Publications by authors named "Claudio Franceschi"

492 Publications

Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients.

NPJ Parkinsons Dis 2021 Sep 7;7(1):78. Epub 2021 Sep 7.

Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy.

A prodromal phase of Parkinson's disease (PD) may precede motor manifestations by decades. PD patients' siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings' risk is not elevated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41531-021-00219-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423761PMC
September 2021

Microbiome in Blood Samples From the General Population Recruited in the MARK-AGE Project: A Pilot Study.

Front Microbiol 2021 26;12:707515. Epub 2021 Jul 26.

Department of Biology, Ecology and Earth Sciences (DIBEST), University of Calabria, Rende, Italy.

The presence of circulating microbiome in blood has been reported in both physiological and pathological conditions, although its origins, identities and function remain to be elucidated. This study aimed to investigate the presence of blood microbiome by quantitative real-time PCRs targeting the 16S rRNA gene. To our knowledge, this is the first study in which the circulating microbiome has been analyzed in such a large sample of individuals since the study was carried out on 1285 Randomly recruited Age-Stratified Individuals from the General population (RASIG). The samples came from several different European countries recruited within the EU Project MARK-AGE in which a series of clinical biochemical parameters were determined. The results obtained reveal an association between microbial DNA copy number and geographic origin. By contrast, no gender and age-related difference emerged, thus demonstrating the role of the environment in influencing the above levels independent of age and gender at least until the age of 75. In addition, a significant positive association was found with Free Fatty Acids (FFA) levels, leukocyte count, insulin, and glucose levels. Since these factors play an essential role in both health and disease conditions, their association with the extent of the blood microbiome leads us to consider the blood microbiome as a potential biomarker of human health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2021.707515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350766PMC
July 2021

Aging, Inflammaging and Adaptation: Comment on "Dynamic and thermodynamic models of adaptation" by A.N. Gorban et al.

Phys Life Rev 2021 Sep 15;38:107-110. Epub 2021 Jul 15.

Department of Applied Mathematics, Mathematics of Future Technologies Center, Laboratory of Systems Medicine of Healthy Aging, Lobachevsky University, Nizhny Novgorod 603950, Russia. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plrev.2021.07.001DOI Listing
September 2021

MicroRNA profiles of human peripheral arteries and abdominal aorta in normal conditions: MicroRNAs-27a-5p, -139-5p and -155-5p emerge and in atheroma too.

Mech Ageing Dev 2021 Sep 28;198:111547. Epub 2021 Jul 28.

DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Subcellular Nephro-Vascular Diagnostic Program, Pathology Unit, IRCCS, Policlinico S. Orsola Hospital, Bologna, Italy.

Atherosclerosis may starts early in life and each artery has peculiar characteristics likely affecting atherogenesis. The primary objective of the work was to underpin the microRNA (miR)-profiling differences in human normal femoral, abdominal aortic, and carotid arteries. The secondary aim was to investigate if those identified miRs, differently expressed in normal conditions, may also have a role in atherosclerotic arteries at adult ages. MiR-profiles were performed on normal tissues, revealing that aorta and carotid arteries are more similar than femoral arteries. MiRs emerging from profiling comparisons, i.e., miR-155-5p, -27a-5p, and -139-5p, were subjected to validation by RT-qPCR in normal arteries and also in pathological/atheroma counterparts, considering all the available 20 artery specimens. The three miRs were confirmed to be differentially expressed in normal femoral vs aorta/carotid arteries. Differential expression of those miRs was also observed in atherosclerotic arteries, together with some miR-target proteins, such as vimentin, CD44, E-cadherin and an additional marker SLUG. The different expression of miRs and targets/markers suggests that aorta/carotid and femoral arteries differently activate molecular drivers of pathological condition, thus conditioning the morphology of atheroma in adult life and likely suggesting the future use of artery-specific treatment to counteract atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2021.111547DOI Listing
September 2021

Features of age-related response to sleep deprivation: experimental studies.

Aging (Albany NY) 2021 07 28;13(15):19108-19126. Epub 2021 Jul 28.

Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603022, Russia.

