Multimodal cell atlas of the ageing human skeletal muscle.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

Redox-associated changes in healthy individuals at risk of Alzheimer's disease. A ten-year follow-up study.

Carrying an allele 4 of the apolipoprotein E (ApoE) is the best-established genetic risk factor to develop Alzheimer's disease (AD). Fifty percent of ApoE4/4 individuals develop the disease at 70 years of age. ApoE3/4 carriers have a lower risk of developing the disease, still 50% of them suffer AD at around 80 years. In a previous study we showed that healthy young individuals, who had a parent with AD and were carriers of at least one ApoE4 allele displayed reductive stress. This was evidenced as a decrease in oxidative markers, such as oxidized glutathione, p-p38, and NADP+/NADPH ratio, and an increase of antioxidant enzymes, such as glutathione peroxidase (Gpx1) and both the catalytic and regulatory subunits of glutamyl-cysteinyl (GCLM and GCLC). Moreover, we found an increase in stress-related proteins involved in tau physiopathology. Now, 10 years later, we have conducted a follow-up study measuring the same parameters in the same cohort. Our results show that reductive stress has reversed, as we could now observe an increase in lipid peroxidation and in the oxidation of glutathione along with a decrease in the expression of Gpx1 and SOD1 antioxidant enzymes in ApoE4 carriers. Furthermore, we found an increase in plasma levels of IL1ß levels and in PKR (eukaryotic translation initiation factor 2 alpha kinase 2) gene expression in isolated lymphocytes. Altogether, our results suggest that, in the continuum of Alzheimer's disease, people at risk of developing the disease go through different redox phases, from stablished reductive stress to oxidative stress.

Physical Interventions Restore Physical Frailty and the Expression of CXCL-10 and IL-1ß Inflammatory Biomarkers in Old Individuals and Mice.

BACKGROUND: Frailty is a geriatric syndrome associated with negative health outcomes that represents a dynamic condition with a potential of reversibility after physical exercise interventions. Typically, inflammatory and senescence markers are increased in frail individuals. However, the impact that physical exercise exerts on inflammatory and senescence biomarkers remains unknown. We assessed the effect of physical intervention in old individuals and mice and determined the expression of inflammatory and senescence markers. METHODS: Twelve elderly individuals were enrolled from a primary care setting to a 3-month intervention. Frailty was measured by SPPB and the expression of biomarkers by cytokine array and RT-qPCR. In addition, 12 aged C57BL/6 mice completed an intervention, and inflammation and senescence markers were studied. RESULTS: The physical intervention improved the SPPB score, reducing frail and pre-frail individuals. This was correlated with a reduction in several pro-inflammatory biomarkers such as IL-6, CXCL-1, CXCL-10, IL-1ß, IL-7, GM-CSF as well as p16INK4a and p21CIP1 senescence markers. Otherwise, the levels of anti-inflammatory biomarker IL-4 were significantly increased. Moreover, the physical intervention in mice also improved their functional capacity and restored the expression of inflammatory (Il-1ß, Cxcl-10, Il-6, and Cxcl-1) and senescence (p21Cip1) markers. Additionally, PLSDA and ROC curve analysis revealed CXCL-10 and IL-1ß to be the biomarkers of functional improvement in both cohorts. CONCLUSIONS: Our results showed that a physical intervention improves physical frailty, and reverses inflammation and senescence biomarkers comprising CXCL-10 and IL-1ß.

Pharmacological and genetic increases in liver NADPH levels ameliorate NASH progression in female mice.

