Multidimensional predictors of fatigue among octogenarians and centenarians.

BACKGROUND: Fatigue is a common and frequently observed complaint among older adults. However, knowledge about the nature and correlates of fatigue in old age is very limited. OBJECTIVE: This study examined the relationship of functional indicators, psychological and situational factors and fatigue for 210 octogenarians and centenarians from the Georgia Centenarian Study. METHODS: Three indicators of functional capacity (self-rated health, instrumental activities of daily living, physical activities of daily living), two indicators of psychological well-being (positive and negative affect), two indicators of situational factors (social network and social support), and a multidimensional fatigue scale were used. Blocked multiple regression analyses were computed to examine significant factors related to fatigue. In addition, multi-group analysis in structural equation modeling was used to investigate residential differences (i.e., long-term care facilities vs. private homes) in the relationship between significant factors and fatigue. RESULTS: Blocked multiple regression analyses indicated that two indicators of functional capacity, self-rated health and instrumental activities of daily living, both positive and negative affect, and social support were significant predictors of fatigue among oldest-old adults. The multiple group analysis in structural equation modeling revealed a significant difference among oldest-old adults based on residential status. CONCLUSION: The results suggest that we should not consider fatigue as merely an unpleasant physical symptom, but rather adopt a perspective that different factors such as psychosocial aspects can influence fatigue in advanced later life.

Life events and personality predicting loneliness among centenarians: findings from the Georgia Centenarian Study.

Regarding the purpose of this study, the researchers analyzed the roles that both life events (life-time positive events and life-time negative events) and personality (Neuroticism, Extraversion, Trust, Competence, and Ideas) played in participants of the Georgia Centenarian Study. The researchers analyzed these variables to determine whether they predicted loneliness. Analyses indicated that life-time negative events significantly predicted loneliness. In essence, the higher was the number of life-time negative life events, the higher was the loneliness score. Moreover, Neuroticism, Competence, and Ideas were all significant predictors of loneliness. The higher was the level of Neuroticism and intellectual curiosity, the higher was the level of loneliness, whereas the lower was the level of Competence, the higher was the level of loneliness. In addition, both life-time positive and life-time negative life events were significant predictors of Neuroticism. The higher was the number of life-time positive events, the lower was the level of Neuroticism, and the higher was the number of life-time negative events, the greater was the level of Neuroticism. These results indicated that life-time negative events indirectly affect loneliness via Neuroticism. Last, our results indicated that the Competence facet mediated the relationship between lifetime negative life events and loneliness. Life-time negative life events significantly affected centenarians' perceived competence, and Competence in turn significantly affected the centenarians' loneliness. These results as a whole not only add to our understanding of the link between personality and loneliness, but also provide new insight into how life events predict loneliness.

Family history and adaptation among centenarians and octogenarians.

BACKGROUND: The purpose of this study was to analyze various 'family history' variables (i.e. childhood health, financial situation while growing up, living with grandparents before age 17, and number of children) among participants of the Georgia Centenarian Study. OBJECTIVE: To determine whether family history variables predict critical outcome areas such as cognitive functioning, activities of daily living, mental health, and economic dependence. METHODS: A total of 318 older adults (236 centenarians and 82 octogenarians) were assessed with regard to their mental status, ADL (activities of daily living) functioning, depression, family history, loneliness, and perceived economic status. RESULTS: Analyses indicated that the number of children significantly predicted the ability to engage in activities of daily living and loneliness. In essence, the more children, the higher the activities of the daily living score and the lower the loneliness scores. In addition, childhood health significantly predicted loneliness. The poorer one's health in childhood, the higher the loneliness scores. CONCLUSION: The results of this study confirm the importance of distal family history variables on present-day functioning.

Predicting happiness among centenarians.

