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Investigating the cellular processes anti-ageing compounds interact with can identify genes and pathways involved in ageing. The macrolide lactone FK506 was identified in a phenotypic screen as extending lifespan in yeast and C. elegans through an unknown mechanism. FK506 also ameliorates neurodegeneration and age-related weight gain in rodents. Here, the mechanism of action of FK506 has been investigated in two experimental systems: C. elegans and 3T3-L1 mouse adipocytes. As the general mechanisms of ageing are well conserved between C. elegans and mammals, C. elegans has been used to understand how FK506 acts at an organismal level. Firstly, the result of the phenotypic screen was confirmed. FK506 treatment induced lifespan extension in C. elegans in the presence of population crowding stress, but not in the absence of crowding. FK506 treatment inhibited neither E. coli OP50 growth nor C. elegans pharyngeal pumping, demonstrating that FK506 did not induce dietary restriction to extend lifespan. FK506 treatment increased C. elegans thrashing and pharynx pumping rates in early adulthood and delayed accumulation of gut bacteria, showing that FK506 extended healthspan. A transcriptome analysis of FK506-treated C. elegans allowed the identification of transcripts whose levels change and potential pathways by which FK506 manifests its effect. To explore this and to identify potential targets of FK506, the cellular functions required for FK506 to extend C. elegans lifespan and healthspan were investigated using RNA-seq, RNAi, genetic mutation and co-treatment with small molecule inhibitors and inducers. Interestingly, FK506 was found to have different mechanisms of action on lifespan and healthspan. The mechanism of FK506 on C. elegans thrashing rate was DAF-16 dependent, did not require population crowding stress, had a partial interaction with FUdR and autophagy, and may involve Ca²⁺ flux. The mechanism of FK506-induced C. elegans lifespan extension overlapped with dietary restriction and was dependent on calcineurin, TOR-independent regulation of autophagy and the presence of population crowding stress. FK506 may modulate body weight by influencing metabolism and/or acting on adipocytes directly. FK506-treated aged 3T3-L1 adipocytes accumulated significantly less lipid, indicating that FK506 acts directly on adipocytes. RNA-seq of FK506-treated adipocytes found that translation-associated RNAs were upregulated whilst RNAs associated with lipid metabolism were downregulated. An ER-localised FK506-binding protein was up regulated in both C. elegans and 3T3-L1 adipocytes, fkb-4 and Fkbp2 respectively. In conclusion, FK506 has been confirmed as a potential anti-ageing treatment, through its ability to extend lifespan and healthspan in C. C. elegans. In addition, FK506 has also been shown to act directly on mouse adipocytes, resulting in a reduction in lipid accumulation. This action could explain how FK506 caused weight loss in obese aged rats, restoring body mass to a healthy adult weight.

The functional integrity of the proteome is essential for proper cell functioning. Protein homeostasis, or proteostasis, is maintained by a network of pathways that mediate the biosynthesis, folding and degradation of proteins. Accumulating evidence suggest that ageing is associated with a general decline in protein homeostasis. Proteins are synthesised in the cytosol as extended polypeptide chains, which must then be folded in to their native conformation, before moving to their site of function. Protein folding occurs in different subcellular compartments, such as the cytosol and the endoplasmic reticulum (ER). Due to the nature of the proteins that are processed in the ER (e.g. ionic channels, receptors, hormones, signalling molecules), the function of this compartment can be seen to be of vital importance to the cells. However, the effect of age on ER protein homeostasis is virtually unknown. A combination of post-mortem mouse tissues and cell-based models were used to examine the impact of age on ER protein folding, quality control and the ER stress response. Analysis of the expression level of ER-resident and ER-linked proteins showed a number of age-related changes in mouse tissues, in human fibroblasts aged in vitro by serial passage, and human fibroblasts obtained from young and old donors (in vivo aged cells). Overall, the pattern of changes was variable between different tissues and cell systems. However, a common feature of aged tissues and both cellular models of ageing, was a significant increase in phosphorylation of eIF2alpha, indicating that ER protein homeostasis is affected with age. In addition, ageing in several tissues and in both cellular systems was associated with accumulation of polyubiquitinated substrates, suggesting that degradation of abnormal proteins via the proteasome is deficient. More detailed investigation of ER proteostasis using the cellular models showed that in vitro aged cells had a decreased capacity to fold a temperature sensitive model membrane protein (ts O45 VGV-G) and were less efficient at degrading two model substrates of the ER-associated degradation pathway. Since the ER protein folding and degradation pathways are modulated by ER stress response signalling to restore ER homeostasis, therefore their malfunctioning would impact on the ability of aged cells to cope with stress. Indeed, in the aged cells both PERK and IRE-1 signalling were perturbed. In addition, the level of BiP was not upregulated following ER stress in the aged cells. Moreover, ER stress induction led to decreased cell survival in the case of aged cells, showing that the inability of aged cells to maintain ER protein homeostasis results in increased susceptibility to cell death. All these data together shows how perturbed ER proteostasis can occur with increased age and its impact on overall cell wellbeing, therefore provide new insight into mechanisms of cell ageing.

