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È noto che la corretta organizzazione tridimensionale del genoma influenza l'espressione spazio-temporale dei geni specifici del “lignaggio” durante i processi di differenziamento e invecchiamento delle cellule staminali. Abbiamo messo a punto una nuova versione della tecnica SAMMY-seq per mappare con precisione regioni genomiche separate per proprietà biochimiche. Questa tecnica consente di identificare i domini eterocromatici ed eucromatici e la loro compartimentalizzazione nel nucleo. I vantaggi pratici cruciali di questo metodo includono: la sua applicabilità su appena 10mila cellule; costi ridotti; poche fasi di manipolazione e tempi di esecuzione brevi. Nelle cellule staminali muscolari postnatali (MuSC) abbiamo osservato una distribuzione riproducibile dei domini genomici eucromatici ed eterocromatici, in linea con le modificazioni epigenetiche note. I nostri risultati evidenziano come le MuSCs nel corso della vita presentino un'organizzazione cromatinica globale stabile, accompagnata da cambiamenti di solubilità che favoriscono processi come l'attivazione delle MuSCs, ma che possono diventare ostacoli durante l'invecchiamento per il corretto mantenimento del pool. Inoltre, descriviamo le alterazioni ambientali della nicchia muscolare, sottolineando una popolazione di supporto alle MuSCs, i progenitori fibroadipogenici (FAPs), che presentano drammatiche alterazioni trascrizionali durante l'invecchiamento. La nostra ampia caratterizzazione dell'ambiente e dell'organizzazione cromatinica delle MuSCs amplia la nostra conoscenza dei processi di quiescenza, attivazione e invecchiamento, ponendo le basi per lo studio del ruolo dell'epigenoma in condizioni patologiche. The correct 3D organization of the genome is known to influence the spatiotemporal expression of lineage-specific genes during stem cell differentiation and aging processes. We introduce a novel evolution of the SAMMY-seq technique to precisely map genomic regions separated by their biochemical properties. This single-handedly technique enables the identification of heterochromatic and euchromatic domains and their compartmentalization in the nuclear space. Crucial practical advantages of this method include: its applicability on as little as 10K cells; reduced costs; few manipulation steps and short execution time. In postnatal Muscle Stem Cells (MuSCs) we observed a reproducible distribution of euchromatic and heterochromatic genomic domains, in line with known epigenetic signatures. Our findings highlight how MuSCs over life exhibit a global steady chromatin organization, accompanied by solubility changes that favour processes such as MuSCs activation but may become obstacles during aging for proper pool maintenance. Still, we describe environmental alterations of the muscle niche, emphasizing a supportive population of MuSCs, namely Fibroadipogenic progenitors (FAPs), which exhibit dramatic transcriptional alterations during aging. Our extensive characterization of the environment and chromatin organization in MuSCs expands our understanding of quiescence, activation and aging processes, laying the groundwork for the study of the role of the epigenome in pathological conditions.

The results presented here are part of the outcome of a research project titled Redesign—Frail Elderly, Intergenerational Solidarity and Age-Friendly Communities (https://redesignanziani.com) funded by Fondazione Cariplo and coordinated by the Università Cattolica del Sacro Cuore in Milan, in collaboration with Università degli studi di Verona and Università degli studi del Molise (2019–2022). The research aims to co-acquire knowledge of the transition to old age in vulnerable situations, to develop and implement new community networks of care, and thus promote health and well-being, active ageing, and intergenerational solidarity in eight Italian municipalities. The analysis of the dyadic interviews, conducted with the NVivo software, will provide the image of ageing and old age emerging from an intergenerational dialogue. By analysing results, it will therefore be possible to identify some specific types of representation of old age in relation to the dyad, the stressful events that occurred to the interviewees and in relation to the ways of living the transition. The representation of old age seems closely connected with the quality and intensity of relationships, the environment of associative and local life that the interviewees relate to, and the stressful events that have recently occurred to them.