Insomnia is currently considered one of the potential triggers of accelerated aging. The frequency of registered sleep-wake cycle complaints increases with age and correlates with the quality of life of elderly people. Nevertheless, whether insomnia is actually an age-associated process or whether it acts as an independent stress-factor that activates pathological processes, remains controversial. In this study, we analyzed the effects of long-term sleep deprivation modeling on the locomotor and orienting-exploratory activity, spatial learning abilities and working memory of C57BL/6 female mice of different ages. We also evaluated the modeled stress influence on morphological changes in brain tissue, the functional activity of the mitochondrial apparatus of nerve cells, and the level of DNA methylation and mRNA expression levels of the transcription factor HIF-1α (Hif1) and age-associated molecular marker PLIN2. Our findings point to the age-related adaptive capacity of female mice to the long-term sleep deprivation influence. For young (1.5 months) mice, the modeled sleep deprivation acts as a stress factor leading to weight loss against the background of increased food intake, the activation of animals' locomotor and exploratory activity, their mnestic functions, and molecular and cellular adaptive processes ensuring animal resistance both to stress and risk of accelerated aging development. Sleep deprivation in adult (7-9 months) mice is accompanied by an increase in body weight against the background of active food intake, increased locomotor and exploratory activity, gross disturbances in mnestic functions, and decreased adaptive capacity of brain cells, that potentially increasing the risk of pathological reactions and neurodegenerative processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.203372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386558PMC
July 2021

Expression pattern of perilipins in human brain during aging and in Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 Jul 27. Epub 2021 Jul 27.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Aims: Perilipins are conserved proteins that decorate intracellular lipid droplets and are essential for lipid metabolism. To date, there is limited knowledge on their expression in human brain or their involvement in brain aging and neurodegeneration. The aim of this study was to characterise the expression levels of perilipins (Plin1-Plin5) in different cerebral areas from subjects of different age, with or without signs of neurodegeneration.

Methods: We performed real-time RT-PCR, western blotting, immunohistochemistry and confocal microscopy analyses in autoptic brain samples of frontal and temporal cortex, cerebellum and hippocampus from subjects ranging from 33 to 104 years of age, with or without histological signs of neurodegeneration. To test the possible relationship between Plins and inflammation, correlation analysis with IL-6 expression was also performed.

Results: Plin2, Plin3 and Plin5, but not Plin1 and Plin4, are expressed in the considered brain areas with different intensities. Plin2 appears to be expressed more in grey matter, particularly in neurons in all the areas analysed, whereas Plin3 and Plin5 appear to be expressed more in white matter. Plin3 seems to be expressed more in astrocytes. Only Plin2 expression is higher in old subjects and patients with early tauopathy or Alzheimer's disease and is associated with IL-6 expression.

Conclusions: Perilipins are expressed in human brain but only Plin2 appears to be modulated with age and neurodegeneration and linked to an inflammatory state. We propose that the accumulation of lipid droplets decorated with Plin2 occurs during brain aging and that this accumulation may be an early marker and initial step of inflammation and neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nan.12756DOI Listing
July 2021

Specific features of the oldest old from the Longevity Blue Zones in Ikaria and Sardinia.

Mech Ageing Dev 2021 Sep 12;198:111543. Epub 2021 Jul 12.

University of Sassari, Department of Medical, Surgical and Experimental Sciences, Sassari, Italy.

Human longevity may be found in single individuals as well as in the population as a whole ("population longevity"). Longevity Blue Zones (LBZs), which are areas with an unusually high number of oldest old, have been identified in Sardinia and the Greek island of Ikaria. We compared the lifestyle, health status and some genetic markers of the LBZ populations with those of reference populations from Italy and Greece; the data were extracted from the GEHA database. In the LBZs, the proportion of individuals who never married or were married and still living with their spouse was significantly greater. Nonagenarians males and females with a high self‒perception of optimism and/or a high score for self-rated health were also found in larger proportions in LBZs. Among the variables with lower frequency were the proportion of the widowed, the percentage of subjects who had suffered a stroke and the frequency of Apoε4 and Apoε2 and the TT genotype of FOXO3A gene. Compared to behavioral and health indicators, the impact of genetic factors might be relatively less important in the LBZs. Nevertheless, further research is needed to identify potential epigenetic traits that might play a predominant role due to the interaction between genetics and the human and physical environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2021.111543DOI Listing
September 2021

Circulating miR-19a-3p and miR-19b-3p characterize the human aging process and their isomiRs associate with healthy status at extreme ages.

