Introduction: A common disorder arising most frequently after a left hemisphere stroke is limb apraxia. Limb apraxia is a deficit of skilled movement, such as performance of activities of daily living (ADLs), that is not a result of primary motor or sensory impairments, or deficits in motivation, memory, or comprehension (De Renzi, 1990). Currently, clinical neuropsychological assessment of apraxia relies largely on qualitative analyses of gross movements during the performance of activities of daily living in two task conditions (pantomime and tool). Further, apraxic patients often perform ADLs with their non-dominant limb to avoid often-present right-hand hemiparesis, but the assessment does not adequately account for this. Thus, it is unclear whether movement deficits are due to non-dominant limb use or limb apraxia. Moreover, it is not known how different task conditions and aging influence the performance of ADLs in healthy populations, as well as manual asymmetries. Purpose: The purpose of this thesis was to: 1. determine if age affects the magnitude of manual asymmetry in the performance of two ADLs (drinking water from a cup and slicing a loaf of bread with a knife); 2. determine if different task demands (pantomime and tool condition) affect magnitude of manual asymmetries during the performance of ADLs; and 3. determine if aging affects how task demands are expressed during the performance of ADLs. Methods: Fifty healthy right-hand dominant (as determined via Waterloo Handedness Questionnaire) younger and older adults participated in this study. A grooved pegboard task was completed by all participants prior to performance of the two ADLs using motion tracking. Upper limb movements (dominant and non-dominant limb) were captured at 60 Hz via a motion capture system (Vicon, Oxford, UK). Participants performed two task conditions: 1) pantomime (pretending to perform an ADL without holding the tool); and 2) tool (pretending to perform an ADL while holding the tool) in two ADLs: drinking water from a cup and slicing a loaf of bread with a knife. Each ADL was performed six times by both limbs. ADLs and limbs were randomized, while task conditions were blocked randomized between participants. Results: Overall, this study found that aging slows down motor performance on the Grooved Pegboard task, as well as the performance of both ADLs. Manual asymmetries were task dependent. The cup and knife ADL were both characterized by larger manual asymmetries in older adults relative to the younger adult group, particularly in terms of angular movement. Further, it was found that task demands were expressed differently in older adults relative to younger adults, with the tool condition yielding performance improvements in both groups. Conclusions: Despite the previous research, which has shown that manual asymmetries are reduced in older adults during the performance of motor tasks, this investigation points to the opposite during the performance of activities of daily living. Aging appears to increase the degree to which manual asymmetries are expressed. Further, aging also appears to play a role in the change in temporal and angular aspects of movement during the performance of ADLs in different task conditions. The degree to which task demands as reflected in the two task conditions improve or impair performance in healthy populations should be taken into consideration when evaluating ADL performance in patients with limb apraxia. In accordance with the previous research on aging, this study has shown that upper limb movements become slower as individuals age. Kinematic relationships presented in this study provide researchers and clinicians with an insight into how manual asymmetries, aging and different task demands come into play during the performance of one cyclical and non-cyclical task.