Dal 2002, anno in cui l’Organizzazione mondiale della Sanità ha sancito i principi per promuovere politiche economiche e di welfare orientate all’Active Ageing, anche la letteratura in campo psicologico operante nel settore dell’invecchiamento si è mossa in accordo con questi principi. La tesi di dottorato presenta degli studi inerenti l’invecchiamento che vertono su due tematiche principali: da un lato i fattori psicosociali nell’invecchiamento intesi come atteggiamento e percezione della propria età; dall’altro i processi cognitivi maggiormente colpiti nell’invecchiamento sano, in particolar modo gli aspetti di memoria episodica, e gli strumenti per allenarli e valutarli. La tesi è dunque divisa in due sezioni. Nella prima parte saranno approfonditi i temi dell’ageismo e degli atteggiamenti verso il proprio processo di invecchiamento, attraverso due studi che utilizzano la realtà virtuale come metodologia e approccio in grado di simulare il processo di invecchiamento: in un primo studio attraverso l’utilizzo della realtà virtuale abbiamo indagato l’impatto di una stimolazione di embodiment visuo-tattile nel modificare gli atteggiamenti negativi verso gli anziani in tre gruppi di età differenti. Nel secondo studio, data l’importanza delle caratteristiche degli avatar negli studi di realtà virtuale, abbiamo creato un dataset di corpi e volti digitali che potranno essere utilizzati successivamente per studi che combinano la realtà virtuale e gli atteggiamenti verso gli anziani. Nella seconda parte saranno invece approfondito il dominio della memoria episodica come componente relativa al self e indirettamente legata ai benessere e ai vissuti di preoccupazione e ansia relativi alla perdita di memoria. Verranno presentati due studi: un training cognitivo da noi creato con l’obiettivo di stimolare le componenti di memoria episodica e un compito che, sfruttando la rappresentazione della mental time line e del distance effect, ha l’obiettivo di studiare i meccanismi di apprendimento di eventi simil- personali in giovani e anziani. Since 2002, when the World Health Organisation laid down the principles for promoting active ageing-oriented economic and welfare policies, psychological literature in ageing has also been developed following these principles. The doctoral thesis provides studies on ageing that focused on two main themes: on the one hand, the psychosocial factors in ageing comprehensive of attitudes and perception of one's age; on the other hand, cognitive processes most affected in healthy ageing, especially episodic memory, and tools to train and evaluate them. The thesis is, therefore, divided into two sections. In the first part, the themes of ageism and attitudes towards one's ageing process will be explored through two studies that use virtual reality as a methodology and approach capable of simulating the ageing process. In a first study, we investigated the impact of a visuo-tactile embodiment stimulation in modifying negative attitudes towards the elderly in three different age groups through the use of virtual reality. In a second study, given the importance of avatar characteristics in virtual reality studies, we aimed to create a dataset of digital bodies and faces that can be used later for studies that combine virtual reality and attitudes towards the elderly. In the second part, we will focus on episodic memory as a domain related to the self and well-being. Two studies will be presented: a cognitive training created by us that aims to stimulate the components of episodic memory, and a task that, exploiting the representation of mental timeline and distance effect, has the objective of studying the mechanisms of learning of similar- personal events in young and old.

Introduzione. Col progredire dell’età, la capacità dell’organismo di modificare struttura e funzione di organi e apparati in risposta agli stimoli si modifica. Scopo di questo progetto è indagare l’effetto dell’età sul rimodellamento cardiovascolare in risposta all’allenamento aerobico e valutare gli effetti della corsa sulla patologia del ginocchio. Metodi. 237 volontari sani, sedentari, sono stati valutati al basale e dopo 6 mesi di allenamento non supervisionato e il completamento della loro prima maratona, con: 1) risonanza magnetica cardiaca a 1.5T; 2) misurazione non invasiva della pressione arteriosa (PA) centrale e brachiale; 3) risonanza magnetica (MRI) bilaterale del ginocchio a 3.0T. La “età aortica biologica” è stata calcolata al basale dalla relazione tra l’età anagrafica e la rigidità arteriosa. Modificazioni nella rigidità arteriosa sono state valutate a livello dell’aorta ascendente (Ao-A), discendente (Ao-D), della biforcazione polmonare (Ao-P) e del passaggio diaframmatico (Ao-D).Per l’analisi, i soggetti sono stati divisi in due gruppi in base all’età (≥35 anni: O35; 34 anni: U35). Risultati. Le percentuali di infortunio e completamento della corsa sono state simili nei due gruppi. 138 corridori (U35: n =71, femmine =49%; O35: n =67, femmine =51%) hanno completato la corsa. In media, gli U35 sono stati 37 minuti più veloci (12%). L’allenamento si è associato a un piccolo incremento nella massa del ventricolo sinistro (LV) in entrambi i gruppi (3g/m2, p

