The Association of Nutrition Quality with Frailty Syndrome among the Elderly.

Low diet quality among the elderly may be correlated with some diseases, including Frailty Syndrome (FS). This decline in function restricts the activity of older people, resulting in higher assistance costs. The aim of this study was to increase knowledge of diet quality predictors. Dietary intake was assessed among 196 individuals aged 60+ years using the three-day record method and FS by Fried's criteria. Based on the compliance with the intake recommendation (% of EAR/AI), we distinguished three clusters that were homogeneous in terms of the nutritional quality of the diet, using Kohonen's neural networks. The prevalence of frailty in the entire group was 3.1%, pre-frailty 38.8%, and non-frailty 58.1%. Cluster 1 (91 people with the lowest diet quality) was composed of a statistically significant higher number of the elderly attending day care centers (20.7%), frail (6.9%), pre-frail (51.7%), very low vitamin D intake (23.8% of AI), using sun cream during the summer months (always 19.8% or often 39.6%), having diabetes (20.7%), having leg pain when walking (43.1%), and deteriorating health during the last year (53.5%). The study suggests the need to take initiatives leading to the improvement of the diet of the elderly, especially in day care senior centers, where there are more frail individuals, including nutritional education for the elderly and their caregivers.

Supplementation of Enriched Polyunsaturated Fatty Acids and CLA Cheese on High Fat Diet: Effects on Lipid Metabolism and Fat Profile.

Epidemiological studies have demonstrated a positive relationship between dietary fat intake and the onset of several metabolic diseases. This association is particularly evident in a diet rich in saturated fatty acids, typical of animal foods, such as dairy products. However, these foods are the main source of fatty acids with a proven nutraceutical effect, such as the ω-3 fatty acid α-linolenic acid (ALA) and the conjugated linoleic acid (CLA), which have demonstrated important roles in the prevention of various diseases. In the present study, the effect of a supplementation with cheese enriched with ω-3 fatty acids and CLA on the metabolism and lipid profiles of C57bl/6 mice was evaluated. In particular, the analyses were conducted on different tissues, such as liver, muscle, adipose tissue and brain, known for their susceptibility to the effects of dietary fats. Supplementing cheese enriched in CLA and ω-3 fats reduced the level of saturated fat and increased the content of CLA and ALA in all tissues considered, except for the brain. Furthermore, the consumption of this cheese resulted in a tissue-specific response in the expression levels of genes involved in lipid and mitochondrial metabolism. As regards genes involved in the inflammatory response, the consumption of enriched cheese resulted in a reduction in the expression of inflammatory genes in all tissues analyzed. Considering the effects that chronic inflammation associated with a high-calorie and high-fat diet (meta-inflammation) or aging (inflammaging) has on the onset of chronic degenerative diseases, these data could be of great interest as they indicate the feasibility of modulating inflammation (thus avoiding/delaying these pathologies) with a nutritional and non-pharmacological intervention.

Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population.

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

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

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.

Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging.

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.

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

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 63-80 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 adhoc fortified milk has an overall positive impact on different health parameters related to inflammaging in the elderly.

Inflammaging, hormesis and the rationale for anti-aging strategies.

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.

Mitochondria, immunosenescence and inflammaging: a role for mitokines?

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.

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness.

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.

Both objective and paradoxical insomnia elicit a stress response involving mitokine production.

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.

The smell of longevity: a combination of Volatile Organic Compounds (VOCs) can discriminate centenarians and their offspring from age-matched subjects and young controls.

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.

The Dual Role of the Pervasive "Fattish" Tissue Remodeling With Age.