Most studies that have compared pointing to visible versus remembered targets have involved situations when both the limb and target are present (closed loop-target present), or when both the limb and target are occluded (open loop-target absent). This comparison confounds vision of the target with vision of the hand. In order to dissociate these two sources of visual information in pointing, it is necessary to examine conditions in which only one of these sources of information is occluded, that is, when only vision of the hand (open loop-target present) or vision of the target (closed loop-target absent) is occluded. Some studies have compared subsets of these four conditions to examine, for example, the role of vision of the hand in pointing where the target is present throughout the movement but vision of the hand is occluded (open loop) or not (closed loop). Very few studies to date have compared all of these conditions to examine the relative contribution of these two sources of information in pointing. The purpose of this study was to make these comparisons and to examine whether aging had an effect on how these sources of information were used in pointing. To address this, we asked young (N=10, mean age = 21.8 years, 6 females, 4 males) and older (N=9, mean age = 73.8 years, 4 females, 5 males) right-handed adults to point to each of three targets: one situated at the midline and one each at 45 degrees to the left (contralateral) and right (ipsilateral) of the midline, while manipulating whether participants had vision of their pointing limb, the target, or both. In target-absent trials, the time between target occlusion and movement initiation was also manipulated (movement initiation immediately after occlusion or following a delay of 2 seconds) to examine the time course of the representation of target information in memory. All conditions were randomized between each participant. Results showed vision of the limb significantly affects the movement in a positive manner, such that endpoint error and variability were less than conditions in which the limb was not available during movement. This was true for both target present and absent actions, suggesting limb vision provides crucial visual and proprioceptive information to result in a much more precise and consistent movement to targets. This information may also be more important to the participant than target presence, in terms of accuracy and variability, as there tended to be little differences between target present and target absence trials. Where target presence made a difference was during the decelerative phase of movement time (after peak velocity has been reached), where relatively more time was allotted in this period when the target was visible throughout the movement. Because this time is indicative of online feedback processing, this suggests that vision of the target was contributing some type of information to the movement. Interestingly, there was no significant main effect of age group in this study. However, age did play a role in the way participants moved to the targets. In the directional (x) axis, young adults were more likely to aim to targets that were biased further from their body, whereas elderly adult participants displayed the opposite bias: their accuracy data show they tend to aim closer to their body.

Most studies that have compared pointing to visible versus remembered targets have involved situations when both the limb and target are present (closed loop-target present), or when both the limb and target are occluded (open loop-target absent). This comparison confounds vision of the target with vision of the hand. In order to dissociate these two sources of visual information in pointing, it is necessary to examine conditions in which only one of these sources of information is occluded, that is, when only vision of the hand (open loop-target present) or vision of the target (closed loop-target absent) is occluded. Some studies have compared subsets of these four conditions to examine, for example, the role of vision of the hand in pointing where the target is present throughout the movement but vision of the hand is occluded (open loop) or not (closed loop). Very few studies to date have compared all of these conditions to examine the relative contribution of these two sources of information in pointing. The purpose of this study was to make these comparisons and to examine whether aging had an effect on how these sources of information were used in pointing. To address this, we asked young (N=10, mean age = 21.8 years, 6 females, 4 males) and older (N=9, mean age = 73.8 years, 4 females, 5 males) right-handed adults to point to each of three targets: one situated at the midline and one each at 45 degrees to the left (contralateral) and right (ipsilateral) of the midline, while manipulating whether participants had vision of their pointing limb, the target, or both. In target-absent trials, the time between target occlusion and movement initiation was also manipulated (movement initiation immediately after occlusion or following a delay of 2 seconds) to examine the time course of the representation of target information in memory. All conditions were randomized between each participant. Results showed vision of the limb significantly affects the movement in a positive manner, such that endpoint error and variability were less than conditions in which the limb was not available during movement. This was true for both target present and absent actions, suggesting limb vision provides crucial visual and proprioceptive information to result in a much more precise and consistent movement to targets. This information may also be more important to the participant than target presence, in terms of accuracy and variability, as there tended to be little differences between target present and target absence trials. Where target presence made a difference was during the decelerative phase of movement time (after peak velocity has been reached), where relatively more time was allotted in this period when the target was visible throughout the movement. Because this time is indicative of online feedback processing, this suggests that vision of the target was contributing some type of information to the movement. Interestingly, there was no significant main effect of age group in this study. However, age did play a role in the way participants moved to the targets. In the directional (x) axis, young adults were more likely to aim to targets that were biased further from their body, whereas elderly adult participants displayed the opposite bias: their accuracy data show they tend to aim closer to their body.

