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Glutine e infiammazione intestinale

by luciano

Il glutine induce infiammazione intestinale non solo nei soggetti celiaci ma anche in quelli sani

L’infiammazione intestinale è una condizione del sistema gastro-intestinale che riguarda una platea di persone molto vasta e in continuo costante aumento. Questa condizione rappresenta per l’ndividuo non solo uno stato di malessere che incide sulla qualità della vita ma può -se sottovalutata o trascurata- favorire l’insorgere o l’aggravare malattie gravi.
Un ruolo importante ma ancora da esplorare a fondo lo riveste il glutine in quanto pro-infiammatorio.
Lo studio” The Role of Gluten in Gastrointestinal Disorders: A Review. Sabrina Cenni. Gastrointestinal Disorders: A Review. Nutrients 2023” fornisce un’utile panoramica della sua efficacia nella prevenzione e nella gestione di questi disturbi.

Il glutine è soltanto parzialmente digerito dagli enzimi intestinali e può generare peptidi che alterano la permeabilità intestinale

“Abstract: Gluten is only partially digested by intestinal enzymes and can generate peptides that can alter intestinal permeability, facilitating bacterial translocation, thus affecting the immune system. Few studies addressed the role of diet with gluten in the development of intestinal inflammation and in other gastrointestinal disorders. The aim of this narrative review was to analyse the role of gluten in several gastrointestinal diseases so as to give a useful overview of its effectiveness in the prevention and management of these disorders.”

“Introduction. Gluten is a protein mass made of a complex network of gliadins and glutenins, which are proteins rich in glutamines and prolines found in most grains, such as barley, wheat, and rye [1 ,2]. Due to its high-water binding capacity and its consequent malleability and elasticity, gluten induces the formation of viscoelastic membranes, thus determining the proper consistency of dough, which allows it to be processed in bread and other foods [ 3– 5]. The high content of glutamines and prolines in gliadins make them difficult to cleave, making them able to escape degradation from gastric, pancreatic, and intestinal proteolytic enzymes [3, 4]. Therefore, gluten is what remains after the removal of starch, water-soluble proteins, and albumins [1]. In Western countries, the gluten dietary intake is approximately 5 to 20 g per day [3 , 4]. In the last decades, the literature reports an increased number of reactions following a widespread exposure to gluten [ 6]. Gluten-related diseases affect up to 10% of the general population and can be classified as three different disorders: IgE-mediated wheat allergy, Celiac disease (CD), and non-celiac gluten sensitivity (NCGS) [2, 6]. However, there is increasing evidence that gluten can trigger an innate and adaptative immune response responsible for intestinal inflammation [7]. Notably, along with other dietary elements, gluten may contribute to the development of inflammatory intestinal disorders, such as inflammatory bowel disease (IBD), as well as functional gastrointestinal disorders (FGIDs) and concur in symptom exacerbation, although its exact role is still under investigation.”

“Gluten and intestinsl inflammation. Inflammation is the natural response of the innate immune system to external stimuli, such as microbial pathogens and injuries [8 ]. When the trigger persists and the immune cells are constantly activated, the inflammatory response may become chronic and self-sustainable [8]. The aetiology of inflammation is clear and easily detectable in some health conditions, while in others it can be difficult to identify [ 8]. The pathogenesis of inflammation is multifactorial. Nevertheless, genetic vulnerability, psychological stress, environmental factors, and some dietary patterns have been described as potentially implicated in the development of inflammatory phenotypes [ 8]. There are at least 50 different types of gliadin epitopes that can have an immunomodulatory and cytotoxic role or that can impact the gut permeating activities [ 8 ]; in fact, some of these can stimulate a pro-inflammatory innate immune response and others can activate specific T cells [8]. Gliadins immune cells’ activation is not only observed in celiac patients, as described by Lammers et al. [9, 10]. Indeed, their study concluded that gliadin induced an inflammatory response and, in particular, an important production of pro-inflammatory cytokines (IL-6, IL-13, and interferon-gamma) both in Celiac patients and in healthy controls, even if proinflammatory cytokine levels were higher in Celiac patients [9, 10]. Similarly, Harris et al. showed that incubated peripheral blood mononuclear cells (PMBC) obtained from healthy HLA-DQ2 positive individuals produced proinflammatory cytokines, such as IL-23, IL-1beta, and TNF-α, when exposed to gliadin peptides [ 8, 11]. These cytokines’ production was significantly higher in Celiac patients compared to healthy controls [8,11]. Accordingly, Cinova et al., in their case-control study, demonstrated that gliadin could stimulate a substantial TNF-α and IL-8 production by monocytes, principally in celiac patients, but also, to a lesser extent, in healthy control individuals [12]. Gliadin also has an important role in modifying intestinal permeability through the reorganization of actin filaments and the modified expression of junctional complex proteins [ 8,13 ]. As demonstrated by Drago et al. and Lammers et al., gliadin’s binding to the chemokine receptor CXCR3 determines a release of zonulin, an active protein, which compromises the integrity of the intestinal barrier through the rearrangements of actin filaments, ultimately leading to an altered intestinal permeability both in Celiac and non-Celiac patients [ 9, 10, 14 ]. In conclusion, Ziegler et al. and Junker et al. reported that amylase trypsin inhibitors, found in gluten-containing cereals, have the capacity to activate toll-like receptors, thus stimulating the release of inflammatory cytokines and inducing a T-cell immune response in both celiac and non-celiac patients [15,16].”