Nel corso del mio dottorato sono stata coinvolta principalmente in due progetti con lo scopo di studiare la disfunzione cardiaca indotta da invecchiamento o chemioterapia. Il primo studio aveva lo scopo di riprodurre e caratterizzare i meccanismi dell’invecchiamento utilizzando cardiomiociti (CMs) da cellule staminali pluripotenti indotte umane (hiPSCs) e inoltre testare terapie cardioprotettive, come gli esosomi (Exo) da cellule progenitrici cardiache (CPCs). L’invecchiamento cardiaco coinvolge rimodellamenti a livello dei singoli CMs che predispongono allo scompenso cardiaco e la cui incidenza aumenta con l’avanzare dell’età. Curiosamente, fino ad ora non è stato ancora sviluppato un modello di invecchiamento cardiaco umano. Abbiamo riprogrammato CPCs umane ad iPSC e successivamente le abbiamo differenziate in CMs. Un fenotipo simile alla senescenza (SenCMs) è stato indotto con un breve trattamento (3 ore) con doxorubicina (Dox) a concentrazioni sub-letali (0.2 µM). 24 ore dopo il trattamento, alcuni SenCMs sono stati esposti ad Exo (~2·10^3 particelle/cellula) isolati dal medium di coltura delle CPCs. Il trattamento con Dox induce senescenza, come confermato dall’attivazione di p21 e dalla maggiore positività a SA-β-gal in confronto ai controlli (cCMs). Analisi biochimiche hanno rivelato la presenza di stress ossidativo e un potenziale di membrana mitocondriale depolarizzato nei SenCMs, con una ridotta produzione di ATP dai mitocondri. I SenCMs hanno anche difetti nel calcium handling e un QTc prolungato a causa dell’aumento di INaL. Questi effetti sono mitigati dal trattamento con Exo. Complessivamente, i SenCMs ricapitolano il fenotipo dei CMs invecchiati in termini di markers di senescenza e proprietà elettriche e metaboliche. Inoltre, l’esposizione ad Exo prodotti da CPCs limita molte delle anomalie cardiache indotte dall’invecchiamento. Il secondo studio mirava a valutare la disfunzione cardiaca causata dalla somministrazione in combinazione di Dox e Trastuzumab (Trz) in miociti cardiaci di ratto. Il trattamento combinato con Dox e Trz in pazienti con cancro al seno è limitato a causa della cardiotossicità, che si manifesta con disfunzione contrattile ed aritmie. Il ruolo specifico dei due agenti nella cardiotossicità causata dalla terapia combinata è però non ancora del tutto chiarito. I ratti hanno ricevuto 6 dosi di Dox, Trz o entrambi in maniera sequenziale. La disfunzione del ventricolo sinistro (LV) mediata da Dox era aggravata dalla somministrazione di Trz. Il trattamento con Dox, ma non con Trz, induceva danno ai tubuli T, prolungamento della durata del potenziale d’azione (APD), aumento dell’incidenza di post-depolarizzazioni tardive (DADs), decadimenti dei transienti di Ca2+ più lenti e la fuoriuscita di Ca2+ dal reticolo in Ca2+ sparks o Ca2+ embers. Il trattamento in combinazione esacerbava queste anomalie. Trz, ma non Dox, riduceva l’ampiezza dei transienti di Ca2+ e il contenuto di Ca2+ nel reticolo sarcoplasmatico (SR). Entrambi gli agenti aumentavano le onde di Ca2+ spontanee e diminuivano l’espressione di SERCA. Questi risultati suggeriscono che Dox, ma non Trz, potrebbe causare danno ai tubuli T in vivo e, inoltre, indurre cambiamenti nei parametri elettrici e nel Ca2+-handling. Mentre Dox induceva cambiamenti reversibili nei parametri elettrofisiologici, la successiva somministrazione di Trz impediva il rescue. Questi risultati illustrano il ruolo specifico di Dox e Trz e il loro ruolo nella cardiotossicità. During my PhD I was involved mainly in two research projects aimed to study myocardial dysfunction induced by aging or chemotherapy. The first study aimed to reproduce and characterize mechanisms involved in aging using cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs), and to test cardioprotective therapies, like cardiac progenitor cell (CPC)-derived exosomes (Exo). Aging of the heart involves adverse remodeling in CMs which results in heart failure with incidence that increases with age. Interestingly, till now we lacked a human model of cardiac aging. We reprogrammed CPCs into hiPSCs and subsequently differentiated in hiPSC-derived CMs. A senescence-like phenotype (SenCMs) was induced by short exposure (3 hours) to doxorubicin (Dox) at sub-lethal concentration (0.2 µM). 24h following DOX treatment, SenCMs were exposed to Exo (~2·103 particles/cell) collected from culture media of CPCs by ultracentrifugation. Dox treatment induced senescence, as confirmed by activation of p21 and increased SA-β-gal positivity compared to control CMs (cCMs). Biochemical analysis revealed presence of oxidative stress and a depolarized mitochondrial membrane potential due to the treatment, which resulted in decreased ATP production by mitochondria. SenCMs also showed impaired calcium handling and prolonged QTc vs. cCMs due to upregulation of INaL. These effects were mitigated by exposure to Exo. Overall, SenCMs recapitulate the phenotype of aged CMs in terms of senescence markers and electrical and metabolic properties. Additionally, exposure to CPC-derived Exo limited age-related cardiac anomalies. The second study aimed to study the cardiac dysfunction dependent on the combined administration of Dox and trastuzumab (Trz) through evaluation of cardiac performance, T-tubule organization, and electrophysiological changes in cardiac myocytes from an in-vivo rat model. Combined treatment with Dox and Trz in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythmia. The respective roles of the two agents in the cardiotoxicity of the combined therapy are incompletely understood. Adult rats received 6 doses of either Dox or Trz, or the two agents sequentially. Dox-mediated left ventricular (LV) dysfunction was aggravated by Trz administration. Dox treatment, but not Trz, induced T-tubule disarray. Moreover, Dox, but not Trz monotherapy, induced prolonged action potential duration (APD), increased incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR), and slower Ca2+ transient decay. Although APD, DADs, BVR and Ca2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca2+ transient amplitude and SR Ca2+ content. Both agents increased Ca2+ waves and downregulated SERCA. Finally, Dox increased resting Ca2+ waves, Ca2+ spark frequency, spark-mediated sarcoplasmic reticulum (SR) leak, and long-lasting Ca2+ release events (so-called Ca2+ “embers”). These results suggest that Dox, but not Trz, may cause T-tubule disarray in cardiac myocytes in vivo while also inducing overall larger changes in electrical parameters and intracellular Ca2+ handling. While Dox-induced changes in electrical parameters are reversible, subsequent Trz administration prevents their recovery. These findings illustrate the specific roles of Dox and Trz, and their interactions in cardiotoxicity and arrhythmogenicity.

