Polarized Anti-Inflammatory Mesenchymal Stem Cells Increase Hippocampal Neurogenesis and Improve Cognitive Function in Aged Mice.

Age-related decline in cognitive functions is associated with reduced hippocampal neurogenesis caused by changes in the systemic inflammatory milieu. Mesenchymal stem cells (MSC) are known for their immunomodulatory properties. Accordingly, MSC are a leading candidate for cell therapy and can be applied to alleviate inflammatory diseases as well as aging frailty via systemic delivery. Akin to immune cells, MSC can also polarize into pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. In the present study, we apply pituitary adenylate cyclase-activating peptide (PACAP) to polarize bone-marrow-derived MSC towards an MSC2 phenotype. Indeed, we found that polarized anti-inflammatory MSC were able to reduce the plasma levels of aging related chemokines in aged mice (18-months old) and increased hippocampal neurogenesis following systemic administration. Similarly, aged mice treated with polarized MSC displayed improved cognitive function in the Morris water maze and Y-maze assays compared with vehicle- and naïve-MSC-treated mice. Changes in neurogenesis and Y-maze performance were negatively and significantly correlated with sICAM, CCL2 and CCL12 serum levels. We conclude that polarized PACAP-treated MSC present anti-inflammatory properties that can mitigate age-related changes in the systemic inflammatory milieu and, as a result, ameliorate age related cognitive decline.

Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis.

Schizophrenia is a neurodevelopmental disease with a mixed genetic and environmental aetiology. Impaired adult hippocampal neurogenesis was suggested both as a pathophysiological mechanism and as a target for therapy. In the present study, we utilized intracerebroventricular transplantation of bone marrow-derived mesenchymal stem cells (MSC) as a means to enhance hippocampal neurogenesis in the ketamine-induced neurodevelopmental murine model for schizophrenia. Syngeneic MSC have successfully engrafted and survived for up to 3 months following transplantation. Improvement in social novelty preference and prepulse inhibition was noted after transplantation. In parallel to behavioural improvement, increased hippocampal neurogenesis as reflected in the numbers of doublecortin expressing neurons in the dentate gyrus and gene expression was noted both 2 weeks following transplantation as well as 3 months later compared with nontreated animals. An independent aging effect was observed for both behaviour and neurogenesis, which was attenuated by MSC treatment. As opposed to MSC treatment, short-term treatment with clozapine was efficient only during treatment and diminished 3 months later. Interestingly, while shortly after transplantation (2 weeks) behavioural improvement was correlated mainly to FGF2 gene expression, 3 months later it was mainly correlated to the expression of the notch ligand DLL1. This suggests that long-term effect during ageing may depend on neural stem cell self-renewal. We conclude that a single intracerebroventricular injection of bone marrow-derived MSC can suffice for long-term reversal of changes in adult hippocampal neurogenesis and improve schizophrenia-like behavioural phenotype inflicted by developmental exposure to ketamine in mice.

Correlative links between natural radiation and life expectancy in the US population.

The linear no-threshold (LNT) hypothesis is still the ruling concept which dictates the radiation protection health policy and regulations. However, more and more studies show that not only that low dose radiation pose no danger to our health, but also exhibits clear beneficial health effects. Here, we evaluated the correlative links of the natural sources of radiation-terrestrial radiation (TR), cosmic radiation (CR), and Radon-222, with life expectancy, the most integrative index of population health. The results of this study show that the different sources of natural radiation display positive correlative links to life expectancy, which is in line with the hypothesis of radiation hormesis.

Expression Profiling Suggests Loss of Surface Integrity and Failure of Regenerative Repair as Major Driving Forces for Chronic Obstructive Pulmonary Disease Progression.

