Slow mortality rate accelerations during aging in some animals approximate that of humans.

A general measure of the rate of senescence is the acceleration of mortality rate, represented here by the time required for the mortality rate to double (MRD). Rhesus monkeys have an MRD close to that of humans, about 8 years; their shorter life-span results mainly from higher mortality at all ages. In contrast, some groups with short life-spans (rodents and galliform birds) have shorter MRDs and faster senescence. On the basis of the Gompertz mortality rate model, one may estimate the MRD from the maximum life-span (tmax) and the overall population mortality rate. Such calculations show that certain birds have MRDs that are as long as that of humans. These results show that high overall mortality rates or small body sizes do not preclude slow rates of senescence.

Genetics of aging.

The role of genetics in determining life-span is complex and paradoxical. Although the heritability of life-span is relatively minor, some genetic variants significantly modify senescence of mammals and invertebrates, with both positive and negative impacts on age-related disorders and life-spans. In certain examples, the gene variants alter metabolic pathways, which could thereby mediate interactions with nutritional and other environmental factors that influence life-span. Given the relatively minor effect and variable penetrance of genetic risk factors that appear to affect survival and health at advanced ages, life-style and other environmental influences may profoundly modify outcomes of aging.

Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease.

An ongoing controversy concerns the cellular distribution of the differentially spliced forms of the amyloid protein precursor (APP) mRNAs and changes in prevalence of these transcripts during Alzheimer's disease. In situ hybridization on serial sections was used to prove that most hippocampal pyramidal neurons contain both APP-751 and APP-695 mRNA species. The APP-751/APP-695 mRNA ratio is generally increased during Alzheimer's disease, as shown by RNA gel blot analysis. Moreover, there was a strong linear relation between the increase in APP-751/APP-695 mRNA ratio in pyramidal neurons and the density of senile plaques within the hippocampus and entorhinal cortex. Thus, the increase in APP-751/APP-695 mRNA provides a molecular marker for regional variations in plaque density between individuals diagnosed with Alzheimer's disease by the commonly used composite criteria.

APOE genotype and sex affect microglial interactions with plaques in Alzheimer's disease mice.

Microglia affect Alzheimer's disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E (APOE) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across APOE3 and APOE4 genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male APOE3 mice with significant reductions in coverage observed with both APOE4 genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which APOE4 genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male APOE3 mice and reduced by APOE4 genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with APOE4 genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with APOE4 genotype and female sex.

Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat.

A hippocampal poly(A) RNA, pADHC-9, was cloned by differential screening of a human hippocampal cDNA library. By RNA blot analysis, pADHC-9 was elevated 2-fold in Alzheimer's disease hippocampus. In situ analyses identified pADHC-9 expression in pyramidal and non-pyramidal cells of the hippocampus and entorhinal cortex. Nucleotide sequence analysis identified pADHC-9 as a potential human homolog of rat sulfated glycoprotein 2 (SGP-2). SGP-2 expression increased in rat hippocampus following experimental lesions that mimic intrinsic neuronal loss and/or deafferentation. The function of pADHC-9 in brain has not been defined, but in serum, a similar protein inhibits complement-dependent cytolysis. Increased expression of pADHC-9 in Alzheimer's disease hippocampus may be a compensatory response mounted to retard a complement-driven neurodegenerative cascade.

Ovarian and steroidal influences on neuroendocrine aging processes in female rodents.

Some Mammalian aging processes involve effects of steroids on the brain and pituitary. An ovary-dependent, neuroendocrine aging syndrome of laboratory rats and mice is described in this article. This syndrome can be attenuated during aging by chronic ovariectomy and can be prematurely induced in young rodents by sustained exposure to estradiol (E2). The limited follicular stock in the ovary is proposed to be a major pacemaker of aging in this neuroendocrine syndrome; ovarian aging may interact with neuroendocrine aging. Ovary-independent neuroendocrine changes occur as well. We also discuss developmental influences on adult aging in rodents and other examples in which adult lower mammals are sensitive to long lasting effects of steroids on the brain and pituitary. Possible molecular mechanisms are considered. In view of the long lasting effects of E2 and other steroids on lower mammals, the potential for long term effects of ovarian steroids on the human brain and pituitary warrants continued evaluation.

Comment on "The plateau of human mortality: Demography of longevity pioneers".

Barbi et al (Reports, 29 June 2018, p. 1459) reported that human mortality rate reached a "plateau" after the age of 105, suggesting there may be no limit to human longevity. We show, using their data, that potential lifespans cannot increase much beyond the current 122 years unless future biomedical advances alter the intrinsic rate of human aging.

Prenatal and early life exposure to air pollution induced hippocampal vascular leakage and impaired neurogenesis in association with behavioral deficits.

Exposure to traffic-related air pollution (TRAP) is associated with a range of neurodevelopmental disorders in human populations. In rodent models, prenatal TRAP exposure increased depressive behaviors and increased brain microglial activity. To identify cellular mechanisms, we examined adult neurogenesis and the blood-brain barrier (BBB) in relation to cognition and motivated behaviors in rats that were exposed to a nano-sized TRAP subfraction from gestation into adulthood. At age 5 months, exposed male rats had 70% fewer newly generated neurons in the dentate gyrus (DG) of the hippocampus. Microglia were activated in DG and CA1 subfields (35% more Iba1). The BBB was altered, with a 75% decrease of the tight junction protein ZO-1 in the CA1 layer, and twofold more iron deposits, a marker of microhemorrhages. The exposed rats had impaired contextual memory (novel object in context), reduced food-seeking behavior, and increased depressive behaviors (forced swim). Deficits of de novo neurogenesis were inversely correlated with depressive behavior, whereas increased microbleeds were inversely correlated with deficits in contextual memory. These findings give the first evidence that prenatal and early life exposure to TRAP impairs adult hippocampal neurogenesis and increases microbleeds in association with behavioral deficits.

Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.

Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/-/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral ß-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aß deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aß oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aß production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

Neuron atrophy during aging: programmed or sporadic?

Atrophy of neurons is a common change during aging in laboratory rodents and humans. However, cholinergic neurons of the same type have been found to atrophy, hypertrophy or not change at all, according to various reports on different species and genotypes. Possible factors responsible for these diverse outcomes include species- and genotype-specific aging changes and age-related diseases. An open question is whether slowly evolving changes in neuronal size share any mechanisms with the rapid programmed death of neurons that occurs during development. Progress in the study of neuronal atrophy with aging may be furthered by using fewer rodent genotypes.

Relevance of 'adaptive' mutations arising in non-dividing cells of microorganisms to age-related changes in mutant phenotypes of neurons.

Brattleboro rats do not produce vasopressin (VP) because of a germ-line single-base deletion (di) that causes a frame shift downstream from the VP sequences and a loss of a stop codon. The resulting frame-shifted peptide precursor does not enter the secretory pathway in hypothalamic neurons, thereby blocking the neurosecretion of VP and other peptides. Yet, from birth onwards, a subpopulation of neurons in di/di rats slowly accumulates revertant cells with a hemizygous wild-type phenotype. Because the rate of reversion during aging is slowed by vasopressin infusion, it is of interest to consider these phenomena in relation to recent observations on 'adaptive' mutations in single cell bacteria and yeast that enable reversion of mutations that blocked cell division under conditions of nutrient deficits. In considering mechanisms that could produce revertant phenotypes in non-dividing cells of both pro- and eukaryotes, we note the pertinence of transcription-coupled repair and SOS 'error-prone' repair.

Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration.

Sulfated glycoprotein 2 (SGP-2) from rat, and similar molecules from cow, dog, human, pig, ram and quail are known by 11 or more acronyms. SGP-2 is associated with the responses of brain and other tissues to injury; it and related molecules are also normally secreted by the adrenal gland, the liver and the testes. The mRNA of this protein is found in increased levels in Alzheimer's disease. In rats, after perforant path or excitotoxin lesions, levels of the protein or mRNA are elevated in astrocytes, and also in neurons. In rats, brain SGP-2 is regulated by gonadal and adrenal steroids. However, these increases after brain lesions may relate to a function that is associated with the human protein, namely that of inhibiting complement-mediated cell lysis. Other activities suggested for SGP-2 are lipid transport and cell-cell interactions, which are consistent with sequence data that predict binding of dinucleotides, heparin and lipids. The emerging neurobiology of SGP-2 encompasses the subjects of cell death, synaptic remodelling, neuroendocrinology and neurodegenerative diseases.

Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?

Amyloid beta (Abeta) is a small self-aggregating peptide produced at low levels by normal brain metabolism. In Alzheimer's disease (AD), self-aggregation of Abeta becomes rampant, manifested most strikingly as the amyloid fibrils of senile plaques. Because fibrils can kill neurons in culture, it has been argued that fibrils initiate the neurodegenerative cascades of AD. An emerging and different view, however, is that fibrils are not the only toxic form of Abeta, and perhaps not the neurotoxin that is most relevant to AD: small oligomers and protofibrils also have potent neurological activity. Immuno-neutralization of soluble Abeta-derived toxins might be the key to optimizing AD vaccines that are now on the horizon.

Rust on the Brain from Microbleeds and Its Relevance to Alzheimer Studies: Invited Commentary on Cacciottolo Neurobiology of Aging, 2016.

Cerebral microbleeds (MB) and small vessel disease (SVD) with congophilic arterial angiopathy (CAA) are increasingly recognized as a variable factor in AD cognitive impairments. This commentary on our recent report on sex-ApoE interactions in MBs published this February, briefly explores three aspects of MBs that could not be fully discussed therein: I, A possible gap between the prevalence of MBs as detected by MRI and post mortem analysis; II, The role of hemoglobin-degradation products in amyloid-attributed neurodegenerative changes; and III, Possible assessment of MB by cerebrospinal fluid (CSF) assays for iron-related markers to better screen patient subgroups for AD interventions.

Learning induces a CDC2-related protein kinase, KKIAMRE.

To elucidate molecular mechanisms in learning and memory, we analyzed expression of mRNAs in brains of rabbits undergoing eyeblink conditioning. Infusion of the transcription inhibitor actinomycin D into the cerebellar interpositus nucleus reversibly blocked learning but not performance of the conditioned response. Differential display PCR analysis of cerebellar interpositus RNAs from trained and pseudotrained rabbits identified a 207 bp band that was induced with learning. The fragment was used to isolate a cDNA from a lambdagt11 rabbit brain library containing a 1698 bp open reading frame. The deduced amino acid sequence contains the KKIAMRE motif, which is conserved among cell division cycle 2 (cdc2)-related kinases. These results suggest that there is a new category of cdc2-related kinases in the brain whose function may be important in learning and memory.

Regulation of liver tyrosine aminotransferase by endogenous factors in the mouse.

The levels of mouse liver tyrosine aminotransferase (TAT) are shown to increase rapidly and transiently during and after various challenges (e.g., exposure to cold or shaking) to the homeostatic machinery of the fasted mouse. The increase of TAT is dependent on gene activity. Recent feeding and adrenalectomy are shown to inhibit the induction of TAT during the challenge of cold.

Ageing and the regulation of cell activities during exposure to cold.

The inability to maintain body temperature and a selective pattern of changes in the regulation of cell activities were revealed by briefly exposing ageing C57B1/6J male mice to cold (10 degrees C). The induction of liver tyrosine aminotransferase (TAT) during exposure to cold (a gene-dependent process) was markedly delayed in senescent mice (26 months old) as compared with younger mice (3-16 months old); after the delay, the rate of increase of TAT was similar to that prevailing in younger mice. Direct challenge of the liver with injections of corticosterone or insulin elicited the induction of TAT on an identical time course in young and senescent mice. These experiments provide an example of an age change in a gene-dependent cell process (the delayed induction of TAT in senescent mice during exposure to cold) which is not due to a change in the potential of the genome for responding when exogenous stimulae are supplied (injection of hormones). In contrast to the age-related change in liver cell activities, no significant changes were found in the secretion of corticosterone during exposure to cold. Although the seat of these selective age-related changes in the regulation of cell activities remains unclear, it is argued that generalized damage to the genome of cells throughout the body is not involved. The results of this and other studies showing the selective effect of age on cell activities are considered in terms of the concept that many cellular age changes represent the response of cells to primary age-related changes in humoral factors in the internal environment of the body.

Rapid corticosterone-induced changes in gene expression in rat hippocampus display type II glucocorticoid receptor specificity.

Corticosteroids influence a wide range of neuronal activities by binding to either of two different glucocorticoid receptors found in rat brain. To investigate genomic responses in brain to stress levels of circulating corticosterone (CORT), we isolated hippocampal total RNA and poly(A)-containing RNA from rats treated with 10 mg/day CORT or vehicle. RNA translation products were resolved by 2-dimensional gel electrophoresis and fluorography. Select changes in four translation products after acute CORT treatment were inferred from up to 100-fold increases in three polypeptides and a 2-fold decrease in another. While adrenalectomy decreased levels of the inducible RNA sequences (adrenalectomized vs. intact controls), CORT increased the inducible sequences above their levels in intact controls. Rapid increases within 2 h of CORT treatment were seen for RNAs coding for 35, 33, and 20 kilodalton polypeptides. However, RNA coding for a 50 kilodalton polypeptide had a delayed decrease, first seen after 32 h CORT. The CORT increases displayed type II glucocorticoid receptor-specificity: RU 28362 greater than or equal to CORT greater than aldosterone greater than dihydrotestosterone = control. Since type II receptors are only substantially occupied by stress levels of CORT, these changes in gene expression are candidates for molecular stress responses in the brain.

Castration enhances expression of glial fibrillary acidic protein and sulfated glycoprotein-2 in the intact and lesion-altered hippocampus of the adult male rat.

This study concerns effects of the testes on two macromolecules in the rat hippocampus that were previously not known to be responsive to this endocrine axis. Castration for 3 weeks elevated the expression of glial fibrillary acidic protein (GFAP) and sulfated glycoprotein-2 (SGP-2) in male rat hippocampus, as shown by Northern blots and immunocytochemistry. SGP-2 mRNA was colocalized with GFAP, implying increased prevalence in astrocytes after castration. During hippocampal responses to deafferentation by entorhinal cortex lesions that damage the perforant path and induce synaptic reorganization, both mRNA and protein for SGP-2 and GFAP increase. Moreover, prior castration had an additive effect with entorhinal cortex lesions in the increase in GFAP and SGP-2 mRNA. These data suggest that testicular hormones regulate hippocampal astrocyte activity in intact adult rats as well as during synaptic reorganization in response to deafferenting lesions.

Hepatic glucocorticoid binders in mature and senescent C57BL/6J male mice.

Because of prominent age-related changes in the responses to stress and in steroid metabolism and excretion, the effect of age on fractionated liver glucocorticoid-binding proteins was studied in C57BL/6J male mice. When cytosol, pre-labeled with [3H]corticosterone, was chromatographed on Sephadex G-100, 4 peaks were obtained. Peak 1 (excluded), peak 2 (corresponding to plasma transcortin), and peak 3 corresponding to glucocorticoid receptors isolated from nuclei) showed no significant age differences. This finding is consistent with reports that glucocorticoid-mediated induction of hepatic tyrosine aminotransferase is not altered by aging in rodents. However, there was a striking age-related decrease (80%) in peak 4 (apparent MW 29,000). Competition studies imply that peak 4 binds aldosterone, testosterone, progesterone, and corticosterone (delta4-3-keto steroids), but not estradiol or dt a plasma component. Although the function of peak 4 is not identified, the pattern of highest competition with delta4-3-keto steroids suggests that it is a steroid ring "A" reductase.