Aging Cell 2021 07 23;20(7):e13409. Epub 2021 Jun 23.

DIMES-Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Blood circulating microRNAs (c-miRs) are potential biomarkers to trace aging and longevity trajectories to identify molecular targets for anti-aging therapies. Based on a cross-sectional study, a discovery phase was performed on 12 donors divided into four groups: young, old, healthy, and unhealthy centenarians. The identification of healthy and unhealthy phenotype was based on cognitive performance and capabilities to perform daily activities. Small RNA sequencing identified 79 differentially expressed c-miRs when comparing young, old, healthy centenarians, and unhealthy centenarians. Two miRs, that is, miR-19a-3p and miR-19b-3p, were found increased at old age but decreased at extreme age, as confirmed by RT-qPCR in 49 donors of validation phase. The significant decrease of those miR levels in healthy compared to unhealthy centenarians appears to be due to the presence of isomiRs, not detectable with RT-qPCR, but only with a high-resolution technique such as deep sequencing. Bioinformatically, three main common targets of miR-19a/b-3p were identified, that is, SMAD4, PTEN, and BCL2L11, converging into the FoxO signaling pathway, known to have a significant role in aging mechanisms. For the first time, this study shows the age-related increase of plasma miR-19a/b-3p in old subjects but a decrease in centenarians. This decrease is more pronounced in healthy centenarians and was confirmed by the modified pattern of isomiRs comparing healthy and unhealthy centenarians. Thus, our study paves the way for functional studies using c-miRs and isomiRs as additional parameter to track the onset of aging and age-related diseases using new potential biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282272PMC
July 2021

DLX5/6 GABAergic expression affects social vocalization: implications for human evolution.

Mol Biol Evol 2021 Jun 16. Epub 2021 Jun 16.

Physiologie Moléculaire et Adaptation, CNRS UMR7221, Département AVIV, Muséum National d'Histoire Naturelle, Paris, France.

DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated to neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioural and metabolic phenotypes notably increasing lifespan by 33%. Here, we show that Dlx5/6VgatCre mice present a hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1400 calls/10min with a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals. The characters affected by Dlx5/6 in the mouse (sociability, vocalization, skull and brain shape…) overlap those affected in the "domestication syndrome". We therefore explored the possibility that DLX5/6 played a role in human evolution and "self-domestication" comparing DLX5/6 genomic regions from Neanderthal and modern humans. We identified an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype includes the binding site for GTF2I, a gene associated to Williams-Beuren syndrome, a hyper-sociability and hyper-vocalization neurodevelopmental disorder. The DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (>105y of age), a well-established human model of healthy ageing and longevity, suggesting their involvement in the co-evolution of longevity, sociability and speech.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molbev/msab181DOI Listing
June 2021

No association between frailty index and epigenetic clocks in Italian semi-supercentenarians.

Mech Ageing Dev 2021 07 4;197:111514. Epub 2021 Jun 4.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Centenarians experience successful ageing, although they still present high heterogeneity in their health status. The frailty index is a biomarker of biological age, able to capture such heterogeneity, even at extreme old age. At the same time, other biomarkers (e.g., epigenetic clocks) may be informative the biological age of the individual and potentially describe the ageing status in centenarians. In this article, we explore the relationship between epigenetic clocks and frailty index in a cohort of Italian centenarians. No association was reported, suggesting that these two approaches may describe different aspects of the same ageing process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2021.111514DOI Listing
July 2021

Age-related alterations in muscle architecture are a signature of sarcopenia: the ultrasound sarcopenia index.

J Cachexia Sarcopenia Muscle 2021 Aug 1;12(4):973-982. Epub 2021 Jun 1.