Non-alcoholic steatohepatitis (NASH) is one of the fastest growing liver diseases worldwide, and oxidative stress is one of NASH main key drivers. Nicotinamide adenine dinucleotide phosphate (NADPH) is the ultimate donor of reductive power to a number of antioxidant defences. Here, we explored the potential of increasing NADPH levels to prevent NASH progression. We used nicotinamide riboside (NR) supplementation or a G6PD-tg mouse line harbouring an additional copy of the human G6PD gene. In a NASH mouse model induced by feeding mice a methionine-choline deficient (MCD) diet for three weeks, both tools increased the hepatic levels of NADPH and ameliorated the NASH phenotype induced by the MCD intervention, but only in female mice. Boosting NADPH levels in females increased the liver expression of the antioxidant genes Gsta3, Sod1 and Txnrd1 in NR-treated mice, or of Gsr for G6PD-tg mice. Both strategies significantly reduced hepatic lipid peroxidation. NR-treated female mice showed a reduction of steatosis accompanied by a drop of the hepatic triglyceride levels, that was not observed in G6PD-tg mice. NR-treated mice tended to reduce their lobular inflammation, showed a reduction of the NK cell population and diminished transcription of the damage marker Lcn2. G6PD-tg female mice exhibited a reduction of their lobular inflammation and hepatocyte ballooning induced by the MCD diet, that was related to a reduction of the monocyte-derived macrophage population and the Tnfa, Ccl2 and Lcn2 gene expression. As conclusion, boosting hepatic NADPH levels attenuated the oxidative lipid damage and the exhausted antioxidant gene expression specifically in female mice in two different models of NASH, preventing the progression of the inflammatory process and hepatic injury.

Randomised controlled trial combining vitamin E-functionalised chocolate with physical exercise to reduce the risk of protein-energy malnutrition in predementia aged people: study protocol for Choko-Age.

OBJECTIVE: Protein-energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly. METHODS AND ANALYSIS: In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the 'Joint Programming Initiative A healthy diet for a healthy life'. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9-1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics. ETHICS AND DISSEMINATION: All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects' regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals. TRIAL REGISTRATION NUMBER: NCT05343611.

Pomegranate Extract Administration Reverses Loss of Motor Coordination and Prevents Oxidative Stress in Cerebellum of Aging Mice.

The cerebellum is responsible for complex motor functions, like maintaining balance and stance, coordination of voluntary movements, motor learning, and cognitive tasks. During aging, most of these functions deteriorate, which results in falls and accidents. The aim of this work was to elucidate the effect of a standardized pomegranate extract during four months of supplementation in elderly mice to prevent frailty and improve the oxidative state. Male C57Bl/6J eighteen-month-old mice were evaluated for frailty using the "Valencia Score" at pre-supplementation and post-supplementation periods. We analyzed lipid peroxidation in the cerebellum and brain cortex and the glutathione redox status in peripheral blood. In addition, a set of aging-related genes in cerebellum and apoptosis biomarkers was measured via real-time polymerase chain reaction (RT-PCR). Our results showed that pomegranate extract supplementation improved the motor skills of C57Bl/6J aged mice in motor coordination, neuromuscular function, and monthly weight loss, but no changes in grip strength and endurance were found. Furthermore, pomegranate extract reversed the increase in malondialdehyde due to aging in the cerebellum and increased the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the blood. Finally, aging and apoptosis biomarkers improved in aged mice supplemented with pomegranate extract in the cerebellum but not in the cerebral cortex.

Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.

Plasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome.

Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of "omic" techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30-100 years old; 2: n = 68, 70% females, 19-107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial ß-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.

Glucose 6-P Dehydrogenase Overexpression Improves Aging-Induced Endothelial Dysfunction in Aorta from Mice: Role of Arginase II.

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6-9 months), old WT (21-22 months) and old G6PD-Tg (21-22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing G6PD underexpressed arginase II and also displayed a lower activity of this enzyme. Moreover, histological analyses demonstrated that age causes a thickness of aortic walls, but this did not occur in G6PD-Tg mice. We conclude that the overexpressing G6PD mouse is a model to improve vascular health via the arginase pathway.

Is Frailty Diagnosis Important in Patients with COPD? A Narrative Review of the Literature.