Einkorn wheat is the exception in relation to gluten-induced intestinal inflammation

Einkorn bread evidenced an anti-inflammatory effect. Integrated Evaluation of the Potential Health Benefits of Einkorn-Based Breads A. Gobetti et al. 2017.

Protective effects of ID331 Triticum monococcum. Protective effects of ID331 Triticum monococcum gliadin on in vitro models of the intestinal epithelium. Giuseppe Iacomino et al. (PMID: 27374565 DOI: 10.1016/j.foodchem.2016.06.014 ).

Keywords: glutine, IBS, disordini gastro-intestinali, celiachia

Implicazioni dell’utilizzo del lievito di birra nella panificazione: aspetti fermentativi, strutturali e nutrizionali

by luciano

Abstract
Il lievito di birra (Saccharomyces cerevisiae) rappresenta l’agente lievitante principale nella panificazione tradizionale. La quantità di lievito impiegata, la sua attività metabolica prima della cottura e le caratteristiche dei residui cellulari presenti nel prodotto finito influenzano in modo significativo le proprietà strutturali, sensoriali e nutrizionali del pane. Questo articolo fornisce un’analisi approfondita degli effetti dell’impiego eccessivo di lievito, della composizione dei residui cellulari dopo la cottura e del loro impatto su qualità del prodotto e interazioni fisiologiche.

A. Effetti dell’eccesso di lievito di birra nell’impasto
L’impiego di quantità eccessive di lievito determina una fermentazione accelerata, con ripercussioni negative sulla formazione della struttura e sulla qualità aromatica.
A.1 Conseguenze sulla fermentazione dell’impasto
Produzione rapida di CO₂: L’elevata velocità fermentativa porta a una saturazione precoce della maglia glutinica.
Sovradistensione della rete glutinica: L’espansione meccanica indotta dal gas può superare la capacità elastica del glutine, predisponendo l’impasto al collasso.
Alterazioni reologiche: L’impasto risulta eccessivamente gassoso, appiccicoso e difficile da manipolare.
A.2 Implicazioni sul prodotto finale
Aroma e profilo sensoriale: La fermentazione troppo rapida genera note marcate di lievito o alcol, con riduzione della complessità aromatica.
Struttura della mollica: Sono frequenti alveoli irregolari e zone collassate, tipiche di impasti sovralievitati.
Colorazione della crosta: L’esaurimento precoce degli zuccheri disponibili limita la reazione di Maillard, producendo croste più chiare.
Shelf life ridotta: La debolezza strutturale accelera il raffermamento.
Una fermentazione più lenta e controllata è associata a migliori proprietà sensoriali e strutturali.