Human aging is characterized by dramatic changes in body mass composition that include a general increase of the total fat mass. Within the fat mass, a change in the proportions of adipose tissues also occurs with aging, affecting body metabolism, and playing a central role in many chronic diseases, including insulin resistance, obesity, cardiovascular diseases, and type II diabetes. In mammals, fat accumulates as white (WAT) and brown (BAT) adipose tissue, which differ both in morphology and function. While WAT is involved in lipid storage and immuno-endocrine responses, BAT is aimed at generating heat. With advancing age BAT declines, while WAT increases reaching the maximum peak by early old age and changes its distribution toward a higher proportion of visceral WAT. However, lipids tend to accumulate also within lipid droplets (LDs) in non-adipose tissues, including muscle, liver, and heart. The excess of such ectopic lipid deposition and the alteration of LD homeostasis contribute to the pathogenesis of the above-mentioned age-related diseases. It is not clear why age-associated tissue remodeling seems to lean toward lipid deposition as a "default program." However, it can be noted that such remodeling is not inevitably detrimental. In fact, such a programmed redistribution of fat throughout life could be considered physiological and even protective, in particular at extreme old age. In this regard, it has to be considered that an excessive decrease of subcutaneous peripheral fat is associated with a pro-inflammatory status, and a decrease of LD is associated with lipotoxicity leading to an increased risk of insulin resistance, type II diabetes and cardiovascular diseases. At variance, a balanced rate of fat content and distribution has beneficial effects for health and metabolic homeostasis, positively affecting longevity. In this review, we will summarize the present knowledge on the mechanisms of the age-related changes in lipid distribution and we will discuss how fat mass negatively or positively impacts on human health and longevity.

Recovery from 6-month spaceflight at the International Space Station: muscle-related stress into a proinflammatory setting.

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 2-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 α-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 6-month spaceflight at the International Space Station: muscle-related stress into a proinflammatory setting.

Aging and Imaging Assessment of Body Composition: From Fat to Facts.

The aging process is characterized by the chronic inflammatory status called "inflammaging", which shares major molecular and cellular features with the metabolism-induced inflammation called "metaflammation." Metaflammation is mainly driven by overnutrition and nutrient excess, but other contributing factors are metabolic modifications related to the specific body composition (BC) changes occurring with age. The aging process is indeed characterized by an increase in body total fat mass and a concomitant decrease in lean mass and bone density, that are independent from general and physiological fluctuations in weight and body mass index (BMI). Body adiposity is also re-distributed with age, resulting in a general increase in trunk fat (mainly abdominal fat) and a reduction in appendicular fat (mainly subcutaneous fat). Moreover, the accumulation of fat infiltration in organs such as liver and muscles also increases in elderly, while subcutaneous fat mass tends to decrease. These specific variations in BC are considered risk factors for the major age-related diseases, such as cardiovascular diseases, type 2 diabetes, sarcopenia and osteoporosis, and can predispose to disabilities. Thus, the maintenance of a balance rate of fat, muscle and bone is crucial to preserve metabolic homeostasis and a health status, positively contributing to a successful aging. For this reason, a detailed assessment of BC in elderly is critical and could be an additional preventive personalized strategy for age-related diseases. Despite BMI and other clinical measures, such as waist circumference measurement, waist-hip ratio, underwater weighing and bioelectrical impedance, are widely used as a surrogate measure for body adiposity, they barely reflect the distribution of body fat. Because of the great advantages offered by imaging tools in research and clinics, the attention of clinicians is now moving to powerful imaging techniques such as computed tomography, magnetic resonance imaging, dual-energy X-ray absorptiometry and ultrasound to obtain a more accurate estimation of BC. The aim of this review is to present the state of the art of the imaging techniques that are currently available to measure BC and that can be applied to the study of BC changes in the elderly, outlining advantages and disadvantages of each technique.

Mediterranean diet and inflammaging within the hormesis paradigm.

A coherent set of epidemiological data shows that the Mediterranean diet has beneficial effects capable of preventing a variety of age-related diseases in which low-grade, chronic inflammation/inflammaging plays a major role, but the underpinning mechanism(s) is/are still unclear. It is suggested here that the Mediterranean diet can be conceptualized as a form of chronic hormetic stress, similar to what has been proposed regarding calorie restriction, the most thoroughly studied nutritional intervention. Data on the presence in key Mediterranean foods of a variety of compounds capable of exerting hormetic effects are summarized, and the mechanistic role of the nuclear factor erythroid 2 pathway is highlighted. Within this conceptual framework, particular attention has been devoted to the neurohormetic and neuroprotective properties of the Mediterranean diet, as well as to its ability to maintain an optimal balance between pro- and anti-inflammaging. Finally, the European Commission-funded project NU-AGE is discussed because it addresses a number of variables not commonly taken into consideration, such as age, sex, and ethnicity/genetics, that can modulate the hormetic effect of the Mediterranean diet.

Extracellular proteasome-osteopontin circuit regulates cell migration with implications in multiple sclerosis.

