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Caleb E Finch

Publications and source records attributed to Caleb E Finch.

36 records · Page 2Linked to original sources
PubMed2004

Meat-adaptive genes and the evolution of slower aging in humans.

The chimpanzee life span is shorter than that of humans, which is consistent with a faster schedule of aging. We consider aspects of diet that may have selected for genes that allowed the evolution of longer human life spans with slower aging. Diet has changed remarkably during human evolution. All direct human ancestors are believed to have been largely herbivorous. Chimpanzees eat more meat than other great apes, but in captivity are sensitive to hypercholesterolemia and vascular disease. We argue that this dietary shift to increased regular consumption of fatty animal tissues in the course of hominid evolution was mediated by selection for "meat-adaptive" genes. This selection conferred resistance to disease risks associated with meat eating also increased life expectancy. One candidate gene is apolipoprotein E (apoE), with the E3 allele evolved in the genus Homo that reduces the risks for Alzheimer's and vascular disease, as well as influencing inflammation, infection, and neuronal growth. Other evolved genes mediate lipid metabolism and host defense. The timing of the evolution of apoE and other candidates for meat-adaptive genes is discussed in relation to key events in human evolution.

Adaptation, Biological↗
PubMed2003

Self-assembly of Abeta(1-42) into globular neurotoxins.

Amyloid beta 1-42 (Abeta(1-42)) is a self-associating peptide that becomes neurotoxic upon aggregation. Toxicity originally was attributed to the presence of large, readily formed Abeta fibrils, but a variety of other toxic species are now known. The current study shows that Abeta(1-42) can self-assemble into small, stable globular assemblies free of fibrils and protofibrils. Absence of large molecules was verified by atomic force microscopy (AFM) and nondenaturing gel electrophoresis. Denaturing electrophoresis revealed that the globular assemblies comprised oligomers ranging from trimers to 24mers. Oligomers prepared at 4 degrees C stayed fibril-free for days and remained so when shifted to 37 degrees C, although the spectrum of sizes shifted toward larger oligomers at the higher temperature. The soluble, globular Abeta(1-42) oligomers were toxic to PC12 cells, impairing reduction of MTT and interfering with ERK and Rac signal transduction. Occasionally, oligomers were neither toxic nor recognized by toxicity-neutralizing antibodies, suggesting that oligomers could assume alternative conformations. Tests for oligomerization-blocking activity were carried out by dot-blot immunoassays and showed that neuroprotective extracts of Ginkgo biloba could inhibit oligomer formation at very low doses. The observed neurotoxicity, structure, and stability of synthetic Abeta(1-42) globular assemblies support the hypothesis that Abeta(1-42) oligomers play a role in triggering nerve cell dysfunction and death in Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed2003

Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.

A molecular basis for memory failure in Alzheimer's disease (AD) has been recently hypothesized, in which a significant role is attributed to small, soluble oligomers of amyloid beta-peptide (A beta). A beta oligomeric ligands (also known as ADDLs) are known to be potent inhibitors of hippocampal long-term potentiation, which is a paradigm for synaptic plasticity, and have been linked to synapse loss and reversible memory failure in transgenic mouse AD models. If such oligomers were to build up in human brain, their neurological impact could provide the missing link that accounts for the poor correlation between AD dementia and amyloid plaques. This article, using antibodies raised against synthetic A beta oligomers, verifies the predicted accumulation of soluble oligomers in AD frontal cortex. Oligomers in AD reach levels up to 70-fold over control brains. Brain-derived and synthetic oligomers show structural equivalence with respect to mass, isoelectric point, and recognition by conformation-sensitive antibodies. Both oligomers, moreover, exhibit the same striking patterns of attachment to cultured hippocampal neurons, binding on dendrite surfaces in small clusters with ligand-like specificity. Binding assays using solubilized membranes show oligomers to be high-affinity ligands for a small number of nonabundant proteins. Current results confirm the prediction that soluble oligomeric A beta ligands are intrinsic to AD pathology, and validate their use in new approaches to therapeutic AD drugs and vaccines.

Alzheimer Disease↗
PubMed2003

Evolutionary medicine: from dwarf model systems to healthy centenarians?

Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.

Aging↗
PubMed2003

Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity.

