Healthy Human Aging Research Articles

P 235 - A novel nutrient blend mimics calorie restriction transcriptomics differentially in multiple tissues of mice

Identification of caloric restriction mimetics (CRMs), compounds that mimic the beneficial effects of caloric restriction (CR) without restriction of dietary energy would be an advancement in anti-aging science. The present study investigated whether the transcriptional profiles of a putative CRM nutrient blend could mimic that of CR in diverse tissues following long-term feeding in B6C3F1 male mice. Study design: Young Controls (YC; 5 mo.) and 3 groups treated from 14-30 mo.: Old Controls (OC), Old CR (OCR; 25% CR) and Old Supplemented (OS); n=7/group. Gene expression profiling in cerebral cortex (CCT), skeletal muscle (gastrocnemius)(SKL), heart (HRT), white adipose tissue (WAT) and liver (LVR) was performed using Affymetrix Mouse 2.0ST arrays. Principal component analysis revealed that gene expression profiles of YC and OC were distinct from one another in all tissues at 30 months. Using differential analysis, genes commonly expressed in OCR and OS groups compared to the OC group were identified in CCT (3,468), SKL (2,386), HRT (3,523), LVR (1,276) and WAT (683). The OS group mimicked OCR transcriptional profiles most dramatically in CCT, HRT and SKL, tissues highly relevant to aging and age-associated diseases. These CRM effects, elicited by a mid-life intervention, may have positive implications for healthy human aging or ‘youthspan’ and warrant further investigation.

Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases.

To verify the idea that extracellular free oligosaccharides might be able to reflect the functional status of the endoplasmic reticulum (ER) and lysosomal-endosomal system, HPLC-profiles of serum-derived free oligosaccharides (FOS) in human healthy aging, acute myeloproliferative neoplasms, and cardiovascular pathologies were compared with intracellular glycans. After plasma deproteinization and FOS purification the oligosaccharides were labelled with anthranilic acid, separated into the neutral and charged with QAE Sephadex (Q25-120) chromatography and analysed using high-performance liquid chromatography (HPLC). The charged FOS were digested with a sialidase and compared with free oligosaccharides from transferrin for structural decoding. HPLC-profiles of serum-derived FOS revealed mild delay of the dolichol phosphate cycle in ER, moderate intensification of ER-associated degradation (ERAD) and degradation in endosomal-lysosomal system with aging; an inhibition of the dolichol phosphate cycle, intensification of ERAD and increasing of lysosomal exocytosis in acute myeloproliferative neoplasms; intensification of ERAD and glycocojugate degradation with endosomal-lysosomal system in cardiovascular diseases. As serum free oligosaccharides are able to reflect specifically perturbations in ER and endosomal-lysosomal system under wide range of stressors they can serve as extracellular markers of functionality of these organelles.

Using heat as a therapeutic tool for the aging vascular tree.

Healthy aging in humans is associated with progressive deterioration of various organ systems, the cardiovascular system being one of the most notable. Young arteries have a pronounced ability to dilate and constrict to mediate changes in blood flow in response to various stimuli (e.g. exposure to a cold or hot environment). With increasing age, complex structural and functional changes to the blood vessels occur which are further exacerbated by common comorbidities including hypertension, diabetes mellitus and hypercholesterolemia. These changes in both the endothelial and smooth muscular layers of the vasculature are mediated through impaired dilator signalling pathways (e.g. nitric oxide signaling and endothelium-derived hyperpolarizing factor) along with augmented contractile pathways (e.g. renin-angiotensin system and endothelin-1). These age-related changes along with the intimal accumulation of lipids (i.e., atherosclerosis, which can strongly impede dilator function) are thought to span the entire arterial tree. In older adults, the impairments in cardiovascular function are most evident during passive heat stress and/or exercise. Recent reports have indicated that passive exposure to heat that elicits a marked increase in body core temperature, and therefore dilation of the arterial tree, may improve macro- and microvascular dilator function in young adults. Given that older adults exhibit a greater capacity for improvement in dilator function, it is possible that chronic heat exposure, or heat therapy, could improve dilator function of the arterial tree which may have multiple health benefits.

Declining performance of master athletes: silhouettes of the trajectory of healthy human ageing?