B. Residui del lievito dopo la cottura
Durante la cottura, Saccharomyces cerevisiae viene inattivato termicamente. Le cellule morte restano nel pane come biomassa inerte.
B.1 Componenti residue
Dopo la morte cellulare permangono:
frammenti cellulari contenenti proteine, lipidi, nucleotidi
polisaccaridi di parete (β-glucani e mannani)
metaboliti prodotti durante la fermentazione pre-cottura (esteri, acidi organici, aldeidi, alcoli superiori)
anidride carbonica intrappolata come alveoli della mollica
L’etanolo prodotto viene quasi completamente eliminato per evaporazione.
B.2 Aspetti scientifici
Le cellule morte non fermentano e non hanno attività probiotica.
I residui non influenzano la microflora del pane, poiché la cottura sterilizza l’ambiente.
I costituenti cellulari contribuiscono marginalmente al valore nutrizionale (amminoacidi, vitamine del gruppo B).

C. Eccesso di residui cellulari da lievito in pane ottenuto con troppo lievito
Quando la quantità di lievito utilizzata è superiore ai livelli ottimali, l’accumulo di biomassa inattiva e di metaboliti fermentativi nel prodotto finale produce effetti misurabili su struttura e sensorialità.
C.1 Effetti sulla struttura
Mollica più densa o leggermente gommosa: l’eccesso di particolato cellulare interferisce con la rete glutinica.
Modificazioni dell’idratazione: polisaccaridi di parete e componenti cellulari legano acqua, alterando le proprietà reologiche.
Possibili collassi strutturali: esito indiretto del sovralievitazione.
C.2 Effetti su aroma e gusto
Sapore lievitato o lievemente amaro: dovuto al rilascio di aminoacidi, nucleotidi e composti solforati.
Squilibri aromatici: concentrazioni elevate di esteri e alcoli superiori alterano il profilo aromatico naturale del pane.
C.3 Conseguenze nutrizionali
La biomassa aggiuntiva aumenta il contenuto di:
proteine
vitamine del gruppo B
minerali
β-glucani e mannani
Tuttavia, tali elementi non conferiscono attività probiotica.

D. Analisi scientifica approfondita
D.1 Interazione con il microbiota intestinale
Le cellule di lievito inattivate dal calore vengono digerite come altre macromolecole alimentari.
Non alterano significativamente il microbiota intestinale.
I β-glucani e i mannani possono esercitare modesti effetti prebiotici, ma privi di attività microbica metabolica.
Gli effetti fisiologici del pane sul microbiota derivano principalmente dai processi fermentativi pre-cottura, soprattutto nei pani a lievitazione naturale (sourdough).
D.2 Importanza della corretta dosatura del lievito
La quantità di lievito modula:
lievitazione (produzione di CO₂),
sviluppo aromatico (formazione di esteri, aldeidi, alcoli, acidi),
modificazioni reologiche (attività enzimatica su amidi e proteine).
Carente apporto di lievito:
lievitazione lenta
mollica compatta
prevalenza di acidità (soprattutto in sistemi sourdough)
Eccesso di lievito:
fermentazione troppo rapida e rischio di sovralievitazione
struttura instabile
aroma meno complesso
Nei processi professionali si impiega generalmente lo 0,5–2% di lievito sul peso della farina, variabile in funzione di temperatura, idratazione, contenuto zuccherino e salino.
D.3 Componenti e metaboliti disponibili dopo la morte del lievito
Dopo la cottura rimangono solamente:
metaboliti preformati (esteri, alcoli superiori, acidi organici)
componenti cellulari (amminoacidi, nucleotidi, lipidi, vitamine, minerali, polisaccaridi)
Questi contribuiscono:
all’aroma (tramite precursori delle reazioni di Maillard)
alla struttura (solo se quantitativamente elevati)
al valore nutrizionale (apporto di micronutrienti)
Non si verifica alcuna attività metabolica post-mortem da parte del lievito.

Conclusioni
L’utilizzo del lievito di birra nella panificazione richiede un controllo quantitativo rigoroso, poiché la dinamica fermentativa e la qualità del prodotto finale dipendono in larga misura dalla quantità di lievito impiegata. Le cellule morte presenti nel pane cotto costituiscono biomassa nutriente ma metabolicamente inattiva, senza impatti significativi sul microbiota o sulla sicurezza alimentare. L’ottimizzazione della fermentazione pre-cottura rimane l’elemento chiave per ottenere pane di elevata qualità strutturale e sensoriale.