Ageism and negative attitudes are reported to be institutionally embedded in healthcare. The unprecedented increase in the older population together with social perceptions of later life presents all those involved in the delivery of healthcare with considerable challenges. It was therefore timely to examine attitudes and perceptions of healthcare professionals towards older people. This study presents a critical visual exploration of the perceptions of ageing of undergraduate nursing students at a University in the North of England, based on the findings of a three year longitudinal study. The research employed a pragmatic standpoint where mixed methodology was adopted to explore perceptions and included the use of an attitude towards older people scale (KOP) (Kogan, 1961), visual methods (participants were asked to draw a person aged 75), a Thurstone scale and photo elicitation. The research design and construct was influenced by the epistemology of constructionism and discourse analysis. The research was conducted alongside an undergraduate nursing programme, and followed the natural journey of 310 students from one intake and involved three waves of data collection. The study established that the majority of participants had moderately positive attitudes towards older people the beginning of the programme and that these had improved for a significant number by the end of the study programme. From the quantitative data it was determined that age, gender, educational qualifications, practice learning, branch of nursing and contact with older people influenced the participants’ overall attitude score. The use of visual methods provided a narrative of the participants’ perceptions of later life and appearance dominated the imagery via the physical depiction of ageing and the ascetics of clothing and grooming. The influence of role models was seen to impact upon the production of the image via the depiction of grandparents and people they knew and the drawings identified some older people being active. The visual findings established that the undergraduate nurses in the study viewed older people from a socially constructed phenomenon and used symbols (hairstyle, clothing, mobility aids) to depict old age. The nursing programme was found to positively alter perceptions. The research findings have led to recommendations based on three prominent themes; 1) implications for nurse education and practice, 2) gerontology education and research and 3) future use of the research methods.

Remyelination is the restoration of myelin sheaths to denuded axons following demyelinating events, which occurs spontaneously in adult mammals, including humans. The principal cells which participate in remyelination are the Oligodendrocyte Progenitor Cells (OPCs). Similar to other regenerative processes, remyelination efficiency declines with ageing. It is still unknown how much of this decline can be attributed to intrinsic changes in the OPCs themselves rather than environmental changes arising from changes in the cellular niche. Thus, we currently have a fundamental gap in our knowledge regarding the basic biology of adult OPCs, and therefore the changes that occur to them with ageing. In order to address these questions, I have developed a method to reliably isolate all cell types of the oligodendrocyte (OL) lineage from adult rats. This allowed me to identify the specific transcriptome state unique to adult OPCs, which is different to the transcriptome of neonatal OPCs, upon which previous studies have focused. This included genes which support the notion that following the initial phases of developmental myelination, adult OPCs enter a quiescent mode, in a manner similar to other tissue resident stem cells. Moreover, using a recently established isolation method, I was able to isolate aged OPCs, and develop a transcriptional database that can allow researchers to explore the changes in aged OPCs and identify new targets for enhancing their function. Lastly, I present in this thesis novel ideas regarding the influence of microglia cell surface molecules on OPC differentiation. I show that changes in the cell surface of aged microglia are inhibitory for OPC differentiation into OLs, and that these changes in microglia are a result of the increase in TGFb levels with ageing. In summary, this dissertation introduces new tools and methods that will allow x further in-depth study of adult OPCs, and specifically will help to shed light on the role of adult OPCs in the CNS in homeostasis. Furthermore, I explore the changes that occur within OPCs as they age, and show how such changes reduce aged OPCs ability to efficiently facilitate the process of remyelination.

Tears are formed by a group of glands and ocular epithelia collectively named the lacnmal gland system. The lacrimal glands are paired orbital structures which in the rat consist of an intraorbital and exorbital component. The exorbital gland is responsible for secreting the aqueous components of the tear film, consisting of water, electrolytes and proteins which are responsible for keeping the cornea buffered, lubricated, nourished and protected. Ageing has been associated with lacrimal gland dysfunction, resulting in reduced aqueous tear production, which is associated with dry eye conditions. However, very little is known about ageing effects on the lacrimal gland and in particular the lacrimal gland acinar cells. This study employed light and electron microscopy, immunohistochemical, radiobiological and physiological techniques to investigate ageing changes in the morphology and function of the lacrimal gland and acinar cells. In all experiments animals of 3-5 months were considered normal, control. The light microscopical studies revealed that with ageing to 28 months the gland underwent progressive morphological changes, including; thickening and deposition of the interlobular connective tissue, inflammatory cell infiltration, inflammation, necrosis, enlargement of ducts, patchy destruction of acinar, vascular and ductal tissues and luminal swelling of the acini. These changes were most apparent at 20, 24 and 28 months, only changes to the interlobular connective tissue was observed at 12 months and very little was observed at 9 months. However, in all age groups there was a change in the type and distribution of the acinar cell. Three distinct types of acinar cells were observed in the lacrimal glands; serous, seromucous and mucous (Draper et aL, 1998; 1999).

This thesis examines representations of ageing in women‟s magazines. Although ageing is an inevitable part of the human condition, this thesis takes the position that ageing is culturally constructed and that women‟s magazines are a key site in such constructions. It is noticeable that, within the Academy generally, there has been less work into the social construction of the ageing process than there has been into other relations of „difference‟ such as gender or race. That said, in the last two decades, work in this area has started to emerge. Factors which account for this include the influence of the baby boomer generation, a sizeable age cohort, born between 1945-1964 who are now growing older themselves. The thesis presents a textual and semiotic analysis of the way in which getting older is constituted through written, visual and spoken texts. The primary data in the research consists of articles from women‟s magazines, analysed using a range of semiotic and linguistic tools, most notably the theories of Roland Barthes, particularly his concept of „Myth‟. Metonymy and the function of stereotyping are also key theoretical concepts. In addition, I analyse data from transcriptions of informal interviews with women magazine readers drawing on the same theoretical concepts. In this way, I am able to examine how magazine texts are received by their readership and, moreover, how women position themselves in relation to what they are reading. The analysis is underpinned by three Myths of Ageing: firstly, that ageing is a decline scenario: it involves both mental and physical decline; secondly, that ageing is synonymous with loss of power: sexual, economic and social; and lastly that ageing must be resisted. I show how the „new positive‟ images of growing older that are being drawn out and portrayed in media representations are not necessarily positive in terms of the impact they have on contemporary women. These images are presented as „new‟, but I shall demonstrate that they are, in fact, a re-working of the underlying Myths of Ageing, myths which construct ageing as a culturally very negative experience, particularly for women in this historical moment.

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No / Australian sociology has wrestled with most of the big issues facing this society; however, when it comes to one of the most significant changes to face Australia in the next 30 years, it has suddenly lost its capacity to engage with the nexus between demography, social processes and political structures. While governments have forged ahead with responsibilization agendas in health, welfare and unemployment, sociology has voiced its concern about the implications for Australia¿s most disadvantaged. Yet, when it comes to population ageing, sociology has been, in large part, silent in the face of neoliberal policies of positive ageing, which have framed the `problem¿ as a deficit that must be managed primarily by individuals and their families. This article maps the field of positive ageing, identifies key social concerns with this policy approach and asks, where is Australian sociology?