Analysis of world record performances by master athletes suggests an essentially linear decline with age until around the eighth decade after which performance decline accelerates. Because these records are obtained from highly trained individuals they can be viewed as being reflective of the diminution of integrative physiological prowess that occurs solely as a result of ageing, unaffected by the confounding effects of inactivity. It can also be argued that these performance profiles mirror and provide an insight into the trajectory of the physiology of the human ageing process. Here we propose a set point theory that hypothesises that a given threshold of physical activity is needed to age optimally and to maximise the 'healthspan'. Exercising at levels below the set point will result in ageing being contaminated by the unpredictable and pathological effects of inactivity. Exercise above this threshold stimulates adaptations towards maximising athletic performance, but is unlikely to have further beneficial effects on health. Thus the decades-long, controlled diminution in athletic performance, should not be seen as a disease process. The ageing process is separate from, and independent of, exercise-mediated processes that maintain or adapt physiological function. Whether an understanding of these mechanisms will also help uncover mechanisms underpinning the ageing process itself is open to question. However, any model which does not take into account the effects of activity will not adequately describe the inherent ageing process.

Decoding the RNA Editome of Normal Versus Malignant Progenitor Cell Aging Short Title: RNA Editing in Normal Aging and MDS/AML Stem Cells

IntroductionHuman bone marrow aging is typified by decreased cellularity, stem cell exhaustion and myeloid lineage bias that may set the stage for development of myeloid malignancies. Secondary AML (sAML) arises from prior myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN), and occurs in patients with an average age of >65. Because of the typically advanced age of this population, patients currently have few effective treatment options available after leukemic transformation. We and others have recently identified a key role for enzymatic RNA editing activity in cancer progression, and in particular in leukemia stem cell (LSC) generation. In hematopoietic stem and progenitor cells, adenosine deaminase acting on dsRNA-1 (ADAR1) is the most abundantly expressed RNA editing gene. However, the role of abnormal RNA editing activity has not been elucidated in healthy human bone marrow aging and age-related MDS with a high risk of transforming to sAML. Therefore, we established whole transcriptome-based RNA editing signatures of benign versus malignant bone marrow progenitor cell aging, which provides novel RNA-based functionally relevant biomarkers of aging, MDS and progression to sAML.MethodsWhole transcriptome sequencing (RNA-Seq) was performed on FACS-purified hematopoietic stem (CD34+CD38-Lin- HSC) and progenitor cells (CD34+CD38+Lin- HPC) from aged (average age = 65.9 y/o) versus young (average age = 25.8 y/o) adult healthy bone marrow samples, and in leukemia stem cells (LSC) from patients with sAML (average age = 71.4 y/o) and MDS (average age = 63.8 y/o). Comparative gene set enrichment analyses (GSEA) and RNA editing profiles were identified for normal and malignant progenitor cell aging.ResultsAberrant RNA editing activity has recently been shown to be induced in multiple cancers, and has been implicated as a malignant reprogramming factor. Comparative whole transcriptome RNA sequencing (RNA-seq) and single nucleotide variant analyses revealed widespread increases in RNA editing rates in aged versus young HPC, and in human sAML LSC compared with age-matched normal progenitors. Moreover, RNA editing rates, represented as adenosine (A) to inosine/guanosine (G) changes at known RNA editing loci, were increased in sAML compared with MDS progenitors. The differential expression of certain sites is as high as 70%, which can be readily detected by RESS-qPCR. These data suggest that during aging niche-dependent RNA editing deregulation contributes to MDS progression to sAML. Interestingly, the highly edited loci in sAML LSC were distinct from loci that were differentially edited in aged versus young HPC, suggesting that pro-inflammatory conditions in sAML may trigger RNA editing of a unique set of transcripts, including predominantly RNA processing-related gene products and transcription factors. Notably, several loci in transcripts of APOBEC3C/D that we previously found were associated with blast crisis transformation of chronic myeloid leukemia also displayed enhanced editing in sAML LSC, but not aged versus young HPC.ConclusionsDetection of aberrant RNA processing provides novel biomarkers as well as potential therapeutic targets for sAML LSC eradication with implications for treatment of a variety of human malignancies and other age-related disorders. We have identified commonly RNA-edited transcripts in multiple hematologic malignancies, which could be developed clinically and as companion diagnostic targets for LSC-targeted therapeutics. DisclosuresJamieson:CTI Biopharma: Research Funding; Johnson & Johnson: Research Funding; GlaxoSmithKline: Research Funding.