Frailty is prevalent in older adults and is related to a worsening functionality, quality of life, and health outcomes. Though there is an increasing interest in this field, the relationship between frailty and worsening COPD outcomes remains unknown. A narrative review of the literature with studies published between 2018 and 2022 was carried out to address three questions: the prevalence of frailty and other geriatric syndromes in COPD patients, the link between frailty and worsening health outcomes in COPD patients, and the non-pharmacological interventions performed in order to reverse frailty in these patients. A total of 25 articles were selected. Frailty prevalence ranged from 6% and 85.9%, depending on the COPD severity and the frailty measurement tool used. Frailty in COPD patients was related to a high prevalence of geriatric syndromes and to a high incidence of adverse events such as exacerbations, admissions, readmissions, and mortality. One study showed improvements in functionality after physical intervention. In conclusion, the prevalence of frailty is associated with a high incidence of geriatric syndromes and adverse events in COPD patients. The use of frailty screenings and a comprehensive geriatric assessment of COPD patients is advisable in order to detect associated problems and to establish individualized approaches for better outcomes.

Effect of Familial Longevity on Frailty and Sarcopenia: A Case-Control Study.

Familial longevity confers advantages in terms of health, functionality, and longevity. We sought to assess potential differences in frailty and sarcopenia in older adults according to a parental history of extraordinary longevity. A total of 176 community-dwelling subjects aged 65-80 years were recruited in this observational case-control study, pair-matched 1:1 for gender, age, and place of birth and residence: 88 centenarians' offspring (case group) and 88 non-centenarians' offspring (control group). The main variables were frailty and sarcopenia based on Fried's phenotype and the European Working Group on Sarcopenia in Older People (EWGSOP) definitions, respectively. Sociodemographics, comorbidities, clinical and functional variables, the presence of geriatric syndromes, and laboratory parameters were also collected. Related sample tests were applied, and conditional logistic regression was performed. Cases had a higher percentage of robust patients (31.8% vs. 15.9%), lower percentages of frailty (9.1% vs. 21.6%) and pre-frailty (59.1% vs. 62.5%) (p = 0.001), and lower levels of IL-6 (p = 0.044) than controls. The robust adjusted OR for cases was 3.00 (95% CI = 1.06-8.47, p = 0.038). No significant differences in muscle mass were found. Familial longevity was also associated with less obesity, insomnia, pain, and polypharmacy and a higher education level and total and low-density lipoprotein cholesterol. The results suggest an inherited genetic component in the frailty phenotype, while the sarcopenia association with familial longevity remains challenging.

Real-Life Outcomes of a Multicomponent Exercise Intervention in Community-Dwelling Frail Older Adults and Its Association with Nutritional-Related Factors.

Most of the studies on physical exercise in older adults have been conducted through randomized clinical trials performed under tight experimental conditions. Data regarding Real-Life physical exercise intervention programs in older adults with different conditions and in different settings, are lacking. This is an interventional, prospective and pragmatic Real-Life study in which fifty sedentary and frail individuals were enrolled. We aimed at determining if a Real-Life exercise intervention outweighs previously reported improvements in a Clinical Trial (NCT02331459). We found higher improvements in the Real-Life exercise intervention vs. the Clinical Trial in functional parameters, such as Fried's frailty criteria, Tinetti, Barthel and Lawton & Brody scales. Similar results were found in the dietary habits, emotional and social networking outcomes determined through the Short-MNA, Yesavage, EuroQol and Duke scales. The Real-Life intervention led to a significant reduction in the number of falls, visits to the primary care centers and emergency visits when compared to the results of our previously published Clinical Trial. The implementation of a Real-Life exercise intervention is feasible and should be a major priority to improve health-span in the older population.

Genistein effect on cognition in prodromal Alzheimer's disease patients. The GENIAL clinical trial.

