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Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer’s disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian’ offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging. Supplementary Information The online version of this article (10.1007/s11357-020-00287-w) contains supplementary material, which is available to authorized users.

A global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines. In this review, we summarize the current knowledge on the role of mitokines in modulating immune response and inflammation focusing on GDF15, FGF21 and humanin and their possible involvement in the chronic age-related low-grade inflammation dubbed inflammaging. Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age. Therefore, we hypothesize that they can be considered part of an adaptive and integrated immune-metabolic mechanism activated by mitochondrial dysfunction that acts within the framework of a larger anti-inflammatory network aimed at controlling both acute inflammation and inflammaging.

Aging is characterized by dynamic changes at metabolic level that lead to modifications in the composition of the metabolome. Since the identification of biomarkers that can discriminate people of different age and health status has recently attracted a great interest, we wondered whether age-specific changes in the metabolome could be identified and serve as new and informative biomarkers of aging and longevity. In the last few years, a specific branch of metabonomics devoted to the study of volatile organic compounds (VOCs) has been developed. To date, little is known about the profile of specific VOCs in healthy aging and longevity in humans; therefore, we investigated the profile of VOCs in both urine and feces samples from 73 volunteers of different age including centenarians that represent useful “super-controls” to identify potential biomarkers of successful aging and footprints of longevity. To this purpose, we performed a discriminant analysis by which we were able to identify specific profiles of urinary and fecal VOCs. Such profiles can discriminate different age groups, from young to centenarians, and, even more interesting, centenarians’ offspring from age-matched controls. Moreover, we were able to identify VOCs that are specific for the couples “centenarians – offspring” or the trios “centenarians – offspring – spouse,” suggesting the possible existence of a familiar component also for VOCs profile. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-019-00143-6) contains supplementary material, which is available to authorized users.

Growth differentiation factor 15 (GDF15) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether GDF15 is beneficial or detrimental. The aim of the study was to analyse the levels of circulating GDF15 in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of GDF15 was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of GDF15 increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating GDF15 is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of GDF15 plasma levels, that after the race are similar to that of patients. Moreover, GDF15 plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that GDF15 is associated with decreased muscle performance and increased inflammation.

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 (Plin1-5) 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, while 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.

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., Small RNA deep sequencing on plasma‐derived RNA from 12 donors (young and old subjects, healthy, and unhealthy centenarians) was performed: 79 differentially expressed c‐miRs were identified. MiR‐19a/b‐3p increased at old age but decreased at extreme age, as confirmed by RT‐qPCR in 49 subjects. The decrease was more relevant in healthy centenarians, also confirmed by the modified pattern of isomiRs. Three common targets of miR‐19a/b‐3p were identified converging into the FoxO signaling pathway.

International audience; BackgroundThe 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.MethodsVastus 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/height2) was compared with corresponding USI values.ResultsFor 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/m2).ConclusionsWe 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.

Sex dimorphism in cell response to stress has previously been investigated by different research groups. This dimorphism could be at least in part accounted for by sex-biased expression of regulatory elements such as microRNAs (miRs). In order to spot previously unknown miR expression differences we took advantage of prior knowledge on specialized databases to identify X chromosome-encoded miRs potentially escaping X chromosome inactivation (XCI). MiR-548am-5p emerged as potentially XCI escaper and was experimentally verified to be significantly up-regulated in human XX primary dermal fibroblasts (DFs) compared to XY ones. Accordingly, miR-548am-5p target mRNAs, e.g. the transcript for Bax, was differently modulated in XX and XY DFs. Functional analyses indicated that XY DFs were more prone to mitochondria-mediated apoptosis than XX ones. Experimentally induced overexpression of miR548am-5p in XY cells by lentivirus vector transduction decreased apoptosis susceptibility, whereas its down-regulation in XX cells enhanced apoptosis susceptibility. These data indicate that this approach could be used to identify previously unreported sex-biased differences in miR expression and that a miR identified with this approach, miR548am-5p, can account for sex-dependent differences observed in the susceptibility to mitochondrial apoptosis of human DFs.

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.

Growth differentiation factor 15 (GDF15) is recently emerging not only as a stress-related mitokine, but also as a key player in the aging process, being one of the most up-regulated protein with age and associated with a variety of age-related diseases (ARDs). Many data indicate that GDF15 has protective roles in several tissues during different stress and aging, thus playing a beneficial role in apparent contrast with the observed association with many ARDs. A possible detrimental role for this protein is then hypothesized to emerge with age. Therefore, GDF15 can be considered as a pleiotropic factor with beneficial activities that can turn detrimental in old age possibly when it is chronically elevated. In this review, we summarize the current knowledge on the biology of GDF15 during aging. We also propose GDF15 as a part of a dormancy program, where it may play a role as a mediator of defense processes aimed to protect from inflammatory damage and other stresses, according to the life history theory.

