Browsing by Subject "Aging"

Background

Methods

Results

Conclusion

Abstract

In the face of declines in memory related to specific events, people maintain intact general knowledge into very old age. Older adults often use this knowledge to support their remembering. Semantic illusions involve situations in which presented information contradicts correct knowledge; the illusion occurs when people fail to notice a contradiction with what they know. Compared to younger adults, older adults' later memories are surprisingly less affected by semantic illusions. That is, they use fewer errors seen in the semantic illusions as answers when later asked related general knowledge questions. Why do older adults show this reduced suggestibility, and what role does their intact knowledge play? In 5 experiments, I explored these questions. Older adults' reduced suggestibility was not due to an age difference in error detection: older adults were no better than younger adults at detecting the errors that contradicted their stored knowledge. In addition, episodic memory failures were not a major factor either; the evidence for their direct involvement was mixed. Instead, prior knowledge seems to have been particularly protective for older adults. They demonstrated more knowledge to begin with but also gained access to even more of their stored knowledge across the duration of experiments, leading them to be less suggestible following semantic illusions. There was also an indication that when knowledge was stably accessible, older adults had a tendency to rely on it more than did younger adults. Broadly, these findings indicate that older adults' intact prior knowledge provides important benefits to their remembering and can even protect them against acquiring erroneous information about the world.

Advanced age is associated with substantial changes in the brain. These changes can be attributed to many difference sources, such as detrimental effects of aging, brain’s compensatory responses to such negative effects, and cognitive or neural resources acquired over lifespan. As a result, under the same cognitive task, healthy older adults (OAs) often show recruitment of brain regions that are different from healthy young adults (YAs). These observations have been drawn from functional magnetic resonance imaging (fMRI) studies on aging and cognition, which have been largely based on univariate analysis that relates experimental conditions to activity level in individual brain region. While univariate analysis reveals the age differences in the recruitment of brain regions, much remains unknown regarding how these regions are playing their roles. Meanwhile, recent methodological advances in cognitive neuroscience have provided the opportunities to examine 1) functional communications across brain regions, and 2) information stored in the distributed neural representation in a region. In this dissertation, I described age-related differences in these two novel perspectives in a series of fMRI studies on episodic memory, a domain of cognition that is particularly affected by aging. In these studies, healthy YAs and OAs encoded and later retrieved images of scenes or objects inside the scanner. Analyses on functional brain network and neural representations were conducted on the neuroimaging data. These analyses revealed three main findings. First, neural representation and functional connectivity revealed reduced involvements of the core task regions in OAs. During encoding, early visual cortex (EVC) in OAs exhibited reduced representation of visual information. During retrieval, medial temporal lobe (MTL) in OAs exhibited reduced reconfiguration of functional connectivity associated with successful remembering. Second, enhanced recruitments of additional neural resources in OAs were also observed. During encoding, anterior temporal lobe (ATL) in OAs exhibited enhanced semantic representation. During retrieval, prefrontal cortex (PFC) in OAs showed enhanced functional connectivity and stronger reconfiguration of connectivity associated with successful remembering. Finally, we found that schematic knowledge affected functional communication in PFC and semantic representation in ATL differently in the two age groups, suggesting that schema-related strategies may be preferentially selected by OAs. Taken together, these studies depicted the detrimental effect of aging and brain’s adaptive changes in two novel perspectives: functional communication and information processing, which may contribute to a more comprehensive understanding of episodic memory function in aging populations.