BACKGROUND: Delaying the transition from minimal cognitive impairment to Alzheimer's dementia is a major concern in Alzheimer's disease (AD) therapeutics. Pathological signs of AD occur years before the onset of clinical dementia. Thus, long-term therapeutic approaches, with safe, minimally invasive, and yet effective substances are recommended. There is a need to develop new drugs to delay Alzheimer's dementia. We have taken a nutritional supplement approach with genistein, a chemically defined polyphenol that acts by multimodal specific mechanisms. Our group previously showed that genistein supplementation is effective to treat the double transgenic (APP/PS1) AD animal model. METHODS: In this double-blind, placebo-controlled, bicentric clinical trial, we evaluated the effect of daily oral supplementation with 120 mg of genistein for 12 months on 24 prodromal Alzheimer's disease patients. The amyloid-beta deposition was analyzed using 18F-flutemetamol uptake. We used a battery of validated neurocognitive tests: Mini-Mental State Exam (MMSE), Memory Alteration Test (M@T), Clock Drawing Test, Complutense Verbal Learning Test (TAVEC), Barcelona Test-Revised (TBR), and Rey Complex Figure Test. RESULTS: We report that genistein treatment results in a significant improvement in two of the tests used (dichotomized direct TAVEC, p = 0.031; dichotomized delayed Centil REY copy p = 0.002 and a tendency to improve in all the rest of them. The amyloid-beta deposition analysis showed that genistein-treated patients did not increase their uptake in the anterior cingulate gyrus after treatment (p = 0.878), while placebo-treated did increase it (p = 0.036). We did not observe significant changes in other brain areas studied. CONCLUSIONS: This study shows that genistein may have a role in therapeutics to delay the onset of Alzheimer's dementia in patients with prodromal Alzheimer's disease. These encouraging results indicate that this should be followed up by a new study with more patients to further validate the conclusion that arises from this study. TRIAL REGISTRATION: NCT01982578, registered on November 13, 2013.

Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise.

Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice.

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging.

The radiographic assessment of lung edema score of lung edema severity correlates with inflammatory parameters in patients with coronavirus disease 2019-Potential new admission biomarkers to predict coronavirus disease 2019 worsening.

Background: Coronavirus disease 2019 (COVID-19) has placed enormous pressure on intensive care units (ICUs) and on healthcare systems in general. A deeper understanding of the pathophysiology of the most severe forms of COVID-19 would help guide the development of more effective interventions. Herein, we characterized the inflammatory state of patients with COVID-19 of varying degrees of severity to identify admission biomarkers for predicting COVID-19 worsening. Design: Admission blood samples were obtained from 78 patients with COVID-19. Radiographic assessment of lung edema (RALE) scoring was calculated by imaging. Platelet and leukocyte counts were measured by flow cytometry, and plasma levels of C-reactive protein were assessed by immunoturbidimetry, and interleukin (IL)-8/CXCL8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and monocyte chemoattractant protein-1 (MCP-1/CCL2) levels by enzyme-linked immunosorbent assay (ELISA). Results: The RALE score correlated with several admission hemogram (platelets, neutrophils, and lymphocytes) and inflammatory (IL-8/CXCL8, MCP-1/CCL2, IL-10, and C-reactive protein) parameters. COVID-19 worsening, based on the need for oxygen (Δoxygen supply) during hospitalization, correlated negatively with admission lymphocyte counts but positively with neutrophil-to-lymphocyte ratio and with plasma levels of the inflammatory parameters correlating with RALE score. Conclusion: Our data indicate a correlation between the RALE score and Δoxygen supply and admission inflammatory status. The identification of a panel of biomarkers that reflect COVID severity might be useful to predict disease worsening during hospitalization and to guide clinical management of COVID-19-related complications. Finally, therapies targeting IL-8/CXCL8- or IL-10 activity may offer therapeutic approaches in COVID-19 treatment.

Effects of GH on the Aging Process in Several Organs: Mechanisms of Action.