Chronic obstructive pulmonary disease (COPD) poses a major risk for public health, yet remarkably little is known about its detailed pathophysiology. Definition of COPD as nonreversible pulmonary obstruction revealing more about spatial orientation than about mechanisms of pathology may be a major reason for this. We conducted a controlled observational study allowing for simultaneous assessment of clinical and biological development in COPD. Sixteen healthy control subjects and 104 subjects with chronic bronchitis, with or without pulmonary obstruction at baseline, were investigated. Using both the extent of and change in bronchial obstruction as main scoring criteria for the analysis of gene expression in lung tissue, we identified 410 genes significantly associated with progression of COPD. One hundred ten of these genes demonstrated a distinctive expression pattern, with their functional annotations indicating participation in the regulation of cellular coherence, membrane integrity, growth, and differentiation, as well as inflammation and fibroproliferative repair. The regulatory pattern indicates a sequentially unfolding pathology that centers on a two-step failure of surface integrity commencing with a loss of epithelial coherence as early as chronic bronchitis. Decline of regenerative repair starting in Global Initiative for Chronic Obstructive Lung Disease stage I then activates degradation of extracellular-matrix hyaluronan, causing structural failure of the bronchial wall that is only resolved by scar formation. Although they require independent confirmation, our findings provide the first tangible pathophysiological concept of COPD to be further explored.Clinical trial registered with www.clinicaltrials.gov (NCT00618137).

Background radiation impacts human longevity and cancer mortality: reconsidering the linear no-threshold paradigm.

The current linear no-threshold paradigm assumes that any exposure to ionizing radiation carries some risk, thus every effort should be made to maintain the exposures as low as possible. We examined whether background radiation impacts human longevity and cancer mortality. Our data covered the entire US population of the 3139 US counties, encompassing over 320 million people. This is the first large-scale study which takes into account the two major sources of background radiation (terrestrial radiation and cosmic radiation), covering the entire US population. Here, we show that life expectancy, the most integrative index of population health, was approximately 2.5 years longer in people living in areas with a relatively high vs. low background radiation. (≥ 180 mrem/year and ≤ 100 mrem/year, respectively; p < 0.005; 95% confidence interval [CI]). This radiation-induced lifespan extension could to a great extent be associated with the decrease in cancer mortality rate observed for several common cancers (lung, pancreas and colon cancers for both genders, and brain and bladder cancers for males only; p < 0.05; 95% CI). Exposure to a high background radiation displays clear beneficial health effects in humans. These hormetic effects provide clear indications for re-considering the linear no-threshold paradigm, at least within the natural range of low-dose radiation.

Machine Learning Analysis of Longevity-Associated Gene Expression Landscapes in Mammals.

One of the important questions in aging research is how differences in transcriptomics are associated with the longevity of various species. Unfortunately, at the level of individual genes, the links between expression in different organs and maximum lifespan (MLS) are yet to be fully understood. Analyses are complicated further by the fact that MLS is highly associated with other confounding factors (metabolic rate, gestation period, body mass, etc.) and that linear models may be limiting. Using gene expression from 41 mammalian species, across five organs, we constructed gene-centric regression models associating gene expression with MLS and other species traits. Additionally, we used SHapley Additive exPlanations and Bayesian networks to investigate the non-linear nature of the interrelations between the genes predicted to be determinants of species MLS. Our results revealed that expression patterns correlate with MLS, some across organs, and others in an organ-specific manner. The combination of methods employed revealed gene signatures formed by only a few genes that are highly predictive towards MLS, which could be used to identify novel longevity regulator candidates in mammals.

Metabolic remodelling of mice by hypoxic-hypercapnic environment: imitating the naked mole-rat.