Invecchiamento del sistema immunitario II parte

by luciano

Invecchiamento del sistema immunitario I parte

In evidenza
1 – L’invecchiamento è un processo multifattoriale guidato da vari fattori intrinseci ed estrinseci, tra cui instabilità genomica, accorciamento dei telomeri (modificazioni della sequenza del DNA) [A], alterazioni epigenetiche, perdita di proteostasi, macroautofagia disabilitata, rilevamento dei nutrienti alterato [B], disfunzione mitocondriale, senescenza cellulare, esaurimento delle cellule staminali, comunicazione intercellulare alterata, infiammazione cronica e disbiosi. Questi fattori sono strettamente correlati all’invecchiamento dell’organismo e la ricerca ha dimostrato che indurli può accelerare l’invecchiamento, mentre intervenire su di essi può rallentare, arrestare o persino invertire il processo di invecchiamento.
2 – Le molecole secrete dalle cellule senescenti (fenotipo secretorio associato alla senescenza SASP [C]), promuovono l’infiammazione cronica e possono indurre la senescenza nelle cellule normali. Allo stesso tempo, l’infiammazione cronica accelera la senescenza delle cellule immunitarie, con conseguente indebolimento della funzione immunitaria e incapacità di eliminare le cellule senescenti e i fattori infiammatori, creando un circolo vizioso di infiammazione e senescenza.
3 – L’inflammaging [D] (chronic, low-grade, and persistent inflammation) è un segno distintivo riconosciuto dell’invecchiamento, legato a morbilità e mortalità. L’inflammaging è così strettamente interconnesso con l’invecchiamento dell’organismo che è possibile costruire orologi dell’invecchiamento altamente accurati, predittivi di morbilità e mortalità, utilizzando marcatori di infiammazione.
4. – Sebbene esista una notevole variabilità nell’invecchiamento tra gli individui, il processo di invecchiamento generalmente comporta infiammazione cronica, disturbi dell’omeostasi tissutale e disfunzione del sistema immunitario e disturbi dell’omeostasi degli organi, e disfunzione del sistema immunitario e delle funzioni degli organi, funzioni, causando facilmente malattie cardiovascolari, metaboliche, autoimmuni e neuro degenerative associate all’invecchiamento.
5 – Interventi geroterapici come la restrizione calorica, l’adozione di una dieta chetogenica o l’esercizio fisico possono sostenere la durata della salute in parte attenuando l’invecchiamento immunitario tramite meccanismi immunometabolici unificati.

Le ricerche

5 – Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases. Ping Song. 2020
Le cellule senescenti sono generalmente caratterizzate da arresto permanente del ciclo cellulare, alterazione e attivazione metabolica e resistenza all’apoptosi in diversi organi a causa di vari fattori di stress. L’accumulo eccessivo di cellule senescenti in numerosi tessuti porta a molteplici malattie croniche, disfunzioni tissutali, patologie legate all’età e invecchiamento degli organi. Le cellule immunitarie possono rimuovere le cellule senescenti. L’immunizzazione o l’alterazione delle risposte immunitarie innate e adattative da parte delle cellule senescenti provocano un accumulo persistente di varie cellule senescenti. Sebbene i senolitici – farmaci che rimuovono selettivamente le cellule senescenti inducendone l’apoptosi – siano argomenti di attualità e stiano facendo significativi progressi nella ricerca, le immunoterapie per la senescenza che utilizzano la clearance delle cellule senescenti mediata dalle cellule immunitarie stanno emergendo e rappresentano strategie promettenti per combattere l’invecchiamento e molteplici malattie croniche. Questa breve rassegna fornisce una panoramica dei progressi della ricerca fino ad oggi riguardanti le malattie croniche causate dalle cellule senescenti e l’invecchiamento dei tessuti, nonché la regolazione della senescenza da parte di farmaci a piccole molecole negli studi clinici e i diversi ruoli e la regolazione delle cellule immunitarie nell’eliminazione delle cellule senescenti. Prove sempre più numerose indicano che l’immunoterapia mirata alle cellule senescenti combatte l’invecchiamento e le malattie croniche, prolungando di conseguenza la durata di una vita sana. Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases. Ping Song * , Junqing An and Ming-Hui Zou. Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA; jan14@student.gsu.edu (J.A.); mzou@gsu.edu (M.-H.Z.). * Correspondence: psong@gsu.edu; Tel.: +1-404-413-6636
Received: 29 January 2020; Accepted: 5 March 2020; Published: 10 March 202

6 – Aging of the immune system – focus on inflammation and vaccination. 2016. Marcello Pinti et al.
The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age.Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T-cell or B-cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.