The ‘aging well’ discourse advances the idea of making older people responsible for their capability to stay healthy and active. In the context of an increased ageing population, which poses several challenges to countries’ government, this discourse has become dominant in Europe. We explore the way older people are visually represented aton websites of organizations for older people in seven European countries (Finland, UK, the Netherlands, Spain, Italy, Poland and Romania), using an analytical approached based on visual content analysis, inspired by the dimensional model of national cultural differences from the Hofstede model (1991; 2001; 2011). We used two out of the five Hofstede dimensions: Individualism/Collectivism (IDV) and Masculinity/Femininity (MAS). The results demonstrated that in all seven countries older people are mostly visually represented as healthy/active, which reflects a dominant ‘ageing well’ discourse in Europe. The results also demonstrated that in most cases older people tend to be represented together with others, which is not consonant with the dominant ‘ageing well’ discourse in Europe. A last finding was that the visual representation of older people is in about half of the cases in line with these Hofstede dimensions. We discuss the implications of these findings claiming that the ‘ageing well’ discourse might lead to ‘visual ageism’. Organizations could keep this in mind while using pictures for their website or in other media and consider to use various kind of pictures, or to avoid using pictures of older people that stigmatize, marginalize or injure. They could look into the cultural situatedness and intersectional character of age relations and consider alternative strategies of both visibility and invisibility to talk with and about our ageing societies.

