The impact of aging on memory T cell phenotype and function in the human bone marrow.

Recently, the BM has been shown to play a key role in regulating the survival and function of memory T cells. However, the impact of aging on these processes has not yet been studied. We demonstrate that the number of CD4⁺ and CD8⁺ T cells in the BM is maintained during aging. However, the composition of the T cell pool in the aged BM is altered with a decline of naïve and an increase in T(EM) cells. In contrast to the PB, a highly activated CD8⁺CD28⁻ T cell population, which lacks the late differentiation marker CD57, accumulates in the BM of elderly persons. IL-6 and IL-15, which are both increased in the aged BM, efficiently induce the activation, proliferation, and differentiation of CD8⁺ T cells in vitro, highlighting a role of these cytokines in the age-dependent accumulation of highly activated CD8⁺CD28⁻ T cells in the BM. Yet, these age-related changes do not impair the maintenance of a high number of polyfunctional memory CD4⁺ and CD8⁺ T cells in the BM of elderly persons. In summary, aging leads to the accumulation of a highly activated CD8⁺CD28⁻ T cell population in the BM, which is driven by the age-related increase of IL-6 and IL-15. Despite these changes, the aged BM is a rich source of polyfunctional memory T cells and may thus represent an important line of defense to fight recurrent infections in old age.

GiSAO.db: a database for ageing research.

BACKGROUND: Age-related gene expression patterns of Homo sapiens as well as of model organisms such as Mus musculus, Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster are a basis for understanding the genetic mechanisms of ageing. For an effective analysis and interpretation of expression profiles it is necessary to store and manage huge amounts of data in an organized way, so that these data can be accessed and processed easily. DESCRIPTION: GiSAO.db (Genes involved in senescence, apoptosis and oxidative stress database) is a web-based database system for storing and retrieving ageing-related experimental data. Expression data of genes and miRNAs, annotation data like gene identifiers and GO terms, orthologs data and data of follow-up experiments are stored in the database. A user-friendly web application provides access to the stored data. KEGG pathways were incorporated and links to external databases augment the information in GiSAO.db. Search functions facilitate retrieval of data which can also be exported for further processing. CONCLUSIONS: We have developed a centralized database that is very well suited for the management of data for ageing research. The database can be accessed at https://gisao.genome.tugraz.at and all the stored data can be viewed with a guest account.

Age-specific changes of mesenchymal stem cells are paralleled by upregulation of CD106 expression as a response to an inflammatory environment.

Regeneration, tissue remodeling, and organ repair after injury, which rely on the regulated activity of tissue-borne stem cells, become increasingly compromised with advancing age. Mesenchymal stroma cells were isolated from bone of differently aged healthy donors. The rare population of mesenchymal stem cells (MSCs) contained in the primary cell isolates barely declined in number, yet the stem cells displayed diminished long-term proliferation potential relative to the donor age and the expression of vascular cell adhesion molecule-1 (VCAM-1; CD106) was elevated on primary MSCs. In CD106(bright) MSCs, the abundance of a panel of stemness transcription factors remained unchanged. Because the CD106 level could be further enhanced by proinflammatory cytokines, we considered the rate of VCAM-1 expression to be a good reflection of an endogenous inflammatory milieu to which the MSCs are exposed. Treatment of MSCs with increasing doses of interferon-γ exerted no immediate influence on their self-renewal capacity. However, it impacted on the differentiation potential toward the adipogenic or osteogenic lineage. Moderately elevated levels of inflammatory stimuli supported osteoblastogenesis whereas the same treatment reduced adipogenic differentiation in MSCs from young and intermediately aged donors. In MSCs from elderly donors, however, osteoblastogenesis was greatly diminished in an inflammatory environment whereas adipogenic differentiation remained unchanged. Conclusively, moderate levels of inflammatory stimuli are being interpreted by MSCs at a young age as instructive signals for osteoblastogenesis, whereas at old age, an inflammatory milieu may effectively suppress bone remodeling and repair by tissue-borne MSCs while uninterrupted adipogenic differentiation may lead to adipose upgrowth.

Identification of evolutionarily conserved genetic regulators of cellular aging.