….omissis
What are these basic aging processes? For humans, this question remains formally unanswered. Nevertheless, a very large body of experimental evidence from a wide variety of organisms ranging from yeast to primates strongly suggests there are at least nine evolutionarily conserved hallmarks of aging that almost certainly derive from a small handful of basic aging processes [3]. These hallmarks of aging include stem cell exhaustion, altered intercellular communication, genomic instability and telomere attrition, epigenetic alterations, loss of protein homeostasis (proteostasis), altered nutrient and growth factor sensing, mitochondrial dysfunction and cellular senescence [3]. There are still many open questions regarding the prime causes and ultimate effects of these hallmarks. However, emerging studies are beginning to identify commonalities among the causes and effects of at least some of these hallmarks. One of these commonalities has been linked to the immune system: low levels of chronic inflammation, otherwise known as inflammaging or inflammageing [4].

….omissis

Conclusions
The increase in human lifespan poses several new questions and complex challenges to the medical and scientific community, including for immunologists. Today, the immune system has to defend the organism for several decades, and thus has to work effectively for a substantial number of years; this is a reality that was not considered when Jenner developed the smallpox vaccine. Moreover, every day immune cells have to cope with external insults (such as oxygen, UV light, chronic infection), personal and social behaviors (nutrition, obesity, psychological stress, lack of exercise, hyper-training, pollution, smoking, economic status) and unavoidable internal changes (cell metabolism, turnover and production of DAMPs). Our community is well aware of this challenge, and indeed an unprecedented attention is now paid to aging and longevity, that includes the search for new strategies for an optimal maintenance of immunological performances in the long, last part of our life. Aging of the immune system – focus on inflammation and vaccination. 2016
Marcello Pinti et al. Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Eur J Immunol. 2016 October ; 46(10): 2286–2301. doi:10.1002/eji.201546178.

Invecchiamento del sistema immunitario I parte

by luciano

Panoramica delle più recenti ricerche relative all’invecchiamento del sistema immunitario e della correlazione con l’infiammazione.

In evidenza
1 – L’invecchiamento è un processo multifattoriale guidato da vari fattori intrinseci ed estrinseci, tra cui instabilità genomica, accorciamento dei telomeri (modificazioni della sequenza del DNA) [A], alterazioni epigenetiche, perdita di proteostasi, macroautofagia disabilitata, rilevamento dei nutrienti alterato [B], disfunzione mitocondriale, senescenza cellulare, esaurimento delle cellule staminali, comunicazione intercellulare alterata, infiammazione cronica e disbiosi. Questi fattori sono strettamente correlati all’invecchiamento dell’organismo e la ricerca ha dimostrato che indurli può accelerare l’invecchiamento, mentre intervenire su di essi può rallentare, arrestare o persino invertire il processo di invecchiamento.
2 – Le molecole secrete dalle cellule senescenti (fenotipo secretorio associato alla senescenza SASP [C]), promuovono l’infiammazione cronica e possono indurre la senescenza nelle cellule normali. Allo stesso tempo, l’infiammazione cronica accelera la senescenza delle cellule immunitarie, con conseguente indebolimento della funzione immunitaria e incapacità di eliminare le cellule senescenti e i fattori infiammatori, creando un circolo vizioso di infiammazione e senescenza.
3 – L’inflammaging [D] (chronic, low-grade, and persistent inflammation) è un segno distintivo riconosciuto dell’invecchiamento, legato a morbilità e mortalità. L’inflammaging è così strettamente interconnesso con l’invecchiamento dell’organismo che è possibile costruire orologi dell’invecchiamento altamente accurati, predittivi di morbilità e mortalità, utilizzando marcatori di infiammazione.
4 – Sebbene esista una notevole variabilità nell’invecchiamento tra gli individui, il processo di invecchiamento generalmente comporta infiammazione cronica, disturbi dell’omeostasi tissutale e disfunzione del sistema immunitario e disturbi dell’omeostasi degli organi, e disfunzione del sistema immunitario e delle funzioni degli organi, funzioni, causando facilmente malattie cardiovascolari, metaboliche, autoimmuni e neurodegenerative associate all’invecchiamento.
5 – Interventi geroterapici come la restrizione calorica, l’adozione di una dieta chetogenica o l’esercizio fisico possono sostenere la durata della salute in parte attenuando l’invecchiamento immunitario tramite meccanismi immunometabolici unificati.