We hypothesised that hypoxic-hypercapnic environment (HHE) could induce metabolic suppression and associated benefits for health and longevity, as observed in the naked-mole rat (NMR). We developed a model of self-produced HHE (similar to a natural habitat of NMRs), which is simple, reliable and natural, and does not require external sources of gases or complex technical equipment. Here, we showed for the first time that a chronic exposure of mice to HHE could be a unique tool for NMR-like metabolic remodeling, resulting in a long-term and substantial decrease in metabolic rate, body temperature, and food consumption, without significant changes in expression of stress-related genes. Unexpectedly, the HHE accelerated skin wound healing, despite the lower energy expenditure. The self-produced HHE could be considered a model of voluntary calorie restriction. All in all, a chronic exposure to HHE offers a potential of being a lifespan-extending intervention as well as an efficient tool for treating the overweight and associated metabolic disorders.

Human Ageing Genomic Resources: new and updated databases.

In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR's main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/).

MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity.

Mitochondria are the only organelles in the animal cells that have their own genome. Due to a key role in energy production, generation of damaging factors (ROS, heat), and apoptosis, mitochondria and mtDNA in particular have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases. The rapidly increasing number of species with fully sequenced mtDNA, together with accumulated data on longevity records, provides a new fascinating basis for comparative analysis of the links between mtDNA features and animal longevity. To facilitate such analyses and to support the scientific community in carrying these out, we developed the MitoAge database containing calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop) regions, and codon usage/amino acids frequency for each protein-coding gene. MitoAge includes 922 species with fully sequenced mtDNA and maximum lifespan records. The database is available through the MitoAge website (www.mitoage.org or www.mitoage.info), which provides the necessary tools for searching, browsing, comparing and downloading the data sets of interest for selected taxonomic groups across the Kingdom Animalia. The MitoAge website assists in statistical analysis of different features of the mtDNA and their correlative links to longevity.

De novo assembling and primary analysis of genome and transcriptome of gray whale Eschrichtius robustus.

BACKGROUND: Gray whale, Eschrichtius robustus (E. robustus), is a single member of the family Eschrichtiidae, which is considered to be the most primitive in the class Cetacea. Gray whale is often described as a "living fossil". It is adapted to extreme marine conditions and has a high life expectancy (77 years). The assembly of a gray whale genome and transcriptome will allow to carry out further studies of whale evolution, longevity, and resistance to extreme environment. RESULTS: In this work, we report the first de novo assembly and primary analysis of the E. robustus genome and transcriptome based on kidney and liver samples. The presented draft genome assembly is complete by 55% in terms of a total genome length, but only by 24% in terms of the BUSCO complete gene groups, although 10,895 genes were identified. Transcriptome annotation and comparison with other whale species revealed robust expression of DNA repair and hypoxia-response genes, which is expected for whales. CONCLUSIONS: This preliminary study of the gray whale genome and transcriptome provides new data to better understand the whale evolution and the mechanisms of their adaptation to the hypoxic conditions.

Differential decrease in soluble and DNA-bound telomerase in senescent human fibroblasts.

The role of telomere shortening in the induction of replicative cellular senescence (CS) is well known and as a result, the involvement of telomerase and in particular its catalytic subunit, the telomerase reverse transcriptase (TERT) in CS has also been investigated. However, the majority of studies were conducted on cells that generally express high levels of TERT (cancer and immortalized cells) while the role of telomerase in CS in normal cells has been investigated to a much lesser extent. In particular, it was reported that active TERT is expressed in early passages of cultured human keratinocytes but rapidly diminished towards entry to CS, without telomere shortening. With the putative importance of TERT/telomerase in CS and the aging process in mind, we investigated the expression of TERT and telomerase activity in primary cultures of adult human dermal fibroblasts (HDFs) in the in vitro model of replicative CS. We found that (i) HDFs expressed active TERT; (ii) TERT protein levels and telomerase activity were markedly decreased in senescent HDFs; and (iii) the reduction of TERT in the soluble fraction was more pronounced than in the DNA-bound one. The results suggest the importance of the non-canonical (telomere-unrelated) functions of TERT in cellular senescence.

Middle age enhances expression of innate immunity genes in a female mouse model of pulmonary fibrosis.