European countries have experienced an outstanding increase in life expectancy during the last decades; however, this desirable and laudable societal achievement has challenged pension systems financial sustainability. National governments have almost unanimously responded to this demographic change by limiting access to retirement, mainly increasing statutory pension age. This article explores possible unintended effects of work life extension in the context of ageing population and provides some policy considerations. In particular, the authors focus on the following issues: work ability at older age, the potential negative health consequences of prolonging exposure to occupational hazards, welfare program substitution, shortage of informal caring, and, finally, the inequity innate in pension systems which disregard differences in life expectancy between socio economic groups. Negli ultimi decenni l’Europa ha conosciuto uno straordinario aumento dell’aspettativa di vita. Questo importante risultato ha tuttavia posto i sistemi previdenziali in serie difficolta mettendone a rischio la sostenibilita finanziaria. I governi quasi all’unisono hanno risposto a questa sfida demografica inasprendo i requisiti pensionistici e innalzando l’eta di pensionamento. Questo articolo esplora alcuni possibili effetti indesiderati di questo inatteso allungamento dell’orizzonte lavorativo. In particolare, gli autori si concentrano sulle seguenti questioni: ridotta capacita lavorativa in eta anziana; possibili effetti negativi sulla salute dovuti alla prolungata esposizione a rischi occupazionali; sostituzione fra diversi meccanismi di assistenza sociale; riduzione del lavoro di cura informale; iniquita intrinseca al sistema pensionistico che non considera delle differenze nell’aspettativa di vita fra diversi gruppi sociali.

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.

The author explores the demographic coordinates of a de-synchronization process between two distinct waves of ageing: on one hand, the abrupt prolonging of the life expectancy, on the other hand the slower delay of the disability free life expectancy. As a consequence, dementias play a crucial role in the future challenges of the Welfare in the Western countries, both for the increasing rate of their spread and for the social peculiarity of their medical cases. The social management and caring of these gradually and compulsorily "no more active" ageing people makes undeniable the need of a re-design of the urban "espaces de vie', as a main road to a more active aging.

Il saggio analizza, sulla base dei dati Multiscopo Istat 2012-13, le principali differenze tra gli anziani a seconda del genere e della col-locazione sociale sia rispetto ad alcune specifiche e alla non autosuf-ficienza, sia rispetto alla tipologia familiare, specie in caso di non au-tosufficienza. Mediante analisi multivariate, si rileva una specifica problematicità femminile e dei ceti meno scolarizzati per quanto riguarda la cronicità e la disabilità, mentre, per quanto concerne la condizione di so-litudine, emerge uno specifico rischio di solitudine, anche in caso di non autosufficienza, per le donne, specie molto anziane (over 75).Ne consegue che le politiche socio-sanitarie a sostegno della fragilità e della non autosufficienza nelle fasce anziane hanno un ruolo deter-minante non solo per i ceti sociali più modesti, ma per la popolazione femminile. Through the analysis of the Istat Multipurpose Survey data 2012-2013, this paper investigates how the differences in gender, social position, and family composition affect the elderly population with respect to certain specific diseases and to loss of self-sufficiency. A multivariate analysis reveals that women and the less educated parts of the population are subject to higher risk of chronic diseases and to loss of self-sufficiency. The risk of loneliness is particularly high in the women, especially in the extremely old ones, even in case of longterm care requirements. Thus social and healthcare policies sustaining the elder parts of the population with respect to long term care have a crucial role not only for the poorest segments of the society but especially for the women.

The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap-junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic’s endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyper-permeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis and pathogen transport. Il ruolo dei vasi linfatici e’ di trasportare fluidi, molecule solubili e cellule immunitarie ai linfonodi. In questo studio si dimostra come l’invecchimaneto diminuisca la funzionalità dei vasi linfatici e il flusso della linfa. Analisi ultrastrutturali, biochimiche e proteomiche indicano una diminuizione della matrice extracellulare, delle cellule dei muscoli lisci nei vasi linfatici di roditori adulti, portando a una diminuizione della frequenza di contrazione, velocita’ di trasporto della linfa, come misurato in vivo. Funzionalmente questo comporta una diminuizione nel trasporto dei batteri, come osservato in vivo tramite microscopia time-lapse. Analisi ultrastrutturali e proteomiche, indicano anche una dimunuizione nell spessore del glicocalice e delle proteine gap-junction nei vasi linfatici di roditori adulti. Analisi proteomiche mostrano un aumento delle modificazioni post-traduzionali, quail glicazione, carbonilazione in cellule endoteliali e nella matrice dei vasi linfatici di rodent adulti. Funzionalmente questi modificazioni portano iper-permeabilità dei vasi linfatici adulti, con conseguente uscita di patogeni dai vasi nelle aree circostanti. In conclusione, i nostril dati dimostrano come cambiamenti biochimici e anatomici in vasi linfatici di roditori adulti, influenzino l’omeostasi, il trasporto della linfa e dei patogeni. Dottorato di ricerca in Genetica e biologia cellulare