Le ricerche

1 – The immune system offers a window into aging. 2025 Nature Aging.
The immune system permeates and regulates organs and tissues across the body, and has diverse roles beyond pathogen control, including in development, tissue homeostasis and repair. The reshaping of the immune system that occurs during aging is therefore highly consequential.
During aging, the ability of the immune system to efficiently and precisely respond to new antigenic, infectious or neoplastic challenges wanes, and the reactivation and refinement of memory responses falters. One of the earliest manifestations of aging is the involution of the thymus (the site of T cell development), which occurs during puberty. In later life, the immune system increasingly shifts from its homeostatic and protective roles towards a state that is char acterized by heightened proinflammatory activity, with a propensity for autoreactivity. Rather than safeguarding the host, the aged immune system may contribute to systemic dysfunction and pathology.

In this Focus, Nature Aging introduces a series of reviews and opinions that cover recent advances in immune aging. Building on their studies defining immune aging as a driver of organismal aging, Delgado-Pulido and colleagues explore how aging transforms the immune system ‘from healer to saboteur’, and describe the deterioration of protective functions and the acquisition of pathogenic features of the aged adaptive immune system.
Majewska and Krizhanovsky zoom in on one of these protective immune functions that declines with age: namely, the clearance of senescent cells. Through surveying the interactions between senescent and immune cells (which may deteriorate during aging), the authors highlight the role of the aged immune system in facilitating the accumulation and propagation of senescent cells across tissues with age, and thereby fueling tissue dysfunction and disease pathogenesis.
The effects of immune aging on age-related diseases are far-reaching. The fatal consequences of immune aging were demonstrated by impaired infection control during the COVID-19 pandemic. Immune aging has also been implicated in the pathogenesis of non-infectious age-related diseases, including cardiovascular, fibrotic and metabolic diseases, cancer and dementia. Indeed, both peripheral immunity and central neuroinflammation are recognized as contributors to, markers of and potential therapeutic targets in neurodegenerative conditions, and inflammaging is a recognized hallmark of aging linked to morbidity and mortalityrk. Pa and colleagues call attention to resident tissue macrophages as particular culprits of inflammaging and propose that restoring resident tissue macrophages by targeting the niche or myelopoiesis in the bone marrow could attenuate their contribution to tumori- genesis and promote healthy aging.
Inflammaging is so closely intertwined with organismal aging that highly accurate aging clocks, predictive of morbidity and mortality, can be built using markers of inflammation. Tracking individual immune aging trajectories could inform on disease risks as well as contribute to the suits of biological age-predictive biomarkers. However, both aging and the immune system hold considerable complexity and diversity. Franceschi and colleagues survey immune aging clocks through the lens of personalized inflammaging. They highlight that each individual’s unique combination of genetics, lifetime exposures and lifestyle factors results in heterogeneous manifestations of inflammaging, pose that precision measures and interventions should be prioritized, and spotlight a potential role for artificial intelligence in navigating this complexity.
Research on the biological processes of aging is often conducted using model organisms or in vitro models, yet thanks to the ease of access to human blood samples, the immune system offers a window into aging in humans. Immune aging can also be leveraged in clinical trials of aging, by testing the strength of vaccine responses or infection control. Trials that test emerging tech nologies or gerotherapeutic interventions could not only identify strategies to improve immune responses but also stand to inform our understanding of the plasticity of aging in humans and offer important milestones in refining the design of trials conducted with older adults. Discussing strategies to boost immune responses to vaccination in aging, Hofer and colleagues highlight the potential of enhancing vaccines by using gerotherapies to attenuate immune aging.
As well as providing an overview of the hallmarks of immune aging, Kim and Dixit further explore gerotherapeutic interventions, through an immunometabolic lens. They explore how gerotherapeutic interventions such as calorie restriction, ketogenic diet adoption or exercise may sustain healthspan in part through attenuation of immune aging via unified immunometabolic mechanisms. They also highlight adipose as an immunological organ with considerable physiological influence on aging.
Across these articles, the immune system stands out as an early target during aging: the loss of its protective capacities facilitates tissue degeneration and pathology. Weyand and Goronzy, however, highlight the acquisition of autoreactive functions during immune aging, and reflect on recent data that unexpectedly report an increase in autoimmune conditions with age. They propose that autoimmunity during aging constitutes inappropriate immune youthfulness and suggest that wan ing immune activity during aging could be beneficial in calibrating autoreactivity.
As a tractable and targetable window into aging in humans, the aged immune system holds opportunities for translationally valuable discoveries and constitutes a potential broad target to extend healthspan. We are very grateful to the authors and reviewers who have contributed to this issue. Our goal for this Focus has been to stimulate interest and promote cross-pollination of ideas across disciplines. We look forward to supporting immune aging research and sharing exciting findings from this field in the years to come.
References
1. Yousefzadeh, M. J. et al. Nature 594, 100–105 (2021).
2. Desdín-Micó, G. et al. Science 368, 1371–1376 (2020).
3. Bartleson, J. M. et al. Nat. Aging 1, 769–782 (2021).
4. Sarazin, M. et al. Nat. Aging 4, 761–770 (2024).
5. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Cell 186, 243–278 (2023).
6. Sayed N. et al. Nat. Aging 1, 598–615 (2021).
7. Conrad N. et al. Lancet 401, 1878–1890 (2023).
The immune system offers a window into aging. Volume 5; Agosto 2025 Nature Aging. https://doi.org/10.1038/s43587-025-00948-5