Center for Research in Myology UMRS974, Sorbonne Université, INSERM, Myology Institute, Paris, France.

Background: The assessment of muscle mass is a key determinant of the diagnosis of sarcopenia. We introduce for the first time an ultrasound imaging method for diagnosing sarcopenia based on changes in muscle geometric proportions.

Methods: Vastus lateralis muscle fascicle length (Lf) and thickness (Tm) were measured at 35% distal femur length by ultrasonography in a population of 279 individuals classified as moderately active elderly (MAE), sedentary elderly (SE) (n = 109), mobility impaired elderly (MIE) (n = 43), and in adult young controls (YC) (n = 60). The ratio of Lf/Tm was calculated to obtain an ultrasound index of the loss of muscle mass associated with sarcopenia (USI). In a subsample of elderly male individuals (n = 76) in which corresponding DXA measurements were available (MAE, n = 52 and SE, n = 24), DXA-derived skeletal muscle index (SMI, appendicular limb mass/height ) was compared with corresponding USI values.

Results: For both young and older participants, USI values were found to be independent of sex, height and body mass. USI values were 3.70 ± 0.52 for YC, 4.50 ± 0.72 for the MAE, 5.05 ± 1.11 for the SE and 6.31 ± 1.38 for the MIE, all significantly different between each other (P < 0.0001). Based on the USI Z-scores, with reference to the YC population, the 219 elderly participants were stratified according to their muscle sarcopenic status. Individuals with USI values within a range of 3.70 < USI ≥ 4.23 were classified as non-sarcopenic (prevalence 23.7%), those with USI values within 4.23 < USI ≥ 4.76 were classified as pre-sarcopenic (prevalence 23.7%), those with USI values within 4.76 < USI ≥ 5.29 were classified as moderately sarcopenic (prevalence 15.1%), those with USI values within range 5.29 < USI ≥ 5.82 were classified as sarcopenic (prevalence 27.9%), and those with USI values >5.82 were classified as severely sarcopenic (prevalence 9.6%). The DXA-derived SMI was found to be significantly correlated with USI (r = 0.61, P < 0.0001). Notably, the USI cut-off value for moderate sarcopenia (4.76 a.u.) was found to coincide with the DXA cut-off value of sarcopenia (7.26 kg/m ).

Conclusions: We propose a novel, practical, and inexpensive imaging marker of the loss of muscle mass associated with sarcopenia, called the ultrasound sarcopenic index (USI), based on changes in muscle geometric proportions. These changes provide a useful 'signature of sarcopenia' and allow the stratification of individuals according to the presence and severity of muscle sarcopenia. We are convinced that the USI will be a useful clinical tool for confirming the diagnosis of sarcopenia, of which the assessment of muscle mass is a key-component.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350200PMC
August 2021

Age, sex and BMI influence on copper, zinc and their major serum carrier proteins in a large European population including Nonagenarian Offspring from MARK-AGE study.

J Gerontol A Biol Sci Med Sci 2021 May 13. Epub 2021 May 13.

Translational Research Center of Nutrition and Ageing, IRCCS INRCA, Ancona, Italy.

The analysis of copper (Cu) and zinc (Zn) along with their major serum carriers, albumin (Alb) and ceruloplasmin (Cp), could provide information on the capacity of humans to maintain homeostasis of metals (metallostasis). However, their relationship with aging, sex, BMI, as well as with nutritional and inflammatory markers was never investigated in a large-scale study. Here, we report results from the European large-scale cross-sectional study MARK-AGE in which Cu, Zn, Alb, Cp as well as nutritional and inflammatory parameters were determined in 2424 age-stratified subjects (35-75 years) including the general population (RASIG), nonagenarian offspring (GO), a well-studied genetic model of longevity, and spouses of GO (SGO). In RASIG, Cu to Zn ratio and Cp to Alb ratio were higher in women than in men. Both ratios increased with aging because Cu and Cp increased and Alb and Zn decreased. Cu, Zn, Alb and Cp were found associated with several inflammatory as well as nutritional biomarkers.GO showed higher Zn levels and higher Zn to Alb ratio compared to RASIG, but we did not observe significant differences with SGO, likely as a consequence of the low sample size of SGO and the shared environment. Our results show that aging, sex, BMI and GO status are characterized by different levels of Cu, Zn and their serum carrier proteins. These data and their relationship with inflammatory biomarkers support the concept that loss of metallostasis is a characteristic of inflammaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glab134DOI Listing
May 2021

Whole-genome sequencing analysis of semi-supercentenarians.

