risk. / Graduate / 0566

In yeast, aging appears to be marked by a progressive impairment in cellular mechanisms, resulting in irreversible changes in physiology and morphology. To date, very little has been reported about the biochemical changes that occur in yeast as a function of individual cell aging. To investigate this further, six generations of a brewing yeast strain of Saccharomyces cerevisiae (NCYC 1239) were separated according to cellular age using continuous phased culturing and biotin-streptavidin magnetic cell sorting. / To obtain cells with no bud scars (virgin cells), a concentrated yeast slurry was layered onto sucrose density gradients and centrifuged. The uppermost band from the gradients was collected and cells were biotinylated with biotinamidocaproate- N-hydroxysuccinimide ester, that covalently binds to lysine residues on the yeast cell wall. For continuous phased culturing, biotinylated cells were added to a carbon-limited nutrient medium and growth was synchronized using the doubling time of the cells. Harvested cells were incubated with streptavidin superparamagnetic beads and sorted with a strong permanent magnet. In total, approximately 75% of the biotinylated cells were recovered. Viability testing was conducted using vital staining and plate counts, with >98% viability reported with the vital stain and 37% viability with the agar plates. / In conclusion, continuous phased culture, together with magnetic cell sorting has the potential to become a powerful tool for the study of age-related biochemical changes in yeast. Further studies will focus on ensuring the reproducibility of the method and using the recovered cells to study biochemical changes occurring during yeasts' replicative lifespan.

Purpose: The purpose of this study was to explore the experience of individuals who are aging with a lifelong and/or early-onset physical impairment. Method: A qualitative methodology was utilized consisting of narrative inquiry informed by the Life Course Perspective. The life course perspective is a dynamic approach that encompasses multiple theories including sociology, human development, and aging, highlighting how social, historical, and cultural contexts shape people’s lives. Narratives are storied ways of knowing and communicating that people use to organize events in their lives and make sense out of their experiences. Nine community-dwelling individuals (3 men; 6 women), aged 26-70, with mild to severe Cerebral Palsy were recruited using a combination of purposive and snowball sampling. Multiple (3-4), in-depth interviews were completed with each participant in order to co-construct their life stories. The data analysis was iterative. NVIVO 8 was used to organize the data, supporting a systematic caparison of emerging themes and categories, as well as the central plot that weaves the participants’ experiences together. Findings: “Defying the Odds” emerged as the central narrative that weaved together their experience of growing up and growing older. Their narrative is depicted through the trajectory of the disordered body that manifests itself in peaks and valleys. Their narrative is also weaved together by three central threads: Achieving a Sense of Belonging, Overcoming being Seen but not Heard, and Striving for Self-Reliance. “Normalization” emerged as a key recurring theme in the participants’ life stories. The focus of rehabilitation on "normalizing" movement, particularly walking, during childhood can lead to social psychological challenges as well as problems later in the life course as people encounter increasing fatigue and decreasing functional abilities but no longer have access to rehabilitation services. Implications: Theoretically, the disordered body needs to be reconceptualized in ways that are more positive. Conceptualizing a theory on aging with disability needs to be pursued. Clinically, we need to work towards developing a continuum of care across the life course with a focus on long-term maintenance and prevention of secondary health problems.

To date, research on cognitive aging has treated attention as a unitary resource that operates according to a single mechanism of top-down selection. However, contemporary theoretical models of attention propose that it is a distributed resource, embedded in distinct cortical subsystems, and operates in a manner that reflects the properties of those subsystems. For instance, perceptual attention is thought to originate in posterior sensory subsystems and filter competing unattended input prior to encoding, resulting in early selection of attended information. Executive attention, by contrast, is thought to originate in frontal control subsystems and filter unattended input after encoding, resulting in late selection of attended information. Guided by a distributed resource model, the work described here focuses on how healthy advanced aging influences early selection mechanisms embedded in posterior subsystems, perceptual encoding, and the relationship with frontal subsystems mediating late selection. To examine perceptual attention in isolation, object discrimination tasks were devised in which perceptual competition between repeated objects was manipulated while holding demand on executive control constant. Cortical mechanisms of early selection were probed using functional magnetic resonance imaging (fMRI) indices of neural response and adaptation. Evidence of an age-related impairment in early selection was detected across two fMRI experiments. Unlike young adults, unattended objects not only interfered with perceptual encoding in older adults, but were co-encoded along with the contents of attended input. Age impairments in early selection were also associated with greater reliance on frontally-mediated late selection resources, and, reduced functional connectivity with basal forebrain nuclei. In sum, the results indicate that with increasing age, frontal control subsystems become increasingly encumbered with compensatory redistribution of function from the perceptual cortices, possibly due to loss of central cholinergic integrity. Many well-described age-related deficits of executive attention may therefore represent a consequence of impaired early selection, rather than its cause.