2 – Recent Advances in Aging and Immunosenescence: Mechanisms and Therapeutic Strategies. Shuaiqi Wang1 . Cell. 2025

Introduction
Population aging is currently one of the major global challenges [1]. With the intensification of population aging, delaying aging and improving the quality of life for elderly people have become important tasks. Aging is a multifactorial process driven by various intrinsic and extrinsic factors, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis [2]. These factors are closely related to organismal aging, and research has shown that inducing them can accelerate aging, while intervening in them can slow down, halt, or even reverse the aging process [2]. Thoroughly studying these aging factors to elucidate the mechanisms of aging can help identify interventions to delay aging, such as caloric restriction, nutritional interventions, and gut microbiota transplantation, as well as clinical treatments for aging-related diseases, eases, including senolytics, stem cell therapy, and antioxidant and anti-inflammatory including senolytics, stem cell therapy, and antioxidant and anti-inflammatory treatments.
These approaches can mitigate aging and aging-related diseases, thereby achieving healthy achieving healthy aging and longevity [3–5].
Among these factors, cellular senescence is a key contributor to organismal aging. Targeting senescent cells (SCs) holds promise for developing novel and practical antiaging therapies [6]. Cellular senescence is an irreversible state of cell cycle arrest caused by varivarious factors, such as DNA damage and telomere shortening [7,8]. Additionally, the process whereby immune system function gradually declines or becomes dysregulated whereby immune system function gradually declines or becomes dysregulated with human aging is known as immunosenescence [E] [9]. Although coniderable variability in aging exists among individuals, the aging process generally involves chronic inflammation, tissue homeostasis disorders, and dysfunction of the immune system and organ homeostasis disorders, and dysfunction of the immune system and organ functions, [2] functions, [2] readily causing cardiovascular, metabolic, autoimmune, and neurodegenerative diseases associated with aging [5,10–13]. Existing research indicates that transplanting SCs into young mice induces bodily dysfunction, while transplanting them into aged mice exacerbates aging and increases the risk of death [6].
This suggests that SCs accelerate organismal aging. The specific reason is that SCs release the senescence-associated secretory phenotype (SASP) into the tissue, promoting chronic inflammation and inducing senescence in surrounding tissue cells and immune cells [14]. SCs and chronic inflammation interact and crosstalk, forming a vicious cycle of inflammation and aging.
Therefore, in-depth research into the key characteristics and underlