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A novel, population-specific approach to define frailty.

ABSTRACT: The description of frailty, a syndrome of the elderly due to the decline of homeostatic capacities, has opened new opportunities in the study of the biological basis of human aging. However, the noticeable heterogeneity for this trait in different geographic areas makes it difficult to use standardized methods for measuring the quality of aging in different populations. Consequently, the necessity to carry out population-specific surveys to define tools which are able to highlight groups of subjects with homogeneous aging phenotype within each population has emerged. We carried out an extensive monitoring of the status of the elderly population in Calabria, southern Italy, performing a geriatric multidimensional evaluation of 680 subjects (age range 65-108 years). Then, in order to classify the subjects, we applied a cluster analysis which considered physical, cognitive, and psychological parameters such as classification variables. We identified groups of subjects homogeneous for the aging phenotypes. The diagnostic and predictive soundness of our classification was confirmed by a 3-year longitudinal study. In fact, both Kaplan-Meier estimates of the survival functions and Cox proportional hazard models indicate higher survival chance for subjects characterized by lower frailty. The availability of operative frailty phenotypes allows a reappraisal of the biological basis of healthy aging as it regards both biomarkers correlated with the frail phenotype and the genetic variability associated with the phenotypes identified. Indeed, we found that the frailty phenotype is strongly correlated with clinical parameters associated with the nutritional status.

SUBMITTER: Montesanto A

PROVIDER: S-EPMC2926861 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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A novel, population-specific approach to define frailty.

Montesanto Alberto A Lagani Vincenzo V Martino Cinzia C Dato Serena S De Rango Francesco F Berardelli Maurizio M Corsonello Andrea A Mazzei Bruno B Mari Vincenzo V Lattanzio Fabrizia F Conforti Domenico D Passarino Giuseppe G

Age (Dordrecht, Netherlands) 20100306 3

The description of frailty, a syndrome of the elderly due to the decline of homeostatic capacities, has opened new opportunities in the study of the biological basis of human aging. However, the noticeable heterogeneity for this trait in different geographic areas makes it difficult to use standardized methods for measuring the quality of aging in different populations. Consequently, the necessity to carry out population-specific surveys to define tools which are able to highlight groups of subj ...[more]

PMID: 20640550

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Project description:In Huntington’s disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors. Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability. Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability. Mouse striatum and cerebellum, 10 weeks old, Affymetrix MG430 2.0 arrays, gcRMA.

Dataset Information

A novel, population-specific approach to define frailty.

Publications

A novel, population-specific approach to define frailty.

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