The lungs are highly sensitive to tissue fibrosis, with a clear age-related component. Among the possible triggers of pulmonary fibrosis are repeated inhalations of fine organic particles. How age affects this response, is still far from being fully understood. We examined the impact of middle-age on gene expression in pulmonary fibrosis, using the novel "inhalation challenge set" mouse model. Our results demonstrate that the response of female mice to exposure of Pantoea agglomerans extract primarily involves various immune-related pathways and cell-cell/cell-extracellular matrix interactions. We found that middle-age had a strong effect on the response to the P. agglomerans-induced lung fibrosis, featured by a more rapid response and increased magnitude of expression changes. Genes belonging to innate immunity pathways (such as the TLR signaling and the NK-cell mediated cytotoxicity) were particularly up-regulated in middle-aged animals, suggesting that they may be potential targets for the treatment of pulmonary fibrosis caused by inhalations of organic particles. Our analysis also highlights the relevance of the "inhalation challenge set" mouse model to lung aging and related pathology.

LongevityMap: a database of human genetic variants associated with longevity.

Understanding the genetic basis of human longevity remains a challenge but could lead to life-extending interventions and better treatments for age-related diseases. Toward this end we developed the LongevityMap (http://genomics.senescence.info/longevity/), the first database of genes, loci, and variants studied in the context of human longevity and healthy ageing. We describe here its content and interface, and discuss how it can help to unravel the genetics of human longevity.

Middle age has a significant impact on gene expression during skin wound healing in male mice.

The vast majority of research on the impact of age on skin wound healing (WH) compares old animals to young ones. The middle age is often ignored in biogerontological research despite the fact that many functions that decline in an age-dependent manner have starting points in mid-life. With this in mind, we examined gene expression patterns during skin WH in late middle-aged versus young adult male mice, using the head and back punch models. The rationale behind this study was that the impact of age would first be detectable at the transcriptional level. We pinpointed several pathways which were over-activated in the middle-aged mice, both in the intact skin and during WH. Among them were various metabolic, immune-inflammatory and growth-promoting pathways. These transcriptional changes were much more pronounced in the head than in the back. In summary, the middle age has a significant impact on gene expression in intact and healing skin. It seems that the head punch model is more sensitive to the effect of age than the back model, and we suggest that it should be more widely applied in aging research on wound healing.

Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing.

The Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for >4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction. Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. The completely redesigned interface, more intuitive and more integrative of HAGR resources, is also presented. Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology.

Stem cell-derived extracellular vesicles as senotherapeutics.

Cellular senescence (CS) is recognized as one of the hallmarks of aging, and an important player in a variety of age-related pathologies. Accumulation of senescent cells can promote a pro-inflammatory and pro-cancerogenic microenvironment. Among potential senotherapeutics are extracellular vesicles (EVs) (40-1000 nm), including exosomes (40-150 nm), that play an important role in cell-cell communications. Here, we review the most recent studies on the impact of EVs derived from stem cells (MSCs, ESCs, iPSCs) as well as non-stem cells of various types on CS and discuss potential mechanisms responsible for the senotherapeutic effects of EVs. The analysis revealed that (i) EVs derived from stem cells, pluripotent (ESCs, iPSCs) or multipotent (MSCs of various origin), can mitigate the cellular senescence phenotype both in vitro and in vivo; (ii) this effect is presumably senomorphic; (iii) EVs display cross-species activity, without apparent immunogenic responses. In summary, stem cell-derived EVs appear to be promising senotherapeutics, with a feasible application in humans.

Linking cell polarity, aging and rejuvenation.