Glial activation during aging was analyzed in primary glia cultured from brain regions sampled across the life span. An initial study showed that phenotypes of activated astrocytes and microglia from aging rat cerebral cortex persisted in primary cultures (Neurobiol. Aging 19 (1998), 97). We extend these findings by examining effects of age on the activation of glial cultures from adult rat brain in response to lipopolysaccharide (LPS), an inflammatory stimulus. Mixed glia from F344 male rats, aged 3 and 24 months, cultured from cerebral cortex (Cx), hippocampus (Hc), and striatum (St), were assayed for cytokines implicated in Alzheimer's disease: IL-1alpha, IL-1beta, IL-6, and TNF-alpha. Regional differences across all age groups included consistently lower expression of these cytokines in glia derived from Cx than Hc and St. Aging increased basal IL-6 mRNA and secretion by >or=3-fold in glia from Cx and Hc. Aging also increased LPS-induced IL-1 and IL-6 in Hc more than in Cx, whereas no significant effects of age were seen in St-derived glial cytokines. TNF-alpha secretion did not differ by donor age (basal or LPS-induced). Nitric oxide production by microglia from Cx of aging brains showed a smaller induction in response to LPS, with proportionately less neurotoxicity. Thus, glial activation during aging shows regional selectivity in cytokine expression, with opposite effects of aging on the increased inducibility of IL-1 and IL-6 vs the decreased production of nitric oxide.

Age Factors↗
PubMed2003

Differential patterns of age-related mortality increase in middle age and old age.

It is often assumed that aging is a uniform process throughout adulthood because of the approximately linear increase of logarithmic mortality. We explored this assumption by analyzing cause-specific mortality increases in France (1979-1994). Rising rapidly at ages 30-54 years ("middle age") are death rates from malignant neoplasms at various sites, acute myocardial infarction, hypertensive disease, and liver cirrhosis. Steeply increasing at 65-89 years ("old age") are death rates from certain infectious diseases, particularly of the respiratory system; certain types of accidents; nonalcoholic mental disorders (probably due mainly to Alzheimer's disease and senile dementia); heart failure; cerebrovascular disease; and some "vague" categories. The processes at work may be fundamentally different in these two life history stages, such that the mortality rise in middle age reflects specific chronic diseases that develop prematurely in some high-risk individuals, whereas the mortality increase in old age is dominated by senescent processes that eventually raise the vulnerability of almost all individuals to multiple pathologies.

Adult↗
PubMed2002

Equine estrogens induce apolipoprotein E and glial fibrillary acidic protein in mixed glial cultures.

Premarin, which contains several equine estrogens, as well as estradiol (E2) as a minor component, is widely used for replacement therapy of estrogen deficits, but little is known of its direct actions on brain cells. In mixed glial cultures, apolipoprotein E (apoE) and glial fibrillary acidic protein (GFAP) are induced by estrogens. GFAP induction showed an inverted-U shape E2 dose response, with a maximum induction at 1 pM, whereas apoE mRNA induction was greatest at 100 pM. GFAP and ApoE mRNAs were induced by equine estrogens in the following order: E2=equilin>estrone>17 alpha-dihydroequilenin. However, the induction of apoE secretion by 17 alpha-dihydroequilenin was as effective as by the other estrogens. The greater response of apoE secretion than GFAP mRNA induction to 17 alpha-dihydroequilenin might be therapeutically important because of the glial scarring during brain lesions, in which GFAP induction has a major role in inhibiting neurite outgrowth, whereas apoE secretion supports neurite outgrowth.

Animals↗
PubMed2002

Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia.

The amyloid beta-peptide (Abeta) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha), which can be either neurotoxic or neuroprotective. We show that neuron death in cocultures of rat cortical microglia and neurons activated by lipopolysaccharide (LPS) or Abeta1-42 plus interferon gamma (IFNgamma) is caused by short-lived diffusible molecules and follows the generation of superoxide and/or peroxynitrite as determined by electron paramagnetic spectroscopy. Neurotoxicity induced by LPS or Abeta1-42 plus IFNgamma is blocked by inhibitors of NO synthesis and by the peroxynitrite (ONOO-) decomposition catalysts FeTMPyP [5,10,15,20-tetrakis(n-methyl-4'-pyridyl)porphinato iron (III) chloride] and FeTPPS [5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride] but not by the TNF-alpha inhibitor pentoxifylline. The specificity of FeTMPyP for ONOO- was confirmed by its ability to block the toxicity of a peroxynitrite donor but not of NO donors or of high levels of superoxide in a yeast mutant lacking superoxide dismutase 1. These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Abeta1-42 neurotoxicity and Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed2002

Cytokines and cognition--the case for a head-to-toe inflammatory paradigm.