Considerable evidence suggests that the combinatorial effect dietary bioactive compounds may be useful in preventing or reducing aging features. Therefore, a synergistic multi-target approach in dietary intervention may be effective in slowing down the aging process and increase healthy aging. Functional foods and nutraceuticals can exert specific anti-aging benefits such as improvement in mitochondrial function or induce neuroprotective effects to counteract the deleterious consequences of oxidative stress. In this project, we evaluated a novel treatment strategy by combining two bioactive dietary constituents (resveratrol and equol) to determine their effect on mitochondrial function. The combined use of both compounds increased mitochondrial mass, mitochondrial DNA content, SIRT1 enzymatic activity and induced mitochondrial biogenesis factors such as PGC1-α, TFAM and NRF-1. Therefore, identification of this novel synergism may provide a new perspective for future treatments aiming to modulate the mitochondrial activity. Next, we investigated the combined effect of L-Carnosine and EGCG, two bioactive dietary compounds that have received particular attention because of their potential role in modulating oxidative stress associated with aging. We demonstrated that the neuroprotective effects of EGCG and L-Carnosine are achieved through the modulation of HO-1/Hsp72 systems. Our results indicate that the combined administration of EGCG and L-Carnosine reduces the neuronal damage caused by oxidative stress. Since chronic oxidative stress plays a central role in the pathogenesis of many diseases, including HIV-1 associated disorders, the last part of the project aimed to investigate the age-related patterns of Nrf2 and HO-1 in different brain regions and tissues of HIV-1 transgenic rat. The Nrf2/HO-1 axis constitutes a crucial cell survival mechanism to counteract oxidative stress and several recent studies have shown that bioactive food compounds can modulate Nrf2/HO-1 pathway. However, in the context of HIV-1 infection its role remains largely uncharacterized. In HIV-1 transgenic rat, we observed a significant reduction in the protein levels of Nrf2 and HO-1, suggesting a weakening in the cytoprotection exerted by Nrf2/HO-1 system. Moreover, the declined protein function of Nrf2 and HO-1 was accompanied by the acquisition of premature senescence phenotype in HIV-1 transgenic rat. Dietary inducers of Nrf2 and HO-1 may provide a novel strategy for restoring this pathway and mitigate oxidative stress during HIV-1 infection. Evidenze significative suggeriscono che sfruttare l’effetto combinatoriale di composti bioattivi derivanti dalla dieta può essere utile per prevenire o ridurre alcuni aspetti legati all’invecchiamento. Di conseguenza, interventi nutrizionali con approccio sinergico multi-target potrebbero essere efficaci nel rallentare il processo dell’invecchiamento e promuoverne la qualità. Alimenti funzionali e nutraceutici possono esercitare benefiche proprietà anti-invecchiamento, come miglioramento della funzione mitocondriale o indurre effetti neuroprotettivi per contrastare le conseguenze deleterie dello stress ossidativo. In questo progetto, abbiamo valutato una nuova strategia di trattamento, combinando due composti bioattive della dieta (resveratrolo ed equolo), per determinare il loro effetto sulla funzione mitocondriale. L’uso combinato di entrambi i composti ha incrementato la massa mitocondriale, il DNA mitocondriale, l’attività enzimatica di SIRT1 e indotto fattori di biogenesi mitocondriale come PGC1-α, TFAM and NRF-1. Quindi, l’identificazione di questo sinergismo potrebbe fornire una nuova prospettiva per futuri trattamenti aventi lo scopo di modulare l’attività mitocondriale. Successivamente, abbiamo investigato l’effetto combinato di L-Carnosina ed EGCG, due composti bioattivi presenti nella dieta che hanno ricevuto particolare attenzione dato il loro potenziale ruolo nel modulare lo stress ossidativo associato all’invecchiamento. Abbiamo dimostrato che gli effetti neuroprotettivi di EGCG ed L-Carnosina vengono raggiunti attraverso la modulazione dei sistemi HO-1/Hsp72. I nostri risultati indicano che l’amministrazione combinata di EGCG ed L-Carnosina riduce il danno neuronale causato dallo stress ossidativo. Dato che lo stress ossidativo gioca un ruolo centrale nella patogenesi di molte patologie, compresi i disturbi associati all’HIV-1, l’ultima parte del progetto ha avuto come scopo investigare i “patterns” di Nrf2 ed HO-1, in relazione all’età, in diversi tessuti e regioni del cervello di un ratto HIV-1 transgenico. L’asse Nrf2/HO-1 costituisce un meccanismo essenziale di sopravvivenza cellulare per contrastare lo stress ossidativo e diversi studi recenti hanno mostrato come composti alimentari bioattivi possono modulare il pathway dell’Nrf2/HO-1. Tuttavia, il suo ruolo nel contesto dell’infezione da HIV-1 rimane ampiamente non caratterizzato. Nel ratto HIV-1 transgenico abbiamo osservato un riduzione significativa dei livelli proteici di Nrf2 ed HO-1, suggerendo un indebolimento della citoprotezione esercitata dal sistema Nrf2/HO-1. Inoltre, il declino della funzione proteica di Nrf2 ed HO-1 è stata accompagnata dall’acquisizione di un fenotipo senescente. Induttori di Nrf2 ed HO-1, presenti nella dieta, potrebbero fornire una nuova strategia per ripristinare questo pathway e ridurre lo stress ossidativo durante l’infezione da HIV-1. Dottorato di ricerca in Scienze per la salute (XXVI ciclo)

