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Biomedical subjects

Caleb E Finch

Publications and source records attributed to Caleb E Finch.

At least 19 recordsLinked to original sources
PubMed2006

Gene Aging Nexus: a web database and data mining platform for microarray data on aging.

The recent development of microarray technology provided unprecedented opportunities to understand the genetic basis of aging. So far, many microarray studies have addressed aging-related expression patterns in multiple organisms and under different conditions. The number of relevant studies continues to increase rapidly. However, efficient exploitation of these vast data is frustrated by the lack of an integrated data mining platform or other unifying bioinformatic resource to enable convenient cross-laboratory searches of array signals. To facilitate the integrative analysis of microarray data on aging, we developed a web database and analysis platform 'Gene Aging Nexus' (GAN) that is freely accessible to the research community to query/analyze/visualize cross-platform and cross-species microarray data on aging. By providing the possibility of integrative microarray analysis, GAN should be useful in building the systems-biology understanding of aging. GAN is accessible at http://gan.usc.edu.

Aging↗
PubMed2006

A perspective on sporadic inclusion-body myositis: the role of aging and inflammatory processes.

Sporadic inclusion-body myositis (sIBM) is an age-related condition manifested after midlife. This review points out salient features of sIBM that are shared with normal aging in muscle and with inflammatory changes in vascular atheromas and senile plaques of Alzheimer disease (AD). The amyloid precursor protein (APP) and derived Abeta peptides are found in both AD and sIBM. Because transgenic expression of human APP induces sIBM like changes, it is of potential interest that an inducer of APP, IL-1, increases during aging in mouse muscle. Because various subsets of the usual aging changes in aging brain, muscle, and vessels can be attenuated in rodents by caloric intake and possibly in humans by drugs with anti-inflammatory and anticoagulant activities, this study suggests that diet and inflammation may be useful experimental variations in exploring the pathogenesis of sIBM.

Aged↗
PubMed2005

Infection, inflammation, height, and longevity.

Using historical data from cohorts born before the 20th century in four northern European countries, we show that increasing longevity and declining mortality in the elderly occurred among the same birth cohorts that experienced a reduction in mortality at younger ages. Concurrently, these cohorts also experienced increasing adult height. We hypothesize that both the decline in old-age mortality and the increase in height were promoted by the reduced burden of infections and inflammation. Thus, early growth and cardiovascular diseases of old age may share infectious and inflammatory causes rooted in the external environment.

Adolescent↗
PubMed2005

Macrosialin increases during normal brain aging are attenuated by caloric restriction.

During normal aging, microglia develop an activated phenotype characterized by morphologic changes and induction of CD11b, MHC II, and other inflammatory markers. We show that macrosialin (CD68), a macrophage-specific protein, is increased by aging in selected brain regions of male C57BL/6NNia mice. In corpus callosum and striatum, macrosialin mRNA and protein increased >or=50% (24 months versus 4 months); hippocampus and cerebellum were unchanged. Caloric restriction (CR) attenuated these age-related increases. Since CR attenuates age-related increases in oxidative damage and inflammation, we examined whether oxidized lipoproteins and inflammatory processes regulate macrosialin using murine BV-2 microglial cells as a model. Oxidized low-density lipoproteins (oxLDL) induced macrosialin protein by 50%. Moreover, macrosialin was induced in response to lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) which activates inflammatory pathways in BV-2 cells. Thus, the previously documented increase in oxidized lipoproteins, inflammation, and microglial activation during normal aging may contribute to the age-related increase in macrosialin expression.

Aging↗
PubMed2005

Functional annotation and network reconstruction through cross-platform integration of microarray data.

The rapid accumulation of microarray data translates into a need for methods to effectively integrate data generated with different platforms. Here we introduce an approach, 2(nd)-order expression analysis, that addresses this challenge by first extracting expression patterns as meta-information from each data set (1(st)-order expression analysis) and then analyzing them across multiple data sets. Using yeast as a model system, we demonstrate two distinct advantages of our approach: we can identify genes of the same function yet without coexpression patterns and we can elucidate the cooperativities between transcription factors for regulatory network reconstruction by overcoming a key obstacle, namely the quantification of activities of transcription factors. Experiments reported in the literature and performed in our lab support a significant number of our predictions.

