A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.

Relationship between Diet, Microbiota, and Healthy Aging.

Due to medical advances and lifestyle changes, population life expectancy has increased. For this reason, it is important to achieve healthy aging by reducing the risk factors causing damage and pathologies associated with age. Through nutrition, one of the pillars of health, we are able to modify these factors through modulation of the intestinal microbiota. The Mediterranean and Oriental diets are proof of this, as well as the components present in them, such as fiber and polyphenols. These generate beneficial effects on the body thanks, in part, to their interaction with intestinal bacteria. Likewise, the low consumption of products with high fat content favors the state of the microbiota, contributing to the maintenance of good health.

The Relationship between Diet and Frailty in Aging.

The increase in lifespan in the 20th century entails an increase in the elderly population. This brings a new challenge for society, causing people to have physical and mental limitations caused by age-related diseases, such as frailty. Frailty is clinically characterized by multisystem pathophysiological processes, such as chronic inflammation, immune activation, dysregulation of the musculoskeletal and endocrine systems, oxidative stress, energy imbalances, mitochondrial dysfunction, and sarcopenia. The elderly should consume energy in amounts close to those in what is currently accepted as a balanced diet. However, an increase in protein intake may be recommended for elderly people as long as there is no kidney damage. This increase could help fight the loss of muscle mass associated with age. Additionally, vitamin and mineral intakes are often insufficient in their diets. Therefore, the diet should be adapted not only to their age, but also to the pathologies associated with aging. Through these measures, we can reduce the prevalence of comorbidity and thereby increase health span. Therefore, both physical and nutritional interventions, including functional foods and nutraceuticals, should be taken into account.

Identificación de polimorfismos de nucleótido simple en centenarios / Identification of single nucleotide polymorphisms in centenarians

Introducción. La longevidad viene determinada por la genética propia de cada especie y por factores externos, tales como nutricionales, ambientales, sociales, etc. Sin embargo, los individuos más longevos se caracterizan por presentar una mayor adaptación al entorno condicionada predominantemente por su propia genética. Dentro de una misma población con relativa homogeneidad genotípica, podemos encontrar cambios sutiles en la secuencia de ADN que afectan únicamente a un nucleótido. Estos cambios denominados polimorfismos de nucleótido simple (Single Nucleotide Polimorphisim [SNP]) se encuentran con una prevalencia mayor al 1-5% de la población. Por ello, nos planteamos estudiar en individuos centenarios si las posibles variaciones genéticas, analizando SNP, podrían tener alguna relevancia en la longevidad extrema que experimentan. Material y métodos. Se reclutó a 92 sujetos: 28 centenarios y 64 controles. Se les extrajo sangre, se aisló y amplificó ADN para el análisis de SNP mediante la tecnología Axiom™ Genotyping de Affymetrix. Los análisis estadísticos se realizaron mediante el programa Plink y varias bibliotecas de R para Windows (library SNPassoc, skatMeta). Resultados. Los resultados del análisis muestran 12 SNP que presentan un valor de p inferior a 0,001, donde 5 de ellos (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) tienen funciones reguladoras de la expresión de otros genes. Conclusiones. Así pues, los resultados sugieren que las variaciones genéticas observadas entre centenarios y controles tienen lugar en 5 genes que están implicados en la regulación de la expresión génica, capacitándolos a adaptarse a diferentes condiciones ambientales con mejor éxito (AU)

Introduction. Longevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population. Material and methods. A total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta. Results. Our results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes. Conclusions. Therefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls (AU)

[Identification of single nucleotide polymorphisms in centenarians]. / Identificación de polimorfismos de nucleótido simple en centenarios.

INTRODUCTION: Longevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population. MATERIAL AND METHODS: A total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta. RESULTS: Our results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes. CONCLUSIONS: Therefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls.

Histone h3 glutathionylation in proliferating mammalian cells destabilizes nucleosomal structure.

AIMS: Here we report that chromatin, the complex and dynamic eukaryotic DNA packaging structure, is able to sense cellular redox changes. Histone H3, the only nucleosomal protein that possesses cysteine(s), can be modified by glutathione (GSH). RESULTS: Using Biotin labeled glutathione ethyl ester (BioGEE) treatment of nucleosomes in vitro, we show that GSH, the most abundant antioxidant in mammals, binds to histone H3. BioGEE treatment of NIH3T3 cells indicates that glutathionylation of H3 is maximal in fast proliferating cells, correlating well with enhanced levels of H3 glutathionylation in different tumor cell lines. Furthermore, glutathionylation of H3 in vivo decreases in livers from aged SAMP8 and C57BL/6J mice. We demonstrate biochemically and by mass spectrometry that histone variants H3.2/H3.3 are glutathionylated on their cysteine residue 110. Furthermore, circular dichroism, thermal denaturation of reconstituted nucleosomes, and molecular modeling indicate that glutathionylation of histone H3 produces structural changes affecting nucleosomal stability. INNOVATION: We characterize the implications of histone H3 glutathionylation in cell physiology and the modulation of core histone proteins structure affected by this modification. CONCLUSION: Histone H3 senses cellular redox changes through glutathionylation of Cys, which increases during cell proliferation and decreases during aging. Glutathionylation of histone H3 affects nucleosome stability structure leading to a more open chromatin structure.

Lymphocytes from young healthy persons carrying the ApoE4 allele overexpress stress-related proteins involved in the pathophysiology of Alzheimer's disease.

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for the development of Alzheimer's disease (AD). The aim of this work was to find if carrying ApoE4 alleles correlates with molecular changes associated with specific processes involved in AD pathophysiology and whether they are useful as early biomarkers of AD. Fifty four young healthy adults (aged 20-55) were recruited. Of these, 33 carried at least one ApoE4 allele and 21 did not (ApoE 3/3). We also recruited eleven patients with clinical diagnoses of probable AD and nine persons of similar age without dementia who served as controls of the AD patients. Using peripheral lymphocytes, we measured RNA expression of glycogen synthase kinase 3ß (GSK3ß), the regulator of calcineurin 1 (RCAN1), calcineurin, and RNA-dependent protein kinase (PKR) by PCR and protein levels of RCAN1, calcineurin, GSK3ß, and phospho-tau by western blotting. Young healthy persons carrying the ApoE 4/4 genotype express more RNA for RCAN1, calcineurin, and PKR and higher protein levels of calcineurin, RCAN1, GSK3ß, and phospho-tau than controls (ApoE 3/3). Moreover, we found that carrying one or two alleles for ApoE4 is associated with subjective cognitive impairment. We conclude that lymphocytes from young, non-demented persons carrying the ApoE 4/4 genotype show molecular changes that are involved in specific processes associated with the pathophysiology of AD such as increased phosphorylation of tau or increased expression of stress-related proteins like calcineurin, GSK3ß, or RCAN1. These changes may help to understand the development of AD and in the early diagnosis of the disease.