Elife 2021 May 4;10. Epub 2021 May 4.

Department of Medicine, Unit of Internal Medicine, University of Verona, Verona, Italy.

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.57849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096429PMC
May 2021

Ageing affects subtelomeric DNA methylation in blood cells from a large European population enrolled in the MARK-AGE study.

Geroscience 2021 06 19;43(3):1283-1302. Epub 2021 Apr 19.

Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.

Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11357-021-00347-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190237PMC
June 2021

A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration.

Front Aging Neurosci 2021 11;13:639428. Epub 2021 Mar 11.

Istituto di Ricovero e Cura a Carattere Scientifico Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2021.639428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006465PMC
March 2021

Circulating perilipin 2 levels are associated with fat mass, inflammatory and metabolic markers and are higher in women than men.

Aging (Albany NY) 2021 03 17;13(6):7931-7942. Epub 2021 Mar 17.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Perilipin 2 (PLIN2) is a protein involved in lipid storage and metabolism in non-adipose tissues. Detectable levels of circulating PLIN2 (cPLIN2) have been reported to be associated with some types of cancer, but no systematic analysis of age-related modifications in cPLIN2 levels has ever been performed. We measured serum cPLIN2 in a group of old people including centenarians in comparison with young subjects and tested possible correlations with parameters of body composition, fat and glucose metabolism, and inflammation. We found that: i. levels of cPLIN2 do not change with age, but women have higher levels of cPLIN2 with respect to men; ii. cPLIN2 levels strongly correlate to BMI, as well as fat and lean mass; iii. cPLIN2 levels strongly correlate with the proinflammatory adipokine leptin. Due to the adipogenic activity of leptin, it is hypothesized that cPLIN2 is affected and possibly regulated by this pleiotropic adipokine. Moreover, these results suggest that cPLIN2 (possibly together with leptin) could be assumed as a proxy for body adiposity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034884PMC
March 2021

Proteomics in aging research: A roadmap to clinical, translational research.

Aging Cell 2021 04 17;20(4):e13325. Epub 2021 Mar 17.

Biomedical Research Centre, National Institute on Aging, NIH, Baltimore, MD, USA.

The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational "omics" since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)-based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O-Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age-associated across studies. Enrichment analysis of the 232 age-associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin-like growth factor (IGF) signaling, mitogen-activated protein kinases (MAPK), hypoxia-inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age-relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045948PMC
April 2021

Elevated gut microbiome abundance of is associated with reduced visceral adipose tissue and healthier metabolic profile in Italian elderly.

Gut Microbes 2021 Jan-Dec;13(1):1-19

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna , Bologna, Italy.

Aging is accompanied by physiological changes affecting body composition and functionality, including accumulation of fat mass at the expense of muscle mass, with effects upon morbidity and quality of life. The gut microbiome has recently emerged as a key environmental modifier of human health that can modulate healthy aging and possibly longevity. However, its associations with adiposity in old age are still poorly understood. Here we profiled the gut microbiota in a well-characterized cohort of 201 Italian elderly subjects from the NU-AGE study, by 16S rRNA amplicon sequencing. We then tested for association with body composition from dual-energy X-ray absorptiometry (DXA), with a focus on visceral and subcutaneous adipose tissue. Dietary patterns, serum metabolome and other health-related parameters were also assessed. This study identified distinct compositional structures of the elderly gut microbiota associated with DXA parameters, diet, metabolic profiles and cardio-metabolic risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19490976.2021.1880221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889099PMC
February 2021

Distinct profile of CD34 cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease.

J Exp Clin Cancer Res 2021 Feb 1;40(1):49. Epub 2021 Feb 1.

Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy.

Background: Myelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10-15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer. To identify a biomolecular signature of TN patients, we comparatively evaluated the circulating HSPCs and their functional interplay with the microenvironment focusing on EV analysis.

Methods: Peripheral blood was collected from MF patients (n = 29; JAK2 mutation, n = 23; TN, n = 6) and healthy donors (HD, n = 10). Immunomagnetically isolated CD34 cells were characterized by gene expression profiling analysis (GEP), survival, migration, and clonogenic ability. EVs were purified from platelet-poor plasma by ultracentrifugation, quantified using the Nanosight technology and phenotypically characterized by flow cytometry together with microRNA expression. Migration and survival of CD34 cells from patients were also analyzed after in vitro treatments with selected inflammatory factors, i.e. (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, IL6) or after co-culture with EVs from MF patients/HD.

Results: The absolute numbers of circulating CD34 cells were massively increased in TN patients. We found that TN CD34 cells show in vitro defective functions and are unresponsive to the inflammatory microenvironment. Of note, the plasma levels of crucial inflammatory cytokines are mostly within the normal range in TN patients. Compared to JAK2-mutated patients, the GEP of TN CD34 cells revealed distinct signatures in key pathways such as survival, cell adhesion, and inflammation. Importantly, we observed the presence of mitochondrial components within plasma EVs and a distinct phenotype in TN-derived EVs compared to the JAK2-mutated MF patients and HD counterparts. Notably, TN EVs promoted the survival of TN CD34 cells. Along with a specific microRNA signature, the circulating EVs from TN patients are enriched with miR-361-5p.

Conclusions: Distinct EV-driven signals from the microenvironment are capable to promote the TN malignant hemopoiesis and their further investigation paves the way toward novel therapeutic approaches for rare MF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-020-01776-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849077PMC
February 2021

Vitamin B-6 intake is related to physical performance in European older adults: results of the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) study.

Am J Clin Nutr 2021 04;113(4):781-789

Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands.

Background: Maintenance of high physical performance during aging might be supported by an adequate dietary intake of niacin, vitamins B-6 and B-12, and folate because these B vitamins are involved in multiple processes related to muscle functioning. However, not much is known about the association between dietary intake of these B vitamins and physical performance.

Objectives: The objectives of this study were to investigate the association between dietary intake of niacin, vitamins B-6 and B-12, and folate and physical performance in older adults and to explore mediation by niacin status and homocysteine concentrations.

Methods: We used baseline data from the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) trial, which included n = 1249 healthy older adults (aged 65-79 y) with complete data on dietary intake measured with 7-d food records and questionnaires on vitamin supplement use and physical performance measured with the short physical performance battery and handgrip dynamometry. Associations were assessed by adjusted linear mixed models.

Results: Intake of vitamin B-6 was related to lower chair rise test time [β: -0.033 ± 0.016 s (log); P = 0.043]. Vitamin B-6 intake was also significantly associated with handgrip strength, but for this association, a significant interaction effect between vitamin B-6 intake and physical activity level was found. In participants with the lowest level of physical activity, higher intake of vitamin B-6 tended to be associated with greater handgrip strength (β: 1.5 ± 0.8 kg; P = 0.051), whereas in participants in the highest quartile of physical activity, higher intake was associated with lower handgrip strength (β: -1.4 ± 0.7 kg; P = 0.041). No evidence was found for an association between intake of niacin, vitamin B-12, or folate and physical performance or for mediation by niacin status or homocysteine concentrations.

Conclusions: Vitamin B-6 intake was associated with better chair rise test time in a population of European healthy older adults and also with greater handgrip strength in participants with low physical activity only. Homocysteine concentrations did not mediate these associations. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqaa368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024000PMC
April 2021

A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project.

Mech Ageing Dev 2021 03 29;194:111426. Epub 2020 Dec 29.

Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine (CIRMMP), Florence, Italy.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2020.111426DOI Listing
March 2021

Age-related DNA methylation changes are sex-specific: a comprehensive assessment.

Aging (Albany NY) 2020 12 3;12(23):24057-24080. Epub 2020 Dec 3.

Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky University, Nizhniy Novgorod, Russia.