Chronic insomnia is the most common sleep disorder in the elderly population. From 9 to 50% of patients suffer of paradoxical insomnia, with the same symptoms and ailments, though characterized by normal sleep patterns. We have investigated the level of parameters related to stress in a group of post-menopausal female patients (age range 55-70 years) suffering by either objective or paradoxical insomnia, in particular we have measured 24-hours urinary cortisol, allostatic load index, Perceived Stress Scale (PSS) score, and, for the first time, mitokines (mitochondrial stress response molecules) such as FGF21, GDF15 and Humanin (HN). Results show that the two groups are different as far as sleep efficiency score, as expected, but not for stress parameters, that in some cases resulted within the normality range, although quite close to the top threshold (such as cortisol) or much higher with respect to normality ranges (such as PSS). Therefore, the consequences of paradoxical insomnia on the expression of these parameters are the same as objective insomnia. As far as the level of mitokines, we showed that FGF21 and HN in particular resulted altered (decreased and increased, respectively) with respect to control population, however with no difference between the two groups of patients.

BACKGROUND: Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments. METHODS: By mean of in vivo Plin2 down-regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery. RESULTS: We found that Plin2 down-regulation was sufficient to induce a 30% increase of myofiber cross-sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients. CONCLUSIONS: Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

The Sarcolab pilot study of 2 crewmembers, investigated before and after a 6-mo International Space Station mission, has demonstrated the substantial muscle wasting and weakness, along with disruption of muscle's oxidative metabolism. The present work aimed at evaluating the pro/anti-inflammatory status in the same 2 crewmembers (A, B). Blood circulating (c-)microRNAs (miRs), c-proteasome, c-mitochondrial DNA, and cytokines were assessed by real-time quantitative PCR or ELISA tests. Time series analysis was performed ( i.e., before flight and after landing) at 1 and 15 d of recovery (R+1 and R+15, respectively). C-biomarkers were compared with an age-matched control population and with two-dimensional proteomic analysis of the 2 crewmembers' muscle biopsies. Striking differences were observed between the 2 crewmembers at R+1, in terms of inflamma-miRs (c-miRs-21-5p, -126-3p, and -146a-5p), muscle specific (myo)-miR-206, c-proteasome, and IL-6/leptin, thus making the 2 astronauts dissimilar to each other. Final recovery levels of c-proteasome, c-inflamma-miRs, and c-myo-miR-206 were not reverted to the baseline values in crewmember A. In both crewmembers, myo-miR-206 changed significantly after recovery. Muscle biopsy of astronaut A showed an impressive 80% increase of ?-1-antitrypsin, a target of miR-126-3p. These results point to a strong stress response induced by spaceflight involving muscle tissue and the proinflammatory setting, where inflamma-miRs and myo-miR-206 mediate the systemic recovery phase after landing.-Capri, M., Morsiani, C., Santoro, A., Moriggi, M., Conte, M., Martucci, M., Bellavista, E., Fabbri, C., Giampieri, E., Albracht, K., Flück, M., Ruoss, S., Brocca, L., Canepari, M., Longa, E., Di Giulio, I., Bottinelli, R., Cerretelli, P., Salvioli, S., Gelfi, C., Franceschi, C., Narici, M., Rittweger, J. Recovery from six-month spaceflight at the International Space Station: muscle-related stress into a proinflammatory setting.

Down syndrome (DS) has been proposed by George Martin as a segmental progeroid syndrome since 1978. In fact, DS persons suffer from several age‐associated disorders much earlier than euploid persons. Furthermore, a series of recent studies have found that DS persons display elevated levels of age biomarkers, thus supporting the notion that DS is a progeroid trait. Nowadays, due to the progressive advancements in social inclusion processes and medical assistance, DS persons live much longer than in the past; therefore, the early‐onset health problems of these persons are becoming an urgent and largely unmet social and medical burden. In particular, the most important ailment of DS persons is the accelerated cognitive decline that starts when they reach about 40 years of age. This decline can be at least in part counteracted by multi‐systemic approaches including early‐onset cognitive training, physical activity, and psychosocial assistance. However, no pharmacological treatment is approved to counteract this decline. According to the most advanced conceptualization of Geroscience, tackling the molecular mechanisms underpinning the aging process should be a smart/feasible strategy to combat and/or delay the great majority of age‐related diseases, including cognitive decline. We think that a debate is needed urgently on if (and how) this strategy could be integrated in protocols to face DS‐associated dementia and overall unhealthy aging. In particular we propose that, on the basis of data obtained in different clinical settings, metformin is a promising candidate that could be exploited to counteract cognitive decline in DS.

We propose in this review that hormesis, a concept profoundly and systematically addressed by Mark Mattson, has to be considered a sort of comprehensive "contact point" capable of unifying several conceptualizations of the aging process, including those focused on the stress response, oxidative stress and chronic inflammation/inflammaging. A major strength of hormesis and inflammaging is that they have a strong evolutionary basis. Moreover, both hormesis and inflammaging frame the aging process within a lifelong perspective of adaptation to different types of stresses. Such adaptation perspective also suggests that the aging process is malleable, and predicts that effective anti-aging strategies should mimic what evolution did in the course of million years and that we have to learn how to exploit the great potential inherent in the hormetic/inflammatory responses. To this regard, new topics such as the production of mitokines to cope with mitochondrial dysfunction are emerging as possible anti-aging target. This approach opens theoretically the door to the possibility of modulating the individual aging rate and trajectory by adopting the most effective scientifically-based lifestyle regarding fundamentally nutrition and physical activity. In this scenario Mark Mattson's lesson and personal example will permanently enlighten the aging field and the quest for a healthy aging and longevity.

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 ad hoc 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&ndash, 80 years. The fortified milk was enriched with &omega, 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 &omega, 3 index of erythrocyte membranes. Conversely, it reduced the amount of arachidonic acid, homocysteine, and &omega, 6/&omega, 3 ratio. Conclusion: Twelve-week daily consumption of adhoc fortified milk has an overall positive impact on different health parameters related to inflammaging in the elderly.

International audience; Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity.

Perilipin 2 (Plin2), a protein associated with the metabolism of intracellular lipid droplets (LDs), has long been considered only for its role in lipid storage. However, the manipulation of its expression affects the severity of a variety of metabolic and age-related diseases, such as fatty liver, insulin resistance and type 2 diabetes (T2D), cardiovascular disease, atherosclerosis, sarcopenia, and cancer, suggesting that this protein may play a role in these pathological conditions. In particular, its downregulation in mice prevents or mitigates some of the above mentioned diseases. Conversely, in humans high levels of Plin2 are present in sarcopenia, hepatic steatosis, atherosclerosis, and some types of cancer. We propose that inhibition of Plin2 might be a strategy to counteract several metabolic and age-related diseases.

Sarcopenia, the progressive loss of muscle mass and strength, is a phenomenon characterizing human aging whose etiology is still not clear. While there is increasing evidence for the influence of inter-muscular adipose tissue infiltration in the development of sarcopenia, much less is known about a possible role for intra-muscular triglycerides (IMTG). IMTG accumulate in form of lipid droplets decorated by proteins such as Perilipins (Plins). In skeletal muscle the most abundant are Plin2 and Plin5. In this study we compared the expression of these two Plins in Vastus lateralis muscle samples of subjects of different age, both healthy donors (HD) and patients with limited lower limb mobility (LLMI). These latter are characterized by a condition of chronic physical inactivity. Plin2 expression resulted higher in old age for both HD and LLMI patients, while Plin5 slightly decreased only in LLMI patients. Moreover, in these patients, only Plin2 was associated with the decrease of muscle strength and the expression of factors related to muscle atrophy (MuRF1, Atrogin and p53). An increase in Plin2 and a concomitant decrease of Plin5 was also observed when we considered animal model of disuse-induced muscle atrophy. As a whole, these data indicate that Plin2 and Plin5 have a different expression pattern during muscle aging and inactivity, and only Plin2 appears to be associated with functional alterations of the muscle.

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm-aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

International audience; Human aging is associated with a progressive loss of muscle mass and strength and a concomitant fat accumulation in form of inter-muscular adipose tissue, causing skeletal muscle function decline and immobilization. Fat accumulation can also occur as intra-muscular triglycerides (IMTG) deposition in lipid droplets, which are associated with perilipin proteins, such as Perilipin2 (Plin2). It is not known whether Plin2 expression changes with age and if this has consequences on muscle mass and strength. We studied the expression of Plin2 in the vastus lateralis (VL) muscle of both healthy subjects and patients affected by lower limb mobility limitation of different age. We found that Plin2 expression increases with age, this phenomenon being particularly evident in patients. Moreover, Plin2 expression is inversely correlated with quadriceps strength and VL thickness. To investigate the molecular mechanisms underpinning this phenomenon, we focused on IGF-1/p53 network/signalling pathway, involved in muscle physiology. We found that Plin2 expression strongly correlates with increased p53 activation and reduced IGF-1 expression. To confirm these observations made on humans, we studied mice overexpressing muscle-specific IGF-1, which are protected from sarcopenia. These mice resulted almost negative for the expression of Plin2 and p53 at two years of age. We conclude that fat deposition within skeletal muscle in form of Plin2-coated lipid droplets increases with age and is associated with decreased muscle strength and thickness, likely through an IGF-1- and p53-dependent mechanism. The data also suggest that excessive intramuscular fat accumulation could be the initial trigger for p53 activation and consequent loss of muscle mass and strength.