To identify new genetic regulators of cellular aging and senescence, we performed genome-wide comparative RNA profiling with selected human cellular model systems, reflecting replicative senescence, stress-induced premature senescence, and distinct other forms of cellular aging. Gene expression profiles were measured, analyzed, and entered into a newly generated database referred to as the GiSAO database. Bioinformatic analysis revealed a set of new candidate genes, conserved across the majority of the cellular aging models, which were so far not associated with cellular aging, and highlighted several new pathways that potentially play a role in cellular aging. Several candidate genes obtained through this analysis have been confirmed by functional experiments, thereby validating the experimental approach. The effect of genetic deletion on chronological lifespan in yeast was assessed for 93 genes where (i) functional homologues were found in the yeast genome and (ii) the deletion strain was viable. We identified several genes whose deletion led to significant changes of chronological lifespan in yeast, featuring both lifespan shortening and lifespan extension. In conclusion, an unbiased screen across species uncovered several so far unrecognized molecular pathways for cellular aging that are conserved in evolution.

miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging.

Aging is a multifactorial process where deterioration of body functions is driven by stochastic damage while counteracted by distinct genetically encoded repair systems. To better understand the genetic component of aging, many studies have addressed the gene and protein expression profiles of various aging model systems engaging different organisms from yeast to human. The recently identified small non-coding miRNAs are potent post-transcriptional regulators that can modify the expression of up to several hundred target genes per single miRNA, similar to transcription factors. Increasing evidence shows that miRNAs contribute to the regulation of most if not all important physiological processes, including aging. However, so far the contribution of miRNAs to age-related and senescence-related changes in gene expression remains elusive. To address this question, we have selected four replicative cell aging models including endothelial cells, replicated CD8(+) T cells, renal proximal tubular epithelial cells, and skin fibroblasts. Further included were three organismal aging models including foreskin, mesenchymal stem cells, and CD8(+) T cell populations from old and young donors. Using locked nucleic acid-based miRNA microarrays, we identified four commonly regulated miRNAs, miR-17 down-regulated in all seven; miR-19b and miR-20a, down-regulated in six models; and miR-106a down-regulated in five models. Decrease in these miRNAs correlated with increased transcript levels of some established target genes, especially the cdk inhibitor p21/CDKN1A. These results establish miRNAs as novel markers of cell aging in humans.

Microarray analysis reveals similarity between CD8+CD28- T cells from young and elderly persons, but not of CD8+CD28+ T cells.

We isolated highly purified CD8+CD28+ and CD8+CD28- T cell populations from healthy young and elderly persons for gene expression profiling using Affymetrix oligonucleotide microarrays. We demonstrate that the gene expression profile of CD8+CD28- T cells is very similar in young and elderly persons. In contrast, CD8+CD28+ in elderly differ from CD8+CD28+ in young persons. Hierarchical clustering revealed that CD8+CD28+ in elderly are located between CD8+CD28+ in young and CD8+CD28- (young and old) T cells regarding their differentiation state. Our study demonstrates a dichotomy of gene expression levels between CD8+CD28+ T cells in young and elderly persons but a similarity between CD8+CD28- T cells in young and elderly persons. As CD8+CD28+ T cells from elderly and young persons are distinct due to a different composition of the population, these results suggest that the gene expression profile does not depend on chronological age but depends on the differentiation state of the individual cell types.

Non-regulatory CD8+CD45RO+CD25+ T-lymphocytes may compensate for the loss of antigen-inexperienced CD8+CD45RA+ T-cells in old age.

The age-related decline in immune system functions is responsible for the increased prevalence of infectious diseases and the low efficacy of vaccination in elderly individuals. In particular, the number of peripheral naive T-cells declines throughout life and they exhibit severe functional defects at advanced age. However, we have recently identified a non-regulatory CD8+CD45RO+ CD25+ T-cell subset that occurs in a subgroup of healthy elderly individuals, who still exhibit an intact humoral immune response following influenza vaccination. Here, we demonstrate that CD8+CD45RO+CD25+ T-cells share phenotypic and functional characteristics with naive CD8+CD45RA+CD28+ T-cells from young individuals, despite their expression of CD45RO. CD8+CD45RO+ CD25+ T-cells also have long telomeres and upon antigenic challenge, they efficiently expand in vitro and differentiate into functional effector cells. The expanded population also maintains a diverse T-cell receptor repertoire. In conclusion, CD8+CD45RO+CD25+ T-cells from elderly individuals compensate for the loss of functional naive T-cells and may therefore be used as a marker of immunological competence in old age.