The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in and genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762479PMC
December 2020

Twelve-Week Daily Consumption of Fortified Milk with ω-3, D, and Group B Vitamins Has a Positive Impact on Inflammaging Parameters: A Randomized Cross-Over Trial.

Nutrients 2020 Nov 22;12(11). Epub 2020 Nov 22.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy.

Background And Aim: A state of chronic, subclinical inflammation known as inflammaging is present in elderly people and represents a risk factor for all age-related diseases. Dietary supplementation with fortified foods seems an appealing strategy to counteract inflammaging. The purpose of this study was to test the efficacy of elderly-tailored fortified milk on inflammaging and different health parameters.

Methods: A double-blind randomized cross-over study was performed on forty-eight volunteers aged 63-80 years. The fortified milk was enriched with ω-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA), vitamins (25-hydroxyvitamin D, E, C, B6, B9, B12), and trace elements (zinc, selenium). The two intervention periods lasted for 12 weeks, with a 16-week washout intermission.

Results: Compared to placebo, the consumption of fortified milk increased the circulating levels of different micronutrients, including vitamins and the ω-3 index of erythrocyte membranes. Conversely, it reduced the amount of arachidonic acid, homocysteine, and ω-6/ω-3 ratio.

Conclusion: Twelve-week daily consumption of fortified milk has an overall positive impact on different health parameters related to inflammaging in the elderly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12113580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700442PMC
November 2020

Inflammaging in Endemic Areas for Infectious Diseases.

Front Immunol 2020 12;11:579972. Epub 2020 Nov 12.

Programa de Pós Graduação em Nutrição e Saúde, Escola de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Immunosenescence is marked by a systemic process named inflammaging along with a series of defects in the immunological activity that results in poor responses to infectious agents and to vaccination. Inflammaging, a state of low-grade chronic inflammation, usually leads to chronic inflammatory diseases and frailty in the elderly. However, some elderly escape from frailty and reach advanced age free of the consequences of inflammaging. This process has been called immunological remodeling, and it is the hallmark of healthy aging as described in the studies of centenarians in Italy. The biological markers of healthy aging are still a matter of debate, and the studies on the topic have focused on inflammatory remodeling processes and molecules. The sub-clinical inflammatory status associated with aging might be a deleterious event for populations living in countries where chronic infectious diseases are not prevalent. Nevertheless, in other parts of the world where they are, two possibilities may occur. Inflammatory responses may have a protective effect against these infectious agents. At the same time, the long-term consequences of protective immune responses during chronic infections may result in accelerated immunosenescence in these individuals. Therefore, the biological markers of healthy aging can vary according to environmental, cultural, and geographical settings that reflect worldwide, and in a non-biased, non-westernized perspective, the changes that we experience regarding our contacts with microorganisms and the outcomes of such contacts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.579972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688519PMC
June 2021

Investigating Mitonuclear Genetic Interactions Through Machine Learning: A Case Study on Cold Adaptation Genes in Human Populations From Different European Climate Regions.

Front Physiol 2020 11;11:575968. Epub 2020 Nov 11.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

Cold climates represent one of the major environmental challenges that anatomically modern humans faced during their dispersal out of Africa. The related adaptive traits have been achieved by modulation of thermogenesis and thermoregulation processes where nuclear (nuc) and mitochondrial (mt) genes play a major role. In human populations, mitonuclear genetic interactions are the result of both the peculiar genetic history of each human group and the different environments they have long occupied. This study aims to investigate mitonuclear genetic interactions by considering all the mitochondrial genes and 28 nuclear genes involved in brown adipose tissue metabolism, which have been previously hypothesized to be crucial for cold adaptation. For this purpose, we focused on three human populations (i.e., Finnish, British, and Central Italian people) of European ancestry from different biogeographical and climatic areas, and we used a machine learning approach to identify relevant nucDNA-mtDNA interactions that characterized each population. The obtained results are twofold: (i) at the methodological level, we demonstrated that a machine learning approach is able to detect patterns of genetic structure among human groups from different latitudes both at single genes and by considering combinations of mtDNA and nucDNA loci; (ii) at the biological level, the analysis identified population-specific nuclear genes and variants that likely play a relevant biological role in association with a mitochondrial gene (such as the "obesity gene" in Finnish people). Further studies are needed to fully elucidate the evolutionary dynamics (e.g., migration, admixture, and/or local adaptation) that shaped these nucDNA-mtDNA interactions and their functional role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.575968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686538PMC
November 2020

Fighting Sarcopenia in Ageing European Adults: The Importance of the Amount and Source of Dietary Proteins.