As human skin ages, its ability to both repair wounds and protect them from infection declines. Several factors play major roles in this, including thinning of epidermis and loss of collagen leading to skin fragility, as well as the decline of innate immune function, though the latter has been less distinctly linked to skin aging. Given the rising aging population globally, understanding how the skin responds to injury across the life spectrum is increasingly important. This work attempts to understand specifically how innate antiviral immunity of the skin is downregulated in age. To do so, we leveraged a discovery where we determined that aging skin has a differential circadian clock, a known immunological regulator, compared to that of younger skin. The circadian rhythm is a biological clock that uses a transcriptional-translational feedback loop to set up patterns of activity throughout the body. This loop uses positive transcription factors BMAL1 and CLOCK, which set up their own repressors, including the PER and CRY family of proteins. This rhythm also influences biological functions throughout the body. In the scope of this work, we became interested in the fact that circadian rhythms were found to influence epithelial repair in injury, antiviral immunity and interferon stimulated genes. To begin our study, we asked whether the known repair and immune dysfunctions of aging skin could be possibly tied to a dysfunctional circadian rhythm. Using qRT-PCR, we found that aging murine skin has a decreased circadian transcription when compared to that of younger skin. Such a phenotype was replicated by human keratinocyte studies using serial passaging as an aging surrogate. Having determined that aging does indeed play a role in regulating cutaneous circadian rhythms, we set out to determine what immune mechanisms of the skin are regulated by this aging-circadian axis. Specifically, we tested circadian regulation of antiviral proteins. Antiviral proteins of distinct families and functions all protect the skin from pathogen invasion. Prior work by our lab had shown that antiviral proteins were induced by skin wounding in a pathway dependent on the cytokine IL-27. Using approaches including qRT-PCR, flow cytometry, and immunofluorescence, we determined that aging skin wounds not only have an attenuated antiviral protein response, but also contained reduced numbers of CD301b+ immune cells that produce IL-27. These distinct immune deficiencies lead to an unprotected skin wound microenvironment in aging skin. However, little is understood about the molecular mechanisms responsible for the antiviral immune deficiencies in the aging skin. To address this, we began by probing publicly available datasets, where we found that the expression of antiviral proteins had 24-hour rhythms of expression in murine skin. Similarly, we found that that rhythmic expression of antiviral proteins occurs in human keratinocytes that were synchronized in a circadian fashion. Additional support for a direct line of circadian regulation of antiviral proteins came from circadian siRNA studies, where we knocked down expression of circadian gene CLOCK and saw an associated downregulation in antiviral proteins within human keratinocytes. Further, we demonstrate via qRT-PCR that murine skin harvested at different time points have different antiviral protein mRNA levels. Subsequent computational analysis showed that Bmal1-/- murine skin is deficient in antiviral protein expression, establishing a direct link between circadian factors and antiviral proteins. In order to better understand the effect of circadian rhythms on wound immune responses, we made use of a number of experimental models, including both Bmal1-/- and ClockΔ19 mutant mice, as well as wild type animals. We wounded wild type animals at distinct time-of-day, and found that the level of antiviral proteins display time-of-day responses, peaking at 8pm. Using circadian mutant mice, we found that these animals have attenuated wound responses with respect to antiviral protein induction; specifically, wounded ClockΔ19 mice do not produce antiviral proteins to the same extent as wild type mice. We were able to tie this directly to IL-27 signaling in two distinct manners. Firstly, using flow cytometry, we found that the CD301b+ cells that produce IL-27 in response to wounding are reduced in number in circadian mutant mouse skin, and moreover, produce less IL-27 as measured by median fluorescence intensity. To determine the role of IL-27 in the time-of-day response of wound-induced antiviral protein expression, we wounded IL-27fl/fl-LysM-Cre mice at two distinct times-of-day and measured antiviral protein production. These mice lack IL-27 production from myeloid cell lineages, including CD301b+ cells. We found that loss of IL-27 diminished time-of-day differential expression of antiviral proteins in wounds, further suggesting that the link between circadian rhythms and antiviral proteins was in fact in part mediated by IL-27. To further our understanding of the cytokine milieu of circadian wounds, we also wounded mice that lacked Type I interferon receptor (IFNAR1) expression and found that loss of Type I interferon signaling also blunted time-of-day antiviral protein responses. These data support a role of both interferons and IL-27 in circadian antiviral protein induction. In order to provide a functional aspect to these findings, we infected wildtype and circadian disrupted keratinocytes and human skin with Herpes Simplex Virus Type I (HSV1). We measured HSV expression in the skin by both immunofluorescence and visual characterization as well by qPCR for viral component UL29. We found that circadian disruption of either BMAL1 or CLOCK sensitizes keratinocytes to HSV1 infection in vitro. On the other side of this spectrum, we questioned whether circadian enhancing drugs, including the compounds SR8278 and nobiletin, can activate circadian rhythms in skin cells and improve skin defense against HSV1 infection. Using a BMAL1:Luciferase reporter, we characterized both drugs as having a circadian augmenting effect in keratinocytes. Upon infection with HSV1, both SR8278 and nobiletin protected human skin from viral spread. Further, we found that SR8278’s antiviral effect was predicated on circadian activity, as BMAL1 and CLOCK siRNA knockdown in keratinocytes lessened the drugs effect. To determine mechanism of circadian drug’s antiviral activity, we tested whether our circadian drugs activate canonical antiviral signaling pathways, such as OAS and IFITM. We found that via qPCR, circadian drugs require the presence of these proteins to fight virus effectively. As a study of clinical relevance, we evaluated the role of acyclovir treatments alongside our circadian drugs. We found that circadian drugs SR8278 and nobiletin did not synergize their effects with acyclovir at a variety of doses tested. We found that acyclovir, as expected, broadly suppressed HSV1 activity at even low doses in keratinocytes, an effect that circadian augmentation was unable to potentiate. This could be due to a number of factors, including dosage optimization and viral susceptibility to drug. However, given the rise of acyclovir resistant HSV, our novel approach may be clinically viable. In particular, we believe this may be a viable treatment platform for aging skin infections; to this end, we tested the ability of SR8278 to suppress HSV1 infection in the skin of mice over a year of age. SR8278 significantly reduced viral spread in this model, suggesting that circadian augmentation may be a useful clinical adjunct in aging skin infections. To determine if these findings were applicable to other non-herpes family viruses that infect the skin, we turned to a model of West Nile Virus infection. West Nile Virus is a mosquito borne illness with increasing range and infection number in the United States. Moreover, it is inoculated through the skin before causing neurological infection, a pathway similar to herpes viruses. Also similar to herpes viruses, West Nile virus is a far more pressing clinical issue in aging populations, who fare worse with this viral infection. Most importantly, there are no currently specific treatments for West Nile Virus infections. Using our HSV infection data as a starting point, we found that circadian drug treatments suppressed West Nile Virus levels in infected keratinocytes. Other work conducted over the course of this PhD encompassed aspects of both circadian and IL-27 signaling in the skin. Using human keratinocytes, we endeavored to understand what environmental factors could drive altered circadian rhythms in the skin, for either elderly or younger tissue. While dogmatically, circadian rhythms are patterned from the brain to the whole body, we built on recent work showing a light dependent murine cutaneous clock by showing that mock sunlight can alter circadian expression in human keratinocytes, without other stimuli present. Further study is needed to understand how our skin’s clock responds to sun mechanistically. Overall, my work over the course of this PhD has established a link between aging, circadian rhythms, and antiviral immunity, and underpinned the important role of the cytokine IL-27 and type I interferon on cutaneous wound responses to a variety of pathogens. This work will provide possible therapeutic avenues, particularly for aging skin, in how to address skin wound care in safe, biologically relevant ways via circadian rhythm exploitation.