This research examines age differences in the use and value of memory compensation strategies for everyday memory tasks. Chapter 1 reviews the literature on memory compensation and aging. According to Selective Optimization with Compensation (SOC) model, older adults may be more likely than younger adults to take advantage of memory compensation strategies when they are available. Chapter 2 describes a diary study in which older and younger participants rated the extent to which they use compensation strategies in everyday life and reported everyday memory errors over the course of a week. Older adults reported fewer memory errors than younger adults and more use of memory aids. However, use of memory aids was unrelated to frequency of memory errors in either age group. Chapter 3 reports a laboratory experiment on the use of memory aids for recalling phone messages. Participants listened to phone messages while simultaneously completing a seating chart, and were asked to report the content of the messages to the experimenter. Participants were either allowed to use a memory aid for the phone message task, or not. Older participants reported using compensation strategies more frequently in everyday life, but they were no more likely than younger participants to search for or employ an aid in the phone message task. Using a memory aid was differentially beneficial, improving performance more for older than younger participants. In Chapter 4, participants completed two phone message recall and two seating plan tasks. Participants were encouraged to use whatever in the room that they might find helpful. On one round of tasks a pen was tied to a clipboard and participants could use it to write down the phone messages. On the other round no pen was available. The order of the trials was counterbalanced across participants. This design examined the calibration between participants’ use of memory aids and their performance on the recall task – whether participants’ performance on the first trial predicted their subsequent use of memory aids, and whether participants who chose to use a memory aid when it was available on the first trial performed particularly poorly on the second trial when no aid was present. As in Study 1, older adults reported using memory aids more frequently in everyday life but age was unassociated with whether or not participants used the pen when one was available. There was little evidence of calibration. Participants’ memory performance on an initial trial had little impact on their use of a memory aid on a subsequent trial. Participants who used a memory aid on the first trial actually recalled more phone message details on the second trial (without the aid) than those who did not. This was true for both age groups. Chapter 5 reflects on older and younger adults self-reported and observed uses of memory compensation strategies. Across all 3 studies older adults reported using external memory aids more frequently in everyday life. However, contrary to the SOC model, in Studies 2 and 3 there were no age differences in older and younger adults’ use of a pen to write down phone messages on the lab task. Nor was participants’ choice to use the memory aid associated with their unaided performance on the task. These results do not support the prediction derived from SOC that older adults use compensation strategies more frequently or more sensitively than younger adults. However, using the memory did improve performance on the task more for older than for younger adults. These results support the hypothesis that external memory aids are a particularly valuable strategy for older adults and suggest the need to better understand why some individuals engage in compensation use and others do not.

Lower body negative pressure (LBNP) is frequently used in the research setting as a means to induce orthostatic stress. This tool is applicable to typical movements during daily living only if the associated responses are comparable to those of actual posture change. The purpose of this project was to investigate the correspondence between these two conditions in a group of elders with mean age of 74 ± 2 years. The primary hypothesis predicted very similar physiologic responses between LBNP and posture change. During LBNP, orthostatic stress was sufficient to reduce stroke volume (SV; p=0.0097), which was related to splanchnic pooling (r=-0.833; p=0.0020). Diastolic cerebral blood flow velocity (CBFV) was directly related to central venous pressure (r=0.683; p=0.0360), strengthening the notion that an important determinant of CBFV during LBNP is incoming pulsatile flow into the cerebral circulation. This is in contrast to what occurred during posture change (p=0.0355), where diastolic CBFV decreased significantly (p=0.0288) and was directly related to diastolic blood pressure (DBP; p=0.0427), highlighting the role of cerebral perfusion pressure (CPP) in maintenance of CBFV particularly during upright posture. In both conditions, DBP was related to cardiac output (Q) and total peripheral resistance (TPR). The relative heart rate (HR) response was higher during posture change than during LBNP (p=0.0397), suggesting that a negative pressure of up to 40 mmHg may not be adequate to elicit the same HR responses as true orthostasis in this elderly population. Contrary to the initial hypothesis, the HR and diastolic CBFV responses were different between the two conditions. Importantly, the results of this study support that in response to both actual orthostasis and simulated orthostasis, elderly persons experienced a drop in CBFV, but for different fundamental reasons, which were directly attributable to distinctions in the effects of gravity during the two postures. Recognizing the mechanistic differences in cerebro- and cardiovascular responses between true and simulated orthostasis is essential, and in this elderly population, there were important differences to consider.