Nutrients 2020 Nov 24;12(12). Epub 2020 Nov 24.

School of Health Sciences, Örebro University, 702 81 Örebro, Sweden.

While an adequate protein intake is important for the maintenance of muscle mass during ageing, the amount and source of protein necessary for optimal prevention of sarcopenia remains to be determined. The present study aimed to investigate the influence of the amount and source of dietary proteins on sarcopenia risk in a cohort of 65-79-year-old European adults within the frame of the NU-AGE study. A total of 986 participants were included in the analysis. Skeletal muscle index (SMI), assessed by dual-energy X-ray absorptiometry (DXA), and handgrip strength (HG) were employed to create a continuous sex-specific sarcopenia risk score (SRS). Total amount together with animal- and plant-derived sources of proteins were obtained from a 7-day food record. Differences in SRS were analysed across groups of total protein intake (<0.8 g/body weight (BW); 0.8-<1.0 g/BW; 1.0-<1.2 g/BW; and ≥1.2 g/BW). The association between SRS and the different sources of protein was assessed using isocaloric substitution models adjusted by demographic, medical, and lifestyle factors. A significant linear dose-response relationship was observed, with a lower SRS linked to higher protein intakes. Based on the isocaloric substitution modelling, a reduced SRS was observed when increasing plant protein to the detriment of animal protein, while holding total protein intake constant. Further, this result remained significant after stratifying the analysis by adherence to different levels of protein intake. Our findings suggest that older adults may benefit from increasing protein intakes above current recommendations. Besides total amount, protein source should be considered when promoting health dietary habits in older adults for the prevention of sarcopenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12123601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760110PMC
November 2020

Associations between Pro- and Anti-Inflammatory Gastro-Intestinal Microbiota, Diet, and Cognitive Functioning in Dutch Healthy Older Adults: The NU-AGE Study.

Nutrients 2020 Nov 12;12(11). Epub 2020 Nov 12.

Laboratory of Microbiology, Wageningen University & Research, 6708WE Wageningen, The Netherlands.

Dietary modulation of the gastro-intestinal microbiota is a potential target in improving healthy ageing and age-related functional outcomes, including cognitive decline. We explored the association between diet, gastro-intestinal microbiota and cognition in Dutch healthy older adults of the 'New dietary strategies addressing the specific needs of the elderly population for healthy aging in Europe' (NU-AGE) study. The microbiota profile of 452 fecal samples from 226 subjects was determined using a 16S ribosomal RNA gene-targeted microarray. Dietary intake was assessed by 7-day food records. Cognitive functioning was measured with an extensive cognitive test battery. We observed a dietary and microbial pro- to anti-inflammatory gradient associated with diets richer in animal- or plant-based foods. Fresh fruits, nuts, seeds and peanuts, red and processed meat and grain products were most strongly associated to microbiota composition. Plant-rich diets containing fresh fruits, nuts, seeds and peanuts were positively correlated with alpha-diversity, various taxa from the Bacteroidetes phylum and anti-inflammatory species, including those related to and and . Animal product-rich diets associated with pro-inflammatory species, including those related to and .. Cognition was neither associated with microbiota composition nor alpha-diversity. In conclusion, diets richer in animal- and plant-based foods were related to a pro- and anti-inflammatory microbial profile, while cognition was associated with neither.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12113471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697493PMC
November 2020

The complex relationship between Immunosenescence and Inflammaging: Special issue on the New Biomedical Perspectives.

Semin Immunopathol 2020 10;42(5):517-520

DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum University of Bologna, Via San Giacomo 12, Bologna, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00281-020-00823-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665088PMC
October 2020
-->