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.

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 β5i/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.

In this study, we investigated proteasome composition and activity in the brain of Macaca fascicularis , in order to test whether this nonhuman primate species might be a suitable animal model for anti-aging therapies in the central nervous system, addressed to the ubiquitin-proteasome system. We detected the catalytic β subunits of constitutive proteasome, as well as the PA28 regulator and a subunit of immunoproteasome (i.e., β 1i [LMP2]), in seven adult, six old, and one young nonhuman primate brains. Subunit expression and proteasome activity were not influenced by the age of the animal in any of the brain regions (temporal and frontal cortex and cerebellum) we studied. However, an area-specific susceptibility to aged-related oxidative stress emerged. On the whole, the results suggest that, compared to humans, Macaca fascicularis primates may have a different age-dependent regulation of the ubiquitin-proteasome system and, possibly, of neuroinflammation in the brain. An in silico model of the 20S immunoproteasome containing the Macaca fascicularis α and β subunits, present in database or identified by our group (i.e., LMP2), has been developed. Additional information was obtained by de novo sequencing of the β 1 (delta) subunit of Macaca fascicularis. A comparison with humans suggests that in multiprotein complexes some functional subunits, such as α subunits, appear to be preferentially conserved during evolution.

Proteasomes (including constitutive proteasome, immunoproteasome, and their regulatory complexes) are multicatalytic complexes crucial for cell and body homeostasis and survival, being responsible for a consistent part of protein degradation. In the central nervous system (CNS), the activity of proteasomes affects a variety of crucial brain activities. While proteasome alteration (content and activity) during aging has been studied in several tissues and cellular models, few data are available regarding human CNS, and the identification of an appropriate and reliable model for the role of proteasome in human brain aging is still lacking. In this review, the available data on proteasome and brain aging in rodents, as well as the few data on non human primates, are critically revised. On the whole, the data regarding changes of proteasome activity and content with age are far from being clear, not only due to the heterogeneity of the models (differences between species, among strains of the same species) but also due to the brain areas considered. We paid particular attention to recent data obtained in human brain of non-demented donors and subjects affected by Alzheimer Disease (AD) demented subjects, as well as to new data on non human primate brain. The study of the possible role of proteasomes in brain aging, and the identification of reliable animal models, is pivotal for the development of possible ad hoc therapeutic interventions capable of retarding/counteracting brain aging and age-related brain pathologies. The therapeutic capability and limits of Vitamin E, the possible set up of proteasome modifiers (activators) as well as the effects on proteasomes of other drugs used for AD therapy are discussed within a scenario which deserves more attention and further investigations.

Immunoproteasome is an emerging biological target that constitutes a key element not only in antigen presentation but also in T cell and cytokine regulation as well as cellular homeostasis. Respect to standard proteasome, the inducible expression and different sensitivity towards activity modulators of immunoproteasome render it a potential therapeutic target for tumours and central nervous system diseases. In this review we report the cutting edge studies for understanding when immunoproteasome expression is induced and how it regulates pivotal pathways involved in tumours and neuropathologies, including apoptosis and inflammation. We emphasize its role as a new pharmacological target by describing the recent medicinal chemistry efforts aimed at design selective small-molecule modulators of both standard- and immuno-proteasome forms. Finally, we also present an in silico model of the human immunoproteasome structure by the major molecular differences with the 20S standard proteasome and discuss the perspective for the design of novel specific smallmolecule modulators for the different proteasome isoforms.