Developing nations in Asia are posed to experience a significant increase in the population of older adults living in their respective societies. Over the coming decades, India, the second most populous country in the entire world, is poised to experience a significant increase in its elder population. India's population of adults 60 years of age or older is projected to increase from 8% to 19% of the countries total population by the year 2050. Figures predict that by mid-century, 323 million people in India will be aged 60 years or older, more than the total current U.S. population. As the demographic structure of India is making a dramatic shift, concerns regarding the health and wellbeing of the growing Indian elder population are emerging, as is the growing concern for social policy. In addition, Sri Lanka is the fastest aging nation in South Asia. Multiple factors, including an increase in the number of people considered to be the "oldest old" (80+ years of age), a decrease in the number of working age adults, and increases in disability amongst the elderly, could necessitate an increased need for institutionalization of elderly Sri Lankans into long-term care facilities.

This project aims to study aging in south Asia from two different perspectives. An analysis of existing data from Southern India was done to examine the attitudes and beliefs of Indian elders towards aging and support systems for the elderly. Mental health of Indian elders was assessed and logistic regression analysis was conducted to examine possible correlations between attitudes and beliefs of the elderly and elder mental health. In addition, a qualitative descriptive study of Sri Lankan elder homes was carried out in the southern district of Galle, Sri Lanka. A convenience sampling method was used to identify six elder homes located in the area, and visits were made to each of the homes. During the visits, elder home mangers were interviewed in order to gain general information on the functioning and history of the elder homes, as well as general information on the residents living at the facilities.

Results from the Kerala Aging Survey revealed that psychological distress was present for over one third of elders in Kerala. Rates of psychological distress were higher for women, the poor, and those with advanced age. Elder women appear to be especially vulnerable to psychological distress in old age. Elders believe that children are responsible for supporting parents in their old age; lack of satisfaction with support received from children was associated with the presence of psychological distress amongst elders. For the qualitative study on Sri Lankan elders homes, it was found that both familial and community support are significant factors in the long-term care of elderly Sri Lankans. Though many elder home residents had been diagnosed with a chronic NCD or disability, lack of familial support was consistently identified as the driving force necessitating the elderly to reside at the long-term care facilities. With little or no financial assistance from the government, the facilities themselves all relied heavily on donations from the community to function on a daily basis.