The Longitudinal Study of Aging in Human Young Adults: Knowledge Gaps and Research Agenda.

To prevent onset of age-related diseases and physical and cognitive decline, interventions to slow human aging and extend health span must eventually be applied to people while they are still young and healthy. Yet most human aging research examines older adults, many with chronic disease, and little is known about aging in healthy young humans. This article explains how this knowledge gap is a barrier to extending health span and puts forward the case that geroscience should invest in researching the pace of aging in young adults. As one illustrative example, we describe an initial effort to study the pace of aging in a young-adult birth cohort by using repeated waves of biomarkers collected across the third and fourth decades to quantify the pace of coordinated physiological deterioration across multiple organ systems (eg, pulmonary, periodontal, cardiovascular, renal, hepatic, metabolic, and immune function). Findings provided proof of principle that it is possible to quantify individual variation in the pace of aging in young adults still free of age-related diseases. This article articulates research needs to improve longitudinal measurement of the pace of aging in young people, to pinpoint factors that slow or speed the pace of aging, to compare pace of aging against genomic clocks, to explain slow-aging young adults, and to apply pace of aging in preventive clinical trials of antiaging therapies. This article puts forward a research agenda to fill the knowledge gap concerning lifelong causes of aging.

Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging

Cognitive decline is a major biomedical challenge as the global population ages. Elevated levels of the longevity factor klotho suppress aging, enhance cognition, and promote synaptic plasticity and neural resilience against aging and Alzheimer’s disease (AD)-related pathogenic proteins. Here, we examined the relationship between human genetic variants of KLOTHO and systemic klotho levels – and assessed neuroanatomic correlates of serum klotho in a cohort of healthy older adults. Serum klotho levels were increased with KL-VS heterozygosity, as anticipated. We report, for the first time, that serum klotho levels were paradoxically decreased with KL-VS homozygosity. Further, we found that higher serum klotho levels were associated with measures of greater intrinsic connectivity in key functional networks of the brain vulnerable to aging and AD such as the fronto-parietal and default mode networks. Our findings suggest that elevated klotho promotes a resilient brain, possibly through increased network connectivity of critical brain regions.

Down with Retirement: Implications of Embodied Cognition for Healthy Aging.

Cognitive and neurocognitive approaches to human healthy aging attribute age-related decline to the biologically caused loss of cognitive-control functions. However, an embodied-cognition approach to aging implies a more interactive view according to which cognitive control emerges from, and relies on a person’s active encounters with his or her physical and social environment. We argue that the availability of cognitive-control resources does not only rely on biological processes but also on the degree of active maintenance, that is, on the systematic use of the available control resources. Unfortunately, there is evidence that the degree of actual use might systematically underestimate resource availability, which implies that elderly individuals do not fully exploit their cognitive potential. We discuss evidence for this possibility from three aging-related issues: the reduction of dopaminergic supply, loneliness, and the loss of body strength. All three phenomena point to a downward spiral, in which losses of cognitive-control resources do not only directly impair performance but also more indirectly discourage individuals from making use of them, which in turn suggests underuse and a lack of maintenance—leading to further loss. On the positive side, the possibility of underuse points to not yet fully exploited reservoirs of cognitive control, which calls for more systematic theorizing and experimentation on how cognitive control can be enhanced, as well as for reconsiderations of societal practices that are likely to undermine the active maintenance of control resources—such as retirement laws.

TAF4b Regulates Oocyte-Specific Genes Essential for Meiosis.

TAF4b is a gonadal-enriched subunit of the general transcription factor TFIID that is implicated in promoting healthy ovarian aging and female fertility in mice and humans. To further explore the potential mechanism of TAF4b in promoting ovarian follicle development, we analyzed global gene expression at multiple time points in the human fetal ovary. This computational analysis revealed coordinate expression of human TAF4B and critical regulators and effectors of meiosis I including SYCP3, YBX2, STAG3, and DAZL. To address the functional relevance of this analysis, we turned to the embryonic Taf4b-deficient mouse ovary where, for the first time, we demonstrate, severe deficits in prophase I progression as well as asynapsis in Taf4b-deficient oocytes. Accordingly, TAF4b occupies the proximal promoters of many essential meiosis and oogenesis regulators, including Stra8, Dazl, Figla, and Nobox, and is required for their proper expression. These data reveal a novel TAF4b function in regulating a meiotic gene expression program in early mouse oogenesis, and support the existence of a highly conserved TAF4b-dependent gene regulatory network promoting early oocyte development in both mice and women.

Human longevity: Genetics or Lifestyle? It takes two to tango.

Healthy aging and longevity in humans are modulated by a lucky combination of genetic and non-genetic factors. Family studies demonstrated that about 25 % of the variation in human longevity is due to genetic factors. The search for genetic and molecular basis of aging has led to the identification of genes correlated with the maintenance of the cell and of its basic metabolism as the main genetic factors affecting the individual variation of the aging phenotype. In addition, studies on calorie restriction and on the variability of genes associated with nutrient-sensing signaling, have shown that ipocaloric diet and/or a genetically efficient metabolism of nutrients, can modulate lifespan by promoting an efficient maintenance of the cell and of the organism. Recently, epigenetic studies have shown that epigenetic modifications, modulated by both genetic background and lifestyle, are very sensitive to the aging process and can either be a biomarker of the quality of aging or influence the rate and the quality of aging.On the whole, current studies are showing that interventions modulating the interaction between genetic background and environment is essential to determine the individual chance to attain longevity.

Nutritional issues for older adults: addressing degenerative ageing with long-term studies.

The ageing process is influenced by a variety of factors, including extrinsic, malleable lifestyle variables. The present paper deals with the epidemiological evidence for the role of dietary patterns and key nutritional concerns in relation to survival and ageing-related disorders that present themselves in later life. Healthful dietary patterns appear to be most relevant in old age. Specific nutritional concerns are related to vitamin D, vitamin B12 and protein malnutrition. An important challenge to further expand the knowledge base is currently addressed by the NuAge project, acknowledging the complexity of the ageing process and integrating different dimensions of research into human healthy ageing. In the meantime, reversing poor adherence to existing guidelines for a healthy diet remains a first challenge in public health nutritional practices.

Live strong and prosper: the importance of skeletal muscle strength for healthy ageing.

Due to improved health care, diet and infrastructure in developed countries, since 1840 life expectancy has increased by approximately 2 years per decade. Accordingly, by 2050, a quarter of Europe’s population will be over 65 years, representing a 10 % rise in half a century. With this rapid rise comes an increased prevalence of diseases of ageing and associated healthcare expenditure. To address the health consequences of global ageing, research in model systems (worms, flies and mice) has indicated that reducing the rate of organ growth, via reductions in protein synthetic rates, has multi-organ health benefits that collectively lead to improvements in lifespan. In contrast, human pre-clinical, clinical and large cohort prospective studies demonstrate that ageing leads to anabolic (i.e. growth) impairments in skeletal muscle, which in turn leads to reductions in muscle mass and strength, factors directly associated with mortality rates in the elderly. As such, increasing muscle protein synthesis via exercise or protein-based nutrition maintains a strong, healthy muscle mass, which in turn leads to improved health, independence and functionality. The aim of this review is to critique current literature relating to the maintenance of muscle mass across lifespan and discuss whether maintaining or reducing protein synthesis is the most logical approach to support musculoskeletal function and by extension healthy human ageing.

Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring.

Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. Semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock". We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6 ± 1.6 years), 63 semi-supercentenarians' offspring (mean age: 71.8 ± 7.8 years), and 47 age-matched controls (mean age: 69.8 ± 7.2 years). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference=5.1 years, p=0.00043) and that centenarians are younger (8.6 years) than expected based on their chronological age. By contrast, no significant difference could be observed for estimated blood cell counts (such as naïve or exhausted cytotoxic T cells or helper T cells). Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.

Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults

Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1years; mean±SE, 53–79years) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4mg) following eplerenone (100mg/dose, 2 doses, 24h between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6%, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOSSer1177 to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5%, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77±4/2mmHg, P≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure.

Change in N-Glycosylation of Plasma Proteins in Japanese Semisupercentenarians.