The brain is not only immunologically active of its own accord, but also has complex peripheral immune interactions. Given the central role of cytokines in neuroimmmunoendocrine processes, it is hypothesized that these molecules influence cognition via diverse mechanisms. Peripheral cytokines penetrate the blood-brain barrier directly via active transport mechanisms or indirectly via vagal nerve stimulation. Peripheral administration of certain cytokines as biological response modifiers produces adverse cognitive effects in animals and humans. There is abundant evidence that inflammatory mechanisms within the central nervous system (CNS) contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Cytokines mediate cellular mechanisms subserving cognition (e.g., cholinergic and dopaminergic pathways) and can modulate neuronal and glial cell function to facilitate neuronal regeneration or neurodegeneration. As such, there is a growing appreciation of the role of cytokine-mediated inflammatory processes in neurodegenerative diseases such as Alzheimer's disease and vascular dementia. Consistent with their involvement as mediators of bidirectional communication between the CNS and the peripheral immune system, cytokines play a key role in the hypothalamic-pituitary-adrenal axis activation seen in stress and depression. In addition, complex cognitive systems such as those that underlie religious beliefs, can modulate the effects of stress on the immune system. Indirect means by which peripheral or central cytokine dysregulation could affect cognition include impaired sleep regulation, micronutrient deficiency induced by appetite suppression, and an array of endocrine interactions. Given the multiple levels at which cytokines are capable of influencing cognition it is plausible that peripheral cytokine dysregulation with advancing age interacts with cognitive aging.

Aging↗
PubMed2002

Aging and increased hypothalamic glial fibrillary acid protein (GFAP) mRNA in F344 female rats. Dissociation of GFAP inducibility from the luteinizing hormone surge.

During reproductive aging, female rodents show impaired inducibility of the estradiol (E2)-induced (preovulatory) surge of luteinizing hormone (LH), which is associated with hypothalamic neuronal impairments of aging. To evaluate if astrocytes show comparable age changes, we analyzed the regulation of glial fibrillary acidic protein (GFAP) mRNA which is transiently increased in the arcuate nucleus in association with the proestrus LH surge in young rats. In aging (18-month-old) F344 rats in persistent estrus, the loss of the E2-induced LH surge was paralleled by the lack of increased GFAP mRNA in the arcuate nucleus (in situ hybridization with X-ray film). We then tested the hypothesis that restoration of the LH surge by chronic ovariectomy (OVX) in aging rats would restore or block GFAP mRNA induction, respectively. Despite restoration of the inducible LH surge in aging rats by chronic OVX, there was no induction of GFAP mRNA in the arcuate nucleus. Moreover, young rats given chronic E2 implants for 6 weeks as a model for persistent estrus, retained induction of arcuate nucleus GFAP mRNA, despite loss of the induced LH surge. The aging rats were highly sensitive to gross pituitary enlargement from chronic E2 with 50% mortality; thus, the F344 genotype is not optimum for studies of aging-E2 interactions that require prolonged E2 treatments. More detailed cellular level analysis of GFAP mRNA is needed to define the relationship of GFAP expression to synaptic reorganization during the LH surge. The aging rats also showed higher levels of GFAP mRNA in the arcuate nucleus and ventromedial nucleus, consistent with the general trend for elevated GFAP mRNA during aging in other brain regions and in both sexes.

Aging↗
PubMed2002

Estradiol (E2) enhances neurite outgrowth by repressing glial fibrillary acidic protein expression and reorganizing laminin.

Neuronal remodeling in response to deafferenting lesions in the brain can be enhanced by estradiol (E2). Astrocytes are among the targets of E2 in complex interactions with neurons and may support or inhibit neuronal remodeling. In ovariectomized female rats given entorhinal cortex lesions, E2 replacement inhibited the increase of glial fibrillary acidic protein (GFAP) protein. To model the role of E2 in these complex processes, we used the "wounding-in-a-dish" of astrocyte-neuron cocultures. Low physiological E2 (1 pM) blocks the wound-induced increase of GFAP expression (transcription and protein) and enhances neurite outgrowth. The transcriptional responses to E2 during wounding are mediated by sequences in the 5'-upstream region of the rat GFAP promoter. Concurrently, E2 reorganized astrocytic laminin into extracellular fibrillar arrays, which others have shown support neurite outgrowth. The inhibition of GFAP expression by E2 in this model is consistent with in vivo findings that E2 enhanced recovery from deafferenting cortical lesions by increased neurite outgrowth in association with decreased GFAP expression. More generally, we hypothesize that physiological variations in E2 levels modulate neuronal plasticity through direct effects on GFAP transcription that, in turn, modify GFAP-containing intermediate filaments and reorganize astrocytic laminin.

Animals↗
PubMedDate not supplied

Neurons, glia, and plasticity in normal brain aging.

Early manifestations of brain aging have received much less attention than the drastic degeneration of AD and MID. During nonpathological changes of normal aging, brain systems differ in the involvement of neuron loss. Spatial learning can become impaired without evidence for neuron loss, whereas eye-blink conditioning deficits are well correlated with Purkinje neuron loss. Glial activation, in particular the increased expression of glial fibrillary acidic protein (GFAP), may be a factor in impaired synaptic plasticity. Lastly, it is discussed how developmental variations in the numbers of Purkinje cells and ovarian oocytes can be factors in outcomes of aging that are not under strict genetic control.

Aging↗