Planarians contain a large population of stem cells, named neoblasts, and use these for continuous turnover of all cell types. In addition, thanks to the amazing flexibility of these cells, planarians respond well to the effects of stressful situations, for example activating regeneration after trauma. How neoblasts respond to stress and support continuous proliferation, maintaining long-term stability, is still an open question. Heat shock proteins (HSPs) are a complex protein family with key roles in maintaining protein homeostasis, as well as in apoptosis and growth-related processes. We recently characterized some planarian homologs of hsp genes that are highly expressed in mammalian stem cells, and observed that some of them are critical for neoblast survival/maintenance. The results of these studies support the notion that some HSPs play crucial roles in the modulation of pathways regulating stem cell activity, regeneration and tissue repair. In this review we compare the evidence available for planarian hsp genes and focus on questions emerging from these results.

During the last 50–60 years, due to development of medical care and hygienically safe living conditions, the average life span of European citizens has substantially increased, with a rapid growth of the population older than 65 years. This trend places ever-growing medical and economical burden on society, as many of the older subjects suffer from age-related diseases and frailty. Coping with these problems requires not only appropriate medical treatment and social support but also extensive research in many fields of aging—from biology to sociology, with involvement of older people as the research subjects. This work anticipates development and application of ethical standards suited to dynamic advances in aging research. The aim of this review is to update the knowledge in ethical requirements toward recruitment of older research subjects, obtaining of informed consent, collection of biological samples, and use of stem cells in preclinical and clinical settings. It is concluded that application of adequate ethical platform markedly facilitates recruitment of older persons for participation in research. Currently, the basic ethical concepts are subjected to extensive discussion, with participation of all interested parties, in order to guarantee successful research on problems of human aging, protect older people from undesired interference, and afford their benefits through supporting innovations in research, therapy, and care.

Context Intravenous fluid administration with peripherally inserted central venous catheters (PICCs) and midline catheters in palliative care. Objectives To evaluate distress and pain perceived by patients during the positioning of a PICC or midline catheter, both in the home and hospice settings. Methods This was a prospective observational study performed by the Palliative Care Network of Pordenone. In addition to evaluating distress and pain, we monitored patient quality of life and the devices used. Quality of life was measured with the European Organization for Research and Treatment of Cancer-Core 15-Palliative scale. Results From May 2012 to July 2013, 48 patients were enrolled in the study. The level of distress during the procedure was null or very low in 95.8% of the patients and completely absent after one week. Pain during insertion was null or very little in 93.8% of the patients and zero after one week in 98% of the patients. Quality of life was significantly improved after one week for certain specific parameters and also globally. The number of catheter days monitored was 3097. The weekly monitoring of the devices revealed a series of minor complications. Only two catheters were removed for serious complications. Conclusion Our results showed a low impact on pain and distress, a low level of local and systemic complications and a favorable impact on patients' quality of life. However, other studies are necessary to evaluate the cost-effectiveness of the use of these devices and their role in palliative care.

Mitochondrial stress elicits the production of stress response molecules indicated as mitokines, including fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), and humanin (HN). Many diseases are characterized by progressive mitochondrial dysfunction with alterations of mitokine secretion. It is still controversial whether healthy aging and extreme longevity are accompanied by an altered production of mitokines. We analyzed FGF21, HN, and GDF15 plasma levels in 693 subjects aged from 21 to 113 years, and the association of these mitokines with parameters of health status. FGF21, HN, and GDF15 resulted increased in old age, with the highest levels found in centenarians. These molecules are associated with worsened parameters (such as handgrip strength, insulin sensitivity, triglycerides), particularly in 70-year-old persons, and their levels are inversely correlated with survival in the oldest subjects. Considering the positive biological effect of these molecules, our results can be interpreted in the framework of the hormetic paradigm as an attempt of the cells/tissues to cope with a stress that can have beneficial or detrimental effects depending on its intensity. Finally, persons with Down Syndrome (characterized by accelerated aging) have higher levels of GDF15 and HN with respect to their siblings, suggesting that these molecules, especially GDF15, could be considered markers of biological age.