An N-glycomic analysis of plasma proteins was performed in Japanese semisupercentenarians (SSCs) (mean 106.7 years), aged controls (mean 71.6 years), and young controls (mean 30.2 years) by liquid chromatography/mass spectrometry (LC/MS) using a graphitized carbon column. Characteristic N-glycans in SSCs were discriminated using a multivariate analysis; orthogonal projections to latent structures (O-PLS). The results obtained showed that multi-branched and highly sialylated N-glycans as well as agalacto- and/or bisecting N-glycans were increased in SSCs, while biantennary N-glycans were decreased. Since multi-branched and highly sialylated N-glycans have been implicated in anti-inflammatory activities, these changes may play a role in the enhanced chronic inflammation observed in SSCs. The levels of inflammatory proteins, such as CRP, adiponectin, IL-6, and TNF-α, were elevated in SSCs. These results suggested that responses to inflammation may play an important role in extreme longevity and healthy aging in humans. This is the first study to show that the N-glycans of plasma proteins were associated with extreme longevity and healthy aging in humans.

IL7R gene expression network associates with human healthy ageing.

BackgroundThe level of expression of the interleukin 7 receptor (IL7R) gene in blood has recently been found to be associated with familial longevity and healthy ageing. IL7R is crucial for T cell development and important for immune competence. To further investigate the IL7R pathway in ageing, we identified the closest interacting genes to construct an IL7R gene network that consisted of IL7R and six interacting genes: IL2RG, IL7, TSLP, CRLF2, JAK1 and JAK3. This network was explored for association with chronological age, familial longevity and immune-related diseases (type 2 diabetes, chronic obstructive pulmonary disease and rheumatoid arthritis) in 87 nonagenarians, 337 of their middle-aged offspring and 321 middle-aged controls from the Leiden Longevity Study (LLS).ResultsWe observed that expression levels within the IL7R gene network were significantly different between the nonagenarians and middle-aged controls (P = 4.6 × 10−4), being driven by significantly lower levels of expression in the elderly of IL7, IL2RG and IL7R. After adjustment for multiple testing and white blood cell composition and in comparison with similarly aged controls, middle-aged offspring of nonagenarian siblings exhibit a lower expression level of IL7R only (P = 0.006). Higher IL7R gene expression in the combined group of middle-aged offspring and controls is associated with a higher prevalence of immune-related disease (P = 0.001). On the one hand, our results indicate that lower IL7R expression levels, as exhibited by the members of long-lived families that can be considered as ‘healthy agers’, are beneficial in middle age. This is augmented by the observation that higher IL7R gene expression associates with immune-related disease. On the other hand, IL7R gene expression in blood is lower in older individuals, indicating that low IL7R gene expression might associate with reduced health. Interestingly, this contradictory result is supported by the observation that a higher IL7R gene expression level is associated with better prospective survival, both in the nonagenarians (Hazard ratio (HR) = 0.63, P = 0.037) and the middle-aged individuals (HR = 0.33, P = 1.9 × 10–4).ConclusionsOverall, we conclude that the IL7R network reflected by gene expression levels in blood may be involved in the rate of ageing and health status of elderly individuals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-015-0048-6) contains supplementary material, which is available to authorized users.

Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P<0.05). Furthermore, central IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P<0.05). Taken together, IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans.

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status.

BackgroundDiagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health.ResultsOne hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83–0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is ‘up-regulated’ in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case–control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA ‘disease signature’, the healthy ageing RNA classifier is diagnostic for AD.ConclusionsWe identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0750-x) contains supplementary material, which is available to authorized users.

The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases

REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer’s disease and Huntington’s disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

Lack of age-dependent decrease in dopamine D3 receptor availability: a [(11)C]-(+)-PHNO and [(11)C]-raclopride positron emission tomography study.

Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [(11)C]-(+)-PHNO (n=72, mean±s.d. age=40±15, range=18 to 73) and the antagonist [(11)C]-Raclopride (n=70, mean±s.d. age =40±14, range=18 to 73) (both, n=33). The contribution of D3R to the [(11)C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [(11)C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate (r(70)=-0.32, P=0.005). No correlations were observed in the other regions. With [(11)C]-Raclopride, negative correlations were observed between age and BPND in the caudate (r(68)=-0.50, P<0.001), putamen (r(68)=-0.41, P<0.001), and ventral striatum (r(68)=-0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age.