Algorithms↗
PubMed2005

What accounts for the wide variation in life span of genetically identical organisms reared in a constant environment?

Individual organisms show marked variability in life span, even when they are of the same genotype and are raised in a common environment protected from extrinsic hazards. This intrinsic variability of life span is thought to arise from the stochastic nature of the cellular and molecular mechanisms controlling development and ageing. In this article we review what is currently understood about the factors underlying the variability of life span and consider the implications for research that aims to improve the predictability of health in old age.

Animals↗
PubMed2005

Developmental origins of aging in brain and blood vessels: an overview.

Emerging evidence suggests a remarkable convergence of inflammatory mechanisms in the etiology of cardiovascular disease and Alzheimer disease. A broad set of NSAIDs and statins used to reduce the risk of vascular occlusion and to slow atherogensis may also be protective for Alzheimer disease. Elevated blood levels of C-reactive protein are risk factors for cardiovascular disease and possibly for Alzheimer disease. Monocyte-lineage cells are also fundamental to both conditions: in blood vessels, macrophages are important to atherogenesis for the accumulation of lipids (foam cells), whereas brain microglia show activation during aging and direct involvement in amyloid metabolism in the senile plaque. Genetic influences are recognized through the apoE4 allele, which is associated with hypercholesterolemia and is a risk factor in vascular events and Alzheimer disease, and is recognized for its proinflammatory profile. ApoE4 also accelerates Alzheimer disease pathogenesis in Down's syndrome and many other chronic neurodegenerative conditions, as is well-supported by animal models. Inflammatory changes are present at the earliest stages of vascular disease and Down's syndrome in human fetuses, and are also prominent early in Alzheimer disease. These findings give a basis for considering inflammatory processes early in life which can lead to fully fired pathogenesis of cardiovascular disease and possibly for Alzheimer disease.

Aging↗
PubMed2005

Reversible age impairments in neurite outgrowth by manipulations of astrocytic GFAP.

Aging is associated with neuron atrophy and impaired sprouting after lesions. In contrast during normal aging without neurodegenerative diseases, astrocytes display increasing activation, with progressive increases of glial fibrillary acidic protein (GFAP) beginning before midlife. Because many neuronal functions depend on astrocytic support, we developed a heterochronic co-culture system to study influences of aging astrocytes on neurons. Neurite outgrowth by embryonic neurons (E18) was markedly less when co-cultured with confluent astrocytes derived from old (24 mo) versus young (3 mo) cortex. These impairments were reversible. Diminishing the GFAP levels of old astrocytes by RNAi restored neurite outgrowth, whereas overexpression of GFAP in young astrocytes modeled these effects of aging by reducing neurite outgrowth. Quantitative relationships were found such that neurites were co-localized with high intensity laminin, which both varied inversely with GFAP. These results implicate increased astrocytic GFAP expression as a proximal cause of neuron atrophy during normal aging.

Age Factors↗
PubMed2004

Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models.

Dietary influences on Alzheimer disease (AD) are gaining recognition. Because many aging processes are attenuated in laboratory mammals by caloric restriction (CR), we examined the effects of short-term CR in two AD-transgenic mice, APP(swe/ind) (J20) and APP(swe) + PS1(M146L) (APP + PS1). CR substantially decreased the accumulation of Abeta-plaques in both lines: by 40% in APP(swe/ind) (CR, 6 weeks), and by 55% in APP + PS1 (CR, 14 weeks). CR also decreased astrocytic activation (GFAP immunoreactivity). These influences of CR on AD-transgenic mice are consistent with epidemiological reports that show that high caloric diets associate with the risk of AD, and suggest that dietary interventions in adult life might slow disease progression.