BACKGROUND: Happiness is believed to evolve from the comparison of current circumstances relative to past achievement. However, gerontological literature on happiness in extreme old age has been limited. OBJECTIVE: The purpose of this study was to determine how perceptions of health, social provisions, and economics link past satisfaction with life to current feelings of happiness among persons living to 100 years of age and beyond. METHODS: A total of 158 centenarians from the Georgia Centenarian Study were included to conduct the investigation. Items reflecting congruence and happiness from the Life Satisfaction Index were used to evaluate a model of happiness. Pathways between congruence, perceived economic security, subjective health, perceived social provisions, and happiness were analyzed using structural equation modeling. RESULTS: Congruence emerged as a key predictor of happiness. Furthermore, congruence predicted perceived economic security and subjective health, whereas perceived economic security had a strong influence on subjective health status. CONCLUSION: It appears that past satisfaction with life influences how centenarians frame subjective evaluations of health status and economic security. Furthermore, past satisfaction with life is directly associated with present happiness. This presents implications relative to understanding how perception of resources may enhance quality of life among persons who live exceptionally long lives.

Depression among centenarians and the oldest old: contributions of cognition and personality.

BACKGROUND: An estimated 20% of adults over the age of 55 experience clinical mental disorders such as depression and anxiety. For older adults, mental health concerns are often undetected, concomitant with physical challenges, and ultimately go untreated. These realities have significant implications for older adults' day-to-day functioning, particularly among the oldest old. OBJECTIVE: The present study examined the ability of cognition and personality in explaining depression within a sample of octogenarians and centenarians. METHODS: Participants were assessed during the most recent cross-sectional data collection of the Georgia Centenarian Study. The final eligible sample included 76 octogenarians (mean: 84.25 years, SD: 2.82; range: 81-90) and 158 centenarians and near centenarians (mean: 99.82 years, SD: 1.72; range: 98-109). RESULTS: Hierarchical regression analyses were conducted to examine the relation between key variables and depressive symptoms in the two age groups. Blocks entered into the analyses included: demographics (i.e. age group, residential status, sex, and ethnicity) and functioning, memory and problem-solving ability, and personality (i.e. extraversion and neuroticism). Models differed for octogenarians and centenarians. Decreased problem-solving ability was related to greater depressive symptoms among octogenarians. For centenarians, institutional residence and increased neurotic tendencies were related to greater depressive symptoms. CONCLUSION: Study findings demonstrate the need to examine a variety of factors which influence mental health in later life and to consider the unique contexts and differential experiences of octogenarians and centenarians.

Distal and proximal resource influences on economic dependency among the oldest old.

BACKGROUND: As exceptional survivors, centenarians may have characteristics that reduce their dependency on family and community support systems despite the expectation that their extreme age creates a burden on those systems. The Georgia Centenarian Study obtained information about assistance for income, medical care, and caregiving of all types for a sample of centenarians and octogenarians. Previous studies have not established which characteristics may contribute to economic dependency among the oldest old. OBJECTIVE: To identify distal and proximal resource influences on economic dependency, considering past lifestyle, proximal health, economic resources, personality, and coping behavior. METHODS: Analysis sample sizes ranged from 109 to 138 octogenarians and centenarians. Blockwise multiple regressions predicted whether they received income assistance, number of medical care events, number of caregiving types, and total caregiving hours. RESULTS: Past life style, gender, ethnicity, socioeconomic status, functional health, and coping were not related to economic dependency. With the exception of the number of types of care, centenarians were not more dependent than octogenarians. Cognitive ability had the strongest effects for medical care and caregiving services. 'Extraversion', 'ideas', 'neuroticism', and 'competence' personality factors had significant effects for caregiving types and total hours of care received. CONCLUSION: Monitoring and intervention to maintain cognitive ability are critical practices for autonomy and reduced economic dependency among the oldest old. Psychological resources are more important influences on social support than functional health and other proximal economic resources.

Social resources and longevity: findings from the Georgia centenarian study.