Perceptual objects often comprise of a visual and auditory signature, which arrives simultaneously through distinct sensory channels, and multisensory features are linked by virtue of being attributed to a specific object. The binding of familiar auditory and visual signatures can be referred to as semantic audiovisual (AV) integration because it involves higher level representations of naturalistic multisensory objects. While integration of semantically related multisensory features is behaviorally advantageous, multisensory competition, or situations of sensory dominance of one modality at the expense of another, impairs performance. Multisensory facilitation and competition effects on performance are exacerbated with age. Older adults show a significantly larger performance gain from bimodal presentations compared to unimodal ones. In the present thesis project, magnetoencephalography (MEG) recordings of semantically related bimodal and unimodal stimuli captured the spatiotemporal patterns underlying both multisensory facilitation and competition in young and older adults. We first demonstrate that multisensory processes unfold in multiple stages: first, posterior parietal neurons respond preferentially to bimodal stimuli; secondly, regions in superior temporal and posterior cingulate cortices detect the semantic category of the stimuli; and finally, at later processing stages, orbitofrontal regions process crossmodal conflicts when complex sounds and pictures are semantically incongruent. Older adults, in contrast to young, are more efficient at integrating semantically congruent multisensory information across auditory and visual channels. Moreover, in these multisensory facilitation conditions, increased neural activity in medial fronto-parietal brain regions predicts faster motor performance in response to bimodal stimuli in older compared to younger adults. Finally, by examining the variability of the MEG signal, we also showed that an increase in local entropy with age is also behaviourally adaptive in the older group as it significantly correlates with more stable and more accurate performance in older compared to young adults.

Perceptual objects often comprise of a visual and auditory signature, which arrives simultaneously through distinct sensory channels, and multisensory features are linked by virtue of being attributed to a specific object. The binding of familiar auditory and visual signatures can be referred to as semantic audiovisual (AV) integration because it involves higher level representations of naturalistic multisensory objects. While integration of semantically related multisensory features is behaviorally advantageous, multisensory competition, or situations of sensory dominance of one modality at the expense of another, impairs performance. Multisensory facilitation and competition effects on performance are exacerbated with age. Older adults show a significantly larger performance gain from bimodal presentations compared to unimodal ones. In the present thesis project, magnetoencephalography (MEG) recordings of semantically related bimodal and unimodal stimuli captured the spatiotemporal patterns underlying both multisensory facilitation and competition in young and older adults. We first demonstrate that multisensory processes unfold in multiple stages: first, posterior parietal neurons respond preferentially to bimodal stimuli; secondly, regions in superior temporal and posterior cingulate cortices detect the semantic category of the stimuli; and finally, at later processing stages, orbitofrontal regions process crossmodal conflicts when complex sounds and pictures are semantically incongruent. Older adults, in contrast to young, are more efficient at integrating semantically congruent multisensory information across auditory and visual channels. Moreover, in these multisensory facilitation conditions, increased neural activity in medial fronto-parietal brain regions predicts faster motor performance in response to bimodal stimuli in older compared to younger adults. Finally, by examining the variability of the MEG signal, we also showed that an increase in local entropy with age is also behaviourally adaptive in the older group as it significantly correlates with more stable and more accurate performance in older compared to young adults.

Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed the landscape of aging and disease biology. They have revealed novel molecular markers of aging, disease state, and drug response. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and the underlying biology of aging and disease is heterogeneous and complex. Methods from integrative computational biology can help diminish these challenges by creating new analytical methods and software tools that leverage the large and diverse quantity of publicly available HTP data. In this thesis I report on four projects that develop and apply strategies from integrative computational biology to identify improved biomarkers and therapeutics for aging and disease. In Chapter 2, I proposed a new network analysis method to identify gene expression biomarkers of aging, and applied it to study the pathway-level effects of aging and infer the functions of poorly-characterized longevity genes. In Chapter 4, I adapted gene-level HTP chemogenomic data to study drug response at the systems level; I connected drugs to pathways, phenotypes and networks, and built the NetwoRx web portal to make these data publicly available. And in Chapters 3 and 5, I developed a novel meta-analysis pipeline to identify new drugs that mimic the beneficial gene expression changes seen with calorie restriction (Chapter 3), or that reverse the pathological gene changes associated with lung cancer (Chapter 5). The projects described in this thesis will help provide a systems-level understanding of the causes and consequences of aging and disease, as well as new tools for diagnosis (biomarkers) and treatment (therapeutics).

We examined how explicit instructions to encode visual context information accompanying visually-presented unrelated target words affected later recognition of the targets presented alone, in younger and older adults. In Experiments 1 and 3, neutral context scenes, and in Experiments 2 and 4, emotionally salient context scenes, were paired with target words during encoding. Experiments 1 and 2 data were collected using within subject design; in Experiments 3 and 4 we used a between subjects design. Across all four experiments, instructions to explicitly make a link (associate) between simultaneously presented context and target words always led to significantly better recognition memory in both younger and older adults compared to deep or shallow levels of processing (LoP) instructions for the context information. In all experiments the age-related deficit in overall memory remained. There was no consistent difference in the effect of a shallow versus deep processing of context in the first three experiments in young adults, although a standard LoP effect, with better memory performance following deep than shallow processing, was demonstrated with both age groups in Experiment 4. Results suggest that an instruction to explicitly link target words to context information will significantly and consistently improve memory recognition for targets. This was demonstrated in all four experiments, in both younger and older adults. Importantly, results suggest that memory in older adults can be improved with specific instructional manipulations during encoding.

Thesis (Ph. D.)--University of Washington, 1989. / Vita. Includes bibliographical references (leaves [215]-245).

Thesis PlanB (M.S.)--University of Wisconsin--Stout, 2007. / Includes bibliographical references.