Osteopontin is a pleiotropic cytokine that is involved in several diseases including multiple sclerosis. Secreted osteopontin is cleaved by few known proteases, modulating its pro-inflammatory activities. Here we show by in vitro experiments that secreted osteopontin can be processed by extracellular proteasomes, thereby producing fragments with novel chemotactic activity. Furthermore, osteopontin reduces the release of proteasomes in the extracellular space. The latter phenomenon seems to occur in vivo in multiple sclerosis, where it reflects the remission/relapse alternation. The extracellular proteasome-mediated inflammatory pathway may represent a general mechanism to control inflammation in inflammatory diseases.

The immunoproteasome ß5i subunit is a key contributor to ictogenesis in a rat model of chronic epilepsy.

The proteasome is the core of the ubiquitin-proteasome system and is involved in synaptic protein metabolism. The incorporation of three inducible immuno-subunits into the proteasome results in the generation of the so-called immunoproteasome, which is endowed of pathophysiological functions related to immunity and inflammation. In healthy human brain, the expression of the key catalytic ß5i subunit of the immunoproteasome is almost absent, while it is induced in the epileptogenic foci surgically resected from patients with pharmaco-resistant seizures, including temporal lobe epilepsy. We show here that the ß5i immuno-subunit is induced in experimental epilepsy, and its selective pharmacological inhibition significantly prevents, or delays, 4-aminopyridine-induced seizure-like events in acute rat hippocampal/entorhinal cortex slices. These effects are stronger in slices from epileptic vs normal rats, likely due to the more prominent ß5i subunit expression in neurons and glia cells of diseased tissue. ß5i subunit is transcriptionally induced in epileptogenic tissue likely by Toll-like receptor 4 signaling activation, and independently on promoter methylation. The recent availability of selective ß5i subunit inhibitors opens up novel therapeutic opportunities for seizure inhibition in drug-resistant epilepsies.

Inflammaging and cancer: a challenge for the Mediterranean diet.

Aging is considered the major risk factor for cancer, one of the most important mortality causes in the western world. Inflammaging, a state of chronic, low-level systemic inflammation, is a pervasive feature of human aging. Chronic inflammation increases cancer risk and affects all cancer stages, triggering the initial genetic mutation or epigenetic mechanism, promoting cancer initiation, progression and metastatic diffusion. Thus, inflammaging is a strong candidate to connect age and cancer. A corollary of this hypothesis is that interventions aiming to decrease inflammaging should protect against cancer, as well as most/all age-related diseases. Epidemiological data are concordant in suggesting that the Mediterranean Diet (MD) decreases the risk of a variety of cancers but the underpinning mechanism(s) is (are) still unclear. Here we review data indicating that the MD (as a whole diet or single bioactive nutrients typical of the MD) modulates multiple interconnected processes involved in carcinogenesis and inflammatory response such as free radical production, NF-κB activation and expression of inflammatory mediators, and the eicosanoids pathway. Particular attention is devoted to the capability of MD to affect the balance between pro- and anti-inflammaging as well as to emerging topics such as maintenance of gut microbiota (GM) homeostasis and epigenetic modulation of oncogenesis through specific microRNAs.

Lifelong maintenance of composition, function and cellular/subcellular distribution of proteasomes in human liver.

Owing to organ shortage, livers from old donors are increasingly used for transplantation. The function and duration of such transplanted livers are apparently comparable to those from young donors, suggesting that, despite some morphological and structural age-related changes, no major functional changes do occur in liver with age. We tested this hypothesis by performing a comprehensive study on proteasomes, major cell organelles responsible for proteostasis, in liver biopsies from heart-beating donors. Oxidized and poly-ubiquitin conjugated proteins did not accumulate with age and the three major proteasome proteolytic activities were similar in livers from young and old donors. Analysis of proteasomes composition showed an age-related increased of ß5i/α4 ratio, suggesting a shift toward proteasomes containing inducible subunits and a decreased content of PA28α subunit, mainly in the cytosol of hepatocytes. Thus our data suggest that, proteasomes activity is well preserved in livers from aged donors, concomitantly with subtle changes in proteasome subunit composition which might reflect the occurrence of a functional remodelling to maintain an efficient proteostasis. Gender differences are emerging and they deserve further investigations owing to the different aging trajectories between men and women. Finally, our data support the safe use of livers from old donors for transplantation.

Immune system, cell senescence, aging and longevity--inflamm-aging reappraised.

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.