BACKGROUND: As the proportion of adults aged 85 and older increases, investigations of resources essential for adapting to the challenges of aging are required. OBJECTIVE: To comprehensively investigate the social resources of cognitively intact centenarians participating in the Georgia Centenarian Study and the association between these resources and residence status. METHODS: Two widely used measures of social resources were investigated among participants living in private homes, personal care facilities, and nursing homes. Logistic regression was used to determine significant predictors of nursing home residence. RESULTS: Differences in levels of social resources were found between centenarians and octogenarians, and among centenarians in different living situations. Analyses revealed differential findings between self- and proxy reports. Controlling for education, activities of daily living, and financial ability to meet needs, only one of the two social resources measures significantly reduced the odds of nursing home residence. CONCLUSION: The findings of this study add to the existing literature on one of the basic adaptive resources (social resources) for centenarians. Whether a more specific assessment of network contact is employed, or a more global assessment is used, differences in these constructs exist between centenarians and octogenarians, among centenarians in differing living conditions, and across types of informants. Researchers examining the different resources that may contribute to extraordinary longevity and positive adaptation may find it essential to differentiate between the oldest old and centenarians, and to account for differences based upon measure, reporter type, and centenarian residence status.

Longevity, genes, and aging.

Until recently, biogerontology was a backwater of biology, but progress in the qualitative and quantitative genetic analysis of longevity has led to a revolution in aging research. This research has revealed that extended longevity is frequently associated with enhanced metabolic capacity and response to stress. Moreover, it suggests that there are multiple mechanisms of aging. Because of its complexity, the aging process takes us into the realm of integrative biology, and thus, biogerontology should prove instrumental in deciphering the functional and regulatory circuitry of the sequenced genome.

Metabolic control and ageing.

There appear to be multiple processes that are limiting for longevity and the associated mechanisms of ageing. Among these processes, metabolic control is coming to the forefront, because it has surfaced in studies in several model systems and because of its relevance to mammalian ageing. The genetic and molecular dissection of ageing in yeast points to mechanisms involving three aspects of metabolism. First, dysfunctional mitochondria signal many changes in nuclear gene expression that result in metabolic adjustments that extend life span. Second, manipulation of nutritional status can also increase longevity in a separate caloric-restriction pathway. Finally, protein synthesis is a third aspect, which depends on the transcriptional state of chromatin and the histone deacetylases that modulate it.

Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae has a limited life-span, which is measured by the number of divisions that individual cells complete. Among the many changes that occur as yeasts age are alterations in chromatin-dependent transcriptional silencing. We have genetically manipulated histone deacetylases to modify chromatin, and we have examined the effect on yeast longevity. Deletion of the histone deacetylase gene RPD3 extended life-span. Its effects on chromatin functional state were evidenced by enhanced silencing at the three known heterochromatic regions of the genome, the silent mating type (HM), subtelomeric, and rDNA loci, which occurred even in the absence of SIR3. Similarly, the effect of the rpd3Delta on life-span did not depend on an intact Sir silencing complex. In fact, deletion of SIR3 itself had little effect on life-span, although it markedly accelerated the increase in cell generation time that is observed during yeast aging. Deletion of HDA1, another histone deacetylase gene, did not result in life-span extension, unless it was combined with deletion of SIR3. The hda1Delta sir3Delta resulted in an increase in silencing, but only at the rDNA locus. Deletion of RPD3 suppressed the loss of silencing in rDNA in a sir2 mutant; however, the silencing did not reach the level found in the rpd3Delta single mutant, and RPD3 deletion did not overcome the life-span shortening seen in the sir2 mutant. Deletion of both RPD3 and HDA1 caused a decrease in life-span, which resulted from a substantial increase in initial mortality of the population. The expression of both of these genes declines with age, providing one possible explanation for the increase in mortality during the life-span. Our results are consistent with the loss of rDNA silencing leading to aging in yeast. The functions of RPD3 and HDA1 do not overlap entirely. RPD3 exerts its effect on chromatin at additional sites in the genome, raising the possibility that events at loci other than rDNA play a role in the aging process.

Molecular mechanisms of yeast longevity.

The genetic analysis of yeast longevity has illuminated the underlying molecular mechanisms of aging that invoke the importance of metabolic regulation, genetic stability and stress resistance in determination of life span. The RAS genes have emerged as important modulators of life-maintenance processes and of life span itself.

Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae.