Aging is a universal biological phenomenon in all living cells. Questions regarding how cells age are beginning to be answered. Thus, great biological interest and practical importance leading to interventions rest on uncovering the molecular mechanism of aging. This would ultimately delay the aging process while maintaining the physical and mental strengths of youth. The conservation of metabolic and signaling pathways between yeast and humans is remarkably high, leading to the expectation that aging mechanisms are also common across evolutionary boundaries. By utilizing the budding yeast, <i>Saccharomyces cerevisiae</i>, one of the best characterized model systems for studying aging, the span in knowledge between yeast and human aging can possibly be bridged. <p>Evidence is accumulating that a genetic program exists for lifespan determination. Model organisms expressing mutations in single specific genes live longer with increased resistance to stress and cancer development. Mutations that accelerate aging in yeast affect the activity of the APC (Anaphase-Promoting Complex). Our finding that the APC is critical for longevity provides us with a potential central mechanism controlling lifespan determination. The APC is required for mitotic progression and genomic stability in presumably all eukaryotes by targeting regulatory proteins, such as cyclin B (Clb2p in yeast) for degradation. The key feature defining the APC as a central mediator of lifespan is the fact that multiple signaling pathways regulate APC activity and many of these pathways influence lifespan. For example, Snf1 and PKA have antagonistic effects on the APC and on lifespan. Thus, it is intriguing to speculate that the APC may link these signaling pathways to downstream targets controlling longevity. <p>Our hypothesis states that the APC targets a protein that reduces lifespan for ubiquitin-dependent degradation. The results from our two-hybrid screen utilizing Apc5p as bait are consistent with this hypothesis, as Fob1p was isolated as an Apc5p binding partner. The FOB1 gene is located on chromosome IV and the well-known molecular function of FOB1 is the creation of a unidirectional block in replication of rDNA. Fob1p binds to the rDNA locus and overall stalls progression of the replication fork, which increases rDNA recombination and the production of toxic extrachromosomal rDNA circles (ERCs). The FOB1 deletion (fob1∆) mutant confers reduced rDNA recombination, and an increased lifespan of more than 50% compared to WT (wild type) cells.<p>In this study, we expanded on the molecular mechanisms controlling lifespan through a genetic approach, and found that Fob1p was targeted by the APC for degradation in order to prolong lifespan. By utilizing the yeast two-hybrid approach, we confirmed the Apc5p-Fob1p interaction, and determined that the C-terminal half of Fob1p was required for the interaction with Apc5p. BLAST search analysis revealed sequence similarity with the Fob1p C-terminus that was shared with many other proteins from yeast to humans. We speculate that this shared domain may serve as an APC interaction domain employed across evolutionary boundaries. A genetic interaction analysis revealed the influence of FOB1 on the APC, and the cell. For example, deletion of FOB1 increased lifespan in apc5CA and apc10∆ mutant cells and partially suppressed the temperature sensitive (ts) growth of apc10∆ cells. On the other hand, increased FOB1 expression reduced the lifespan of WT and cells and was toxic to apc mutants, particularly the more severe apc mutants, apc10∆ and cdc16-1. Interestingly, overexpression of SIR2, which prolongs lifespan and acts antagonistically with Fob1p, was toxic to WT cells, but suppressed apc5CA ts defects, especially when FOB1 was deleted. These observations suggest that accumulation of Fob1p is harmful to yeast cells, especially when the APC is compromised. This notion was borne out when a cell cycle and steady state analysis of Fob1p revealed that Fob1p was an unstable protein, which was stabilized in apc5CA cells. Taken together, the work presented in this thesis supports a model whereby Fob1p is targeted for degradation by the APC in order to prolong lifespan in yeast. In conclusion, the extreme evolutionarily conserved nature of the APC and the Fob1p C-terminal sequence homology observed in human proteins strongly suggests that the mechanism discovered here could be directing human lifespan.

Work by Blanchard-Fields has consistently found that older adults are prone to making dispositional inferences in certain contexts (Blanchard-Fields, 1994; 1996; 1999); however mechanisms underlying these tendencies have yet to be explored. The present study assessed the influence that personal belief has on attitude attributions made by both young and older adults. Using the attitude-attribution paradigm, participants made judgments about a targets actual attitude based on an essay that was written by the target. The essay contained a position on a controversial social issue, i.e. prayer in public school, that the target was instructed to advocate. Replicating past research, older adults rated the targets attitude to be more strongly consistent with the content of the essay than young adults did. Personal beliefs did not have a large effect on attitude attributions, however age and belief related differences appeared in both confidence ratings and as a function of attributional complexity. Fluid reasoning was also found to have an impact on attributions.

While living and working in todays high-tech world, the ability to perform tasks and understand the system structure of technology may affect our lives in many ways. For example, calibrating a medical device such as a blood glucose meter may be infrequently performed but adequate knowledge of the system structure may be critical for doing it correctly. This and other forms of technology vary in complexity and require training for proper use. Due to age-related differences in skill acquisition, the design of proper training may be especially important for older adults when learning to use new technology. One factor to consider when developing age-specific training is the type of information presented during training. In general, little research has addressed the effect of information type on the development of an understanding of the system structure and fewer have examined the influence of age. The current study compared the effects of emphasizing actions or concepts during training on performance on multiple measures of learning. Participants completed one of two tutorials for operating a computer-simulated hydroponic garden control. One tutorial presented participants with instructions that focused specific actions to operate the system. The other tutorial displayed instructions that focused on generalized system concepts. At test, overall participants in the concept training condition were faster and more accurate than those in the action training condition for both novel and familiar tasks. Concept training also reduced age-related differences in performance. Results suggest that concept training may lead to the development of a better understanding of the system structure.

Task-switching studies are a popular measure of executive control, yet the influence of stimulus repetition in these studies is less well recognized. One theory from the literature states that stimuli associated with a certain response interfere with processing of those same stimuli in another task, contributing to task switching costs (Waszak, Hommel, &Allport, 2003). The current study varied stimulus repetition in younger and older adults and found that the previous task associated with a stimulus does influence overall performance but did not find the expected interaction of switch and repetition conditions. Results of this study extend our information about the role of stimulus repetition in task-switching studies as well as how this repetition relates to age differences in switch costs.

Aging is characterized by a progressive impairment of cardiac structure and function. The cardiac remodeling involves loss of cardiac myocytes, reactive hypertrophy of the remaining cells, and increased extracellular matrix (ECM) and fibrosis in the aging heart. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. However, the ability of exercise training to modulate ECM and remodeling in the aging heart remains unknown. Therefore, the purpose of this study was to determine the effects of exercise training on ECM remodeling in the aging heart. We hypothesized that (1) exercise training would attenuate age-related changes in left ventricle morphology including extramyocyte space and collagen contents, and (2) exercise training would ameliorate age-induced changes in ECM-related factors including MMPs, TIMPs, TNF-α, TGF-β1, and α-SMA in the heart. Three and 31 month old Fischer 344 × Brown Norway F1 hybrid rats were assigned to four groups: young sedentary (YS), young exercise-trained (YE), old sedentary (OS), and old exercise-trained (OE). Exercise training groups walked briskly on a treadmill for 45 min/day (12° incline) at 20m/min (young) or 10 m/min (old), 5 d/wk for 12 wk. We found that endurance exercise training might ameliorate the ageinduced increase in extramyocyte space and collagen contents of the left ventricle. Exercise training might protect against age-induced fibrosis by increasing MMP-2, MMP-14 in the soluble fraction and MMP-1, MMP-3, MMP-14 in the insoluble fraction of old rat hearts. Conversely, exercise training might reduce the fibrosis by decreasing TIMP-1 in the soluble fraction of old rat hearts. Further, exercise training reduced potential upstream pro-fibrotic mediators including TNF-α and TGF-β1 in the aging rat hearts. These results are the first to demonstrate that exercise training has a protective effect against age-induced extracellular collagen matrix remodeling in the aging heart, associated with increased MMP-1, -2, -3, -14 and decreased TIMP-1, TNF-α, and TGF- β1.