The past few decades has witnessed a growing scientific interest in genetic studies on human aging and longevity. This growing interest may be explained by the increasing number of elderly subjects in developed countries over the last 50 years due to the continued improvements in health care. Such a fast increase of these population segments represent a huge problem for the societies in terms of social care and welfare. The difficulty in understanding the biological basis of human aging and longevity is mainly represented by (i) the cohort and the population-specificity of human aging and longevity, (ii) the lack of a clear and objective definition of the phenotype, (iii) the polygenic nature of the human longevity. On the basis of these observations, the studies reported here represent new approaches for the study of human aging and longevity. They were carried out on data obtained from the Calabrian population, characterized by high genetic homogeneity and a scarce level of immigration due to geographical, historical and social reasons. The first approach we used was to analyze the spatial distribution of long-lived individuals in Calabria. Using this approach, we verified that the spatial distribution of such individuals in this region is not uniform. In addition, by using surname data, we verified a significant correlation between population inbreeding and male longevity in a particular area of this region. The second approach is based on the application of a Cluster Analysis with well established geriatric parameters to identify aging phenotypes in the Calabrian population. The results obtained show that, the aging phenotypes recognized by Cluster Analysis are consistent from a geriatric point of view and have a clear genetic component.Finally, using a multilocus approach, we analyzed the influence of genetic variability of candidate genes on survival at old age in good health. On the basis of a synthetic survival curve built using historic mortality data from the Italian population and using multiple regression models, we found that genetic factors influence survival at advanced ages in good health in a sex and age specific way. The results reported here show that the application of these new approaches may be useful in human aging and longevity studies. Furthermore, they demonstrate that a multidisciplinary approach is necessary to analyze human aging and longevity. Dottorato di Ricerca in Molecular Bio-Pathology, XIX Ciclo, a.a.2006-2007 Università della Calabria

The field of spatial cognition has been evolving rapidly over the last few years, driven by convergence of results from both basic and clinical research. Spatial ability is involved in many cognitive tasks typically performed in everyday life, so it is important to accurately define and assess spatial ability in the context of everyday life. Recent studies also suggest that spatial abilities decline with normal aging, but it is not yet clear which spatial components decline during normal age-related cognitive decline, which are preserved, and at what point the spatial deficits become severe enough to suggest MCI or another degenerative disease. The main goal of my research projects, developed in three studies, was to investigate different components of spatial ability in a population of healthy older people, in individuals affected by mild cognitive impairment, and in autopsy-verified patients with dementia, in order to (a) develop new, more ecological instruments for the assessment of spatial abilities, (b) verify whether the assessment of spatial abilities may help in discriminating between MCI and controls and be used as a marker of the onset of AD, and (c) be used in differential diagnosis between Alzheimer's Disease and Dementia with Lewy bodies. In Study 1, results confirm the a priori hypothesis, ascertaining the reliability of these new spatial tests in measuring different components of spatial abilities: object memory, simultaneous spatial memory and sequential spatial memory. In the second study, the discriminant analyses revealed an elevated discriminative power of the new spatial battery in identifying MCI. Neuroimaging findings showed that MCI patients present a higher level of cortical atrophy in memory-related regions and a different pattern of brain correlation between visuospatial abilities and grey matter values compared with healthy elderly controls. Finally, results of Study 3 suggest that disproportionately severe visuospatial deficits, which are known to be prevalent in DLB patients, also extend to visuoperceptual abilities that do not involve construction or motor manipulation. This deficit reflects primarily Lewy Body pathology and is not related to the degree of concomitant AD pathology. All of this evidence supports the main idea that visuospatial evaluation should have a greater role in normal and pathological aging, in understanding the daily life abilities of healthy older people, in completing the diagnostic process of MCI, and also helping in the differential diagnosis between different types of dementia.