Cell polarity is a universal biological phenomenon. While much is known about the establishment and maintenance of cell polarity, its role in aging and age-related diseases remains to be fully addressed. Nonetheless, the exciting findings in the budding yeast indicate that the polar processes are intimately linked to both aging of the mother cell and rejuvenation of the daughter cell. This includes polar segregation of damaged proteins and ERCs due to the septin-based diffusion barrier, asymmetric inheritance of MDR proteins and retrograde protein transport. The principal, still unexplored question is whether the same polar mechanisms work during the asymmetric division of germ and stem cells, allowing their rejuvenation across generations. Further strengthening the links between cell polarity and aging is a large number of common genes associated with both polarity and longevity. Given a strong similarity between mechanisms of cell polarity in yeast and higher eukaryotes, the budding yeast Saccharomyces cerevisiae could serve as a convenient model system for studying the links between the cell polarity, aging and rejuvenation. Consequently, exploring the potential mammalian equivalents of yeast-established polarity mechanisms could be the focus for future biogerontological investigations.

Is rate of skin wound healing associated with aging or longevity phenotype?

Wound healing (WH) is a fundamental biological process. Is it associated with a longevity or aging phenotype? In an attempt to answer this question, we compared the established mouse models with genetically modified life span and also an altered rate of WH in the skin. Our analysis showed that the rate of skin WH in advanced ages (but not in the young animals) may be used as a marker for biological age, i.e., to be indicative of the longevity or aging phenotype. The ability to preserve the rate of skin WH up to an old age appears to be associated with a longevity phenotype, whereas a decline in WH-with an aging phenotype. In the young, this relationship is more complex and might even be inversed. While the aging process is likely to cause wounds to heal slowly, an altered WH rate in younger animals could indicate a different cellular proliferation and/or migration capacity, which is likely to affect other major processes such as the onset and progression of cancer. As a point for future studies on WH and longevity, using only young animals might yield confusing or misleading results, and therefore including older animals in the analysis is encouraged.

Systems biology analysis of lung fibrosis-related genes in the bleomycin mouse model.

Tissue fibrosis is a major driver of pathology in aging and is involved in numerous age-related diseases. The lungs are particularly susceptible to fibrotic pathology which is currently difficult to treat. The mouse bleomycin-induced fibrosis model was developed to investigate lung fibrosis and widely used over the years. However, a systematic analysis of the accumulated results has not been performed. We undertook a comprehensive data mining and subsequent manual curation, resulting in a collection of 213 genes (available at the TiRe database, www.tiredb.org ), which when manipulated had a clear impact on bleomycin-induced lung fibrosis. Our meta-analysis highlights the age component in pulmonary fibrosis and strong links of related genes with longevity. The results support the validity of the bleomycin model to human pathology and suggest the importance of a multi-target therapeutic strategy for pulmonary fibrosis treatment.

Small molecules for cell reprogramming: a systems biology analysis.

If somatic stem cells would be able to maintain their regenerative capacity over time, this might, to a great extent, resolve rejuvenation issues. Unfortunately, the pool of somatic stem cells is limited, and they undergo cell aging with a consequent loss of functionality. During the last decade, low molecular weight compounds that are able to induce or enhance cell reprogramming have been reported. They were named "Small Molecules" (SMs) and might present definite advantages compared to the exogenous introduction of stemness-related transcription factors (e.g. Yamanaka's factors). Here, we undertook a systemic analysis of SMs and their potential gene targets. Data mining and curation lead to the identification of 92 SMs. The SM targets fall into three major functional categories: epigenetics, cell signaling, and metabolic "switchers". All these categories appear to be required in each SM cocktail to induce cell reprogramming. Remarkably, many enriched pathways of SM targets are related to aging, longevity, and age-related diseases, thus connecting them with cell reprogramming. The network analysis indicates that SM targets are highly interconnected and form protein-protein networks of a scale-free topology. The extremely high contribution of hubs to network connectivity suggests that (i) cell reprogramming may require SM targets to act cooperatively, and (ii) their network organization might ensure robustness by resistance to random failures. All in all, further investigation of SMs and their relationship with longevity regulators will be helpful for developing optimal SM cocktails for cell reprogramming with a perspective for rejuvenation and life span extension.