Alzheimer Disease↗
PubMed2004

Progressive changes in regulation of apolipoproteins E and J in glial cultures during postnatal development and aging.

Apolipoprotein (Apo) E and ApoJ are lipid- and cholesterol-carriers in the central nervous system and are implicated in age-related neurodegenerative diseases. The primary source of secreted ApoE and ApoJ (clusterin) in the brain is glia. Regulation of these apolipoproteins in mixed glial cultures from rat cerebral cortex differed most strongly between neonatal- and adult-derived glia. Basal secretion of ApoJ was two-fold greater in neonatal than adult glia. Responses to cytokines also differed by donor age. In adult glia, IL-6 increased ApoE secretion, but slightly decreased ApoJ. Both IL-1 beta and TNFalpha treatments increased ApoJ secretion from adult glia, with little effect on ApoE. In contrast to adult glia, neonatal ApoJ secretion did not respond to IL-1 beta, IL-6, or TNFalpha, and ApoE secretion from neonatal glia was slightly increased by IL-6. These differences may contribute to age-related neuroinflammatory processes, and are pertinent to the general use of neonatal-derived primary glia in models for neurodegenerative disease.

Aging↗
PubMed2004

Synaptic targeting by Alzheimer's-related amyloid beta oligomers.

The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid beta (Abeta). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Abeta oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Abeta oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Abeta oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD.

Aged↗
PubMed2004

Inflammatory exposure and historical changes in human life-spans.

Most explanations of the increase in life expectancy at older ages over history emphasize the importance of medical and public health factors of a particular historical period. We propose that the reduction in lifetime exposure to infectious diseases and other sources of inflammation--a cohort mechanism--has also made an important contribution to the historical decline in old-age mortality. Analysis of birth cohorts across the life-span since 1751 in Sweden reveals strong associations between early-age mortality and subsequent mortality in the same cohorts. We propose that a "cohort morbidity phenotype" represents inflammatory processes that persist from early age into adult life.

Adult↗
PubMed2004

Ovarian aging in two species of long-lived rockfish, Sebastes aleutianus and S. alutus.

Little is known about the ovary during aging in long-lived fish with respect to follicular stages and de novo oogenesis. We examined two species of rockfish, Sebastes aleutianus (rougheye rockfish) and Sebastes alutus (Pacific ocean perch). Fish were sampled offshore of British Columbia, age was estimated by otolith annuli, and the ovaries were examined histologically. In S. aleutianus, age up to 80 yr did not markedly alter the frequency distribution of oocytes, follicles, or their total numbers. Similarly, in a larger sample of S. alutus, the abundance of oocytes and follicles showed little age trend up through 77 yr. However, fish older than 50 yr lacked the largest and smallest oocyte size classes (40-60, >80 microm) and the smallest follicle size class (200-350 microm), which results from the later seasonal developmental state of these older fish. These data provide evidence that oogenesis continues at advanced ages in these two species, in contrast with long-held assumptions about mammals. These species represent an iteroparous extreme in the spectrum of life history strategies and merit investigation to determine the mechanisms for such an extended reproductive life span.

Aging↗
PubMed2004

Caliban's heritance and the genetics of neuronal aging.

Although current research on brain aging is dominated by Alzheimer's disease (AD), many other brain changes arise during middle age in humans and in rodent models that are independent of AD-like neurodegeneration. Differences and continuities between normal and pathological aspects of neuronal aging reveal the relative contributions and interactions of genetic and environmental factors. Apolipoprotein E alleles might be prototypes for genetic polymorphisms associated with functional changes that arise during middle age. Mice are valuable models for these aspects of aging because most genotypes show little neurodegeneration, and none accumulate beta-amyloid unless human transgenes are introduced. As further human genes are found to modify normal and pathological neuronal aging, this zoo of aging-animal variants will facilitate analysis both of pathways of age-related neuronal dysfunction and of environmental influences on these pathways.

Aging↗