Replicative capacity, which is the number of times an individual cell divides, is the measure of longevity in the yeast Saccharomyces cerevisiae. In this study, a process that involves signaling from the mitochondrion to the nucleus, called retrograde regulation, is shown to determine yeast longevity, and its induction resulted in postponed senescence. Activation of retrograde regulation, by genetic and environmental means, correlated with increased replicative capacity in four different S. cerevisiae strains. Deletion of a gene required for the retrograde response, RTG2, eliminated the increased replicative capacity. RAS2, a gene previously shown to influence longevity in yeast, interacts with retrograde regulation in setting yeast longevity. The molecular mechanism of aging elucidated here parallels the results of genetic studies of aging in nematodes and fruit flies, as well as the caloric restriction paradigm in mammals, and it underscores the importance of metabolic regulation in aging, suggesting a general applicability.

Mitochondria to nucleus signaling and the role of ceramide in its integration into the suite of cell quality control processes during aging.

Mitochondria to nucleus signaling has been the most extensively studied mode of inter-organelle communication. The first signaling pathway in this category of information transfer to be discovered was the retrograde response, with its own set of signal transduction proteins. The finding that this pathway compensates for mitochondrial dysfunction to extend the replicative lifespan of yeast cells has generated additional impetus for its study. This research has demonstrated crosstalk between the retrograde response and the target of rapamycin (TOR), small GTPase RAS, and high-osmolarity glycerol (HOG) pathways in yeast, all of which are key players in replicative lifespan. More recently, the retrograde response has been implicated in the diauxic shift and survival in stationary phase, extending its operation to the yeast chronological lifespan as well. In this capacity, the retrograde response may cooperate with other, related mitochondria to nucleus signaling pathways. Counterparts of the retrograde response are found in the roundworm, the fruit fly, the mouse, and even in human cells in tissue culture. The exciting realization that the retrograde response is embedded in the network of cellular quality control processes has emerged over the past few years. Most strikingly, it is closely integrated with autophagy and the selective brand of this quality control process, mitophagy. This coordination depends on TOR, and it engages ceramide/sphingolipid signaling. The yeast LAG1 ceramide synthase gene was the first longevity gene cloned as such, and its orthologs hyl-1 and hyl-2 determine worm lifespan. Thus, the involvement of ceramide signaling in quality control gives these findings cellular context. The retrograde response and ceramide are essential components of a lifespan maintenance process that likely evolved as a cytoprotective mechanism to defend the organism from diverse stressors.

The RAS genes: a homeostatic device in Saccharomyces cerevisiae longevity.

The genetic analysis of the yeast replicative life span has revealed the importance of metabolic control and resistance to stress. It has also illuminated the pivotal role in determining longevity that the RAS genes play by the maintenance of homeostasis. This role appears to be performed by the coordination of a variety of cellular processes. Metabolic control seems to occupy a central position among these cellular processes that include stress resistance. Some of the features of metabolic control in yeast resemble the effects of the daf pathway for adult longevity in Caenorhabditis elegans and the metabolic consequences of selection for extended longevity in Drosophila melanogaster, as well as some of the features of caloric restriction in mammals. The distinction between dividing and nondividing cells is proposed to be less important for the aging process than generally believed because these cell types are part of a metabolic continuum in which the total metabolic capacity determines life span. As a consequence, the study of yeast aging may be helpful in understanding processes occurring in the aging brain.

New clues to old yeast.

The yeast Saccharomyces cerevisiae has been used as an experimental model for the genetic and molecular dissecton of the aging process for the past decade. This period has seen the implication of some 30 genes in yeast aging. These genes encode a wide array of biochemical functions, suggesting the participation of multiple molecular mechanisms of aging. However, four principles appear to be at play: metabolism, stress resistance, gene dysregulation, and genetic instability. They unite the broad physiological aspects of yeast aging with those in other species. Genes and environment are not the only players; stochastic change also appears important in determining life span. This element of chance provides opportunities for an integrative approach, which is beginning to appear in yeast aging research.

Metabolic mechanisms of yeast ageing.