In recent years, epidemiological and biochemical studies have shown that eating apples is associated with reduction of occurrence of cancer, degenerative, and cardiovascular diseases. This association is often attributed to the presence of antioxidants such as ascorbic acid (vitamin C) and polyphenols. The substances that hinder the presence of free radicals are also able to protect cells from aging. In our laboratory we used yeast, a unicellular eukaryotic organism, to determinein vivoefficacy of entire apples and their components, such as flesh, skin and polyphenolic fraction, to influence aging and oxidative stress. Our results indicate that all the apple components increase lifespan, with the best result given by the whole fruit, indicating a cooperative role of all apple components.

“Mirror, mirror on the wall, who’s the fairest of them all?“ This is certainly the most cited expression of the 21 century. We do not want to get old, and in this context a lot of hopeful are set on stem cell therapy for tissue regeneration: regeneration of skin, dermis, cartilage, bone, nervous sistem and so on. Most of all on our smile that it is our business card. Rapid and good regeneration of alveolar bone to support new dental implant is up to now ensured by the use adult mesenchymal stem cells. But are they able to conserve their stemness ability for all the age of the donors? In light of such consideration aim of the present work has been the study of the biological properties such as proliferation and stemness ability of human adult dental pulp stem cells (DPSC) in relation to the age of the donors and to the in vitro aging. Human dental pulps derived from adult subjects aged 16–over 66 years have been isolated and cultured in presence of differentiative medium. Results obtained confirmed a correlation between age and conservation of stemness during in vitro aging., Italian Journal of Anatomy and Embryology, Vol 116, No 1 (Supplement) 2011

In this paper, we investigate the way consumption changes around retirement in Italy. Using micro data covering the 1985–1996 period, we document the existence of a one-off drop in consumption at retirement of the household head, as in the UK and the US, but (at 5.44%) smaller in size, and show that consumption of work-related goods falls around retirement and home production of food and other goods increases.

Malnutrition in the elderly is one of the greatest threats to health, well-being and autonomy, it is therefore crucial to understand and to contrast the causal factors of inadequate energy intake. This review focuses on the mechanisms of the so-called ‘anorexia of aging’. In recent years, it has been shown that elderly subjects have abnormal peripheral signal patterns and alterations in central hypothalamic control relays. Negative feedback from impaired gastric motility, exaggerated long-term adiposity signals (leptin, insulin) and postprandial anorexigenic signals (CCK, PYY) seem to prevail over the central feeding drive. If nutritional strategies of intervention are to be improved, these data need to be taken into account.

This article proposes a critical and historical reflexion on the theme of the construction of the age categories and the fixation of the age thresholds. The end of the youth and the beginning of old age are analyzed., Cet article cherche à opérer une déconstruction historique des seuils et catégories d'âge en démographie, en se penchant sur le cas de la transition de jeunesse à l'âge adulte, et sur le seuil d'entrée dans la vieillesse.

The survival of mesenchymal stem cells (MSCs) to tumor necrosis factor alpha (TNFalpha) stimulation was evaluated after a long-term antioxidant treatment, or caloric restriction, in aged rats. MSCs were isolated from bone marrow of 30-month-old rats which orally received N-acetylcysteine in the last 18 months. The necrotic cell death-induced in vitro by TNFalpha, determined by trypan blue exclusion, was markedly attenuated in MSCs obtained from treated vs. control aged rats (percent mean+/-SEM: 10.9+/-2.17 vs. 17.8+/-0.53; p