In order to investigate the possible beneficial effects of GH administration on the aging process, 24-month-old rats of both sexes and 10-month-old SAMP8 mice were used. Male rats showed increased fat content and decreased lean body mass together with enhanced vasoconstriction and reduced vasodilation of their aortic rings compared to young adult animals. Chronic GH treatment for 10 weeks increased lean body mass and reduced fat weight together with inducing an enhancement of the vasodilatory response by increasing eNOS and a reduction of the constrictory responses. Old SAMP8 male mice also showed insulin resistance together with a decrease in insulin production by the endocrine pancreas and a reduced expression of differentiation parameters. GH treatment decreased plasma levels and increased pancreatic production of insulin and restored differentiation parameters in these animals. Ovariectomy plus low calcium diet in rabbits induced osteoporosis Titanium implants inserted into these rabbit tibiae showed after one month lesser bone to implant (BIC) surface and bone mineral density (BMD). Local application of GH in the surgical opening was able to increase BIC in the osteoporotic group. The hippocampus of old rats showed a reduction in the number of neurons and also in neurogenesis compared to young ones, together with an increase of caspases and a reduction of Bcl-2. GH treatment was able to enhance significantly only the total number of neurons. In conclusion, GH treatment was able to show beneficial effects in old animals on all the different organs and metabolic functions studied.

Functional Transcriptomic Analysis of Centenarians' Offspring Reveals a Specific Genetic Footprint That May Explain That They Are Less Frail Than Age-Matched Noncentenarians' Offspring.

Centenarians exhibit extreme longevity and compression of morbidity and display a unique genetic signature. Centenarians' offspring seem to inherit centenarians' compression of morbidity, as measured by lower rates of age-related pathologies. We aimed to ascertain whether centenarians' offspring are less frail and whether they are endowed with a "centenarian genetic footprint" in a case-control study, matched 1:1 for gender, age ±5 years, and place of birth and residence. Cases must have a living parent aged 97 years or older, aged 65-80 years, community dwelling, not suffering from a terminal illness, or less than 6 months of life expectancy. Controls had to meet the same criteria as cases except for the age of death of their parents (not older than 89 years). Centenarians were individuals 97 years or older. Frailty phenotype was determined by Fried's criteria. We collected plasma and peripheral blood mononuclear cells from 63 centenarians, 88 centenarians' offspring, and 88 noncentenarians' offspring. miRNA expression and mRNA profiles were performed by the GeneChip miRNA 4.0 Array and GeneChip Clariom S Human Array, respectively. We found a lower incidence of frailty among centenarians' offspring when compared with their contemporaries' noncentenarians' offspring (p < .01). Both miRNA and mRNA expression patterns in centenarians' offspring were more like those of centenarians than those of noncentenarians' offspring (p < .01). In conclusion, centenarians' offspring are less frail than age-matched noncentenarians' offspring, and this may be explained by their unique genetic endowment.

Blood DNA Methylation Patterns in Older Adults With Evolving Dementia.

Dementia and cognitive disorders are major aging-associated pathologies. The prevalence and severity of these conditions are influenced by both genetic and environmental factors. Reflecting this, epigenetic alterations have been associated with each of these processes, especially at the level of DNA methylation, and such changes may help explain the observed interindividual variability in the development of the 2 pathologies. However, the importance of epigenetic alterations in explaining their etiology is unclear because little is known about the timing of when they appear. Here, using Illumina MethylationEPIC arrays, we have longitudinally analyzed the peripheral blood methylomes of cognitively healthy older adults (>70 year), some of whom went on to develop dementia while others stayed healthy. We have characterized 34 individuals at the prediagnosis stage and at a 4-year follow-up in the postdiagnosis stage (total n = 68). Our results show multiple DNA methylation alterations linked to dementia status, particularly at the level of differentially methylated regions. These loci are associated with several dementia-related genes, including PON1, AP2A2, MAGI2, POT1, ITGAX, PACSIN1, SLC2A8, and EIF4E. We also provide validation of the previously reported epigenetic alteration of HOXB6 and PM20D1. Importantly, we show that most of these regions are already altered in the prediagnosis stage of individuals who go on to develop dementia. In conclusion, our observations suggest that dementia-associated epigenetic patterns that have specific biological features are already present before diagnosis, and thus may be important in the design of epigenetic biomarkers for disease detection based on peripheral tissues.