The genetic analysis of ageing of the yeast Saccharomyces cerevisiae points to several processes important in determining life span. Among these, metabolic control plays a leading role. An examination of the molecular mechanisms underlying metabolic control of longevity has revealed two separate pathways. The retrograde response signals mitochondrial dysfunction to the nucleus resulting in gene regulatory changes that compensate. Nutritional status also modulates life span, adjusting metabolism to efficiently utilize energy resources, in a response that closely resembles the caloric restriction paradigm described in rodents. Although the retrograde response and caloric restriction are distinct pathways of life span extension, there appears to be some overlap of the longevity effectors under their control.

Longevity, genes, and aging: a view provided by a genetic model system.

The genetic analysis of aging in the yeast Saccharomyces cerevisiae has revealed the importance of metabolic capacity, resistance to stress, integrity of gene regulation, and genetic stability for longevity. A balance between these life maintenance processes is sustained by the RAS2 gene, which channels cellular resources among them. This gene cooperates with mitochondria and PHB1 in metabolic adjustments important for longevity. It also modulates stress responses. Transcriptional silencing of heterochromatic regions of the genome is lost during aging, suggesting that gene dysregulation accompanies the aging process. There is evidence that this age change plays a causal role. Aging possesses features of a nonlinear process, and it is likely that application of nonlinear system methodology to aging will be productive.

Genetics of longevity.

Recent studies on the genetics of aging in the yeast Saccharomyces cerevisiae, the roundworm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster have converged revealing the central role of metabolic capacity and resistance to stress in determining life span. Signal transduction has emerged from these studies as an important molecular mechanism underlying longevity. In their broad features, the results obtained in these genetic models are applicable to the dietary restriction paradigm in mammals, suggesting a general significance. It will be of interest to determine whether many of the molecular details will also pertain. The examination of centenarian populations for the frequency of certain alleles of pertinent genes may provide insights into the relevance of the conclusions of studies in invertebrates to human aging. These population genetic studies can be augmented by mechanistic studies in transgenic mice.

Epigenetic stratification: the role of individual change in the biological aging process.

Aging is a complex process. It consists of a diverse assortment of seemingly random manifestations that occur in the individual, the mutual relationship and impact on mortality of which is frequently obscure. We derive a simple equation to model the aging process based on scale invariant and increasing change. The solution to this equation indicates that this change itself, irrespective of its quality, is the cause and not simply the effect of aging. This model establishes loss of homeostasis as a fundamental feature of aging. The model is deterministic, but it supports the stochastic nature of age changes. Paradoxically, this model states that a sufficient augmentation of aging processes results in a lack of aging. Experimental evidence in support of this model is presented that spans the levels of population mortality rates, cellular spatial organization, and gene dysregulation.

Replication control and cellular life span.

Cell proliferation involves both control of progress through the current cell cycle and coordination of successive cell cycles. We have focused our attention on the events that trigger traversal of the G1/S boundary of the cell cycle. A protein kinase activity was found in preparations of the DNA-replicative complex from the budding yeast Saccharomyces cerevisiae. The activity phosphorylated only a few of the proteins present in the replicative fraction, and it displayed a marked preference for a 48-kDa polypeptide. Most importantly, the protein kinase activity was heat-sensitive in replicative fractions from cdc7 cells, a mutant that arrests at the G1/S boundary at restrictive temperature. The results suggest that phosphorylation of components of the replication machinery may play a role in control of initiation of DNA replication during the cell cycle. We have also begun an analysis of cellular aging in yeast, as a means of addressing the problem of coordination of successive cell cycles. Yeast cells have a finite life span defined by reproductive capacity. With age, the generation time of yeast cells lengthened. The cell cycle of the daughter cell was under the control of the mother. This control was transient, and the daughter cell began dividing at the rate characteristic of its own age within three divisions of its birth. This suggests that the senescent phenotype, as manifested by lengthened generation time, is a dominant feature in yeast cells, and that it is determined by a diffusible cytoplasmic molecule(s) that undergoes turnover in young cells. In a search for this putative senescence factor(s), we are cloning genes that differentially expressed during the yeast life span. Several such genes have been isolated and partially characterized. Our goals are to determine whether the expression of one or more of these genes is casually associated with cell longevity. We propose the Cell Spiral model to describe the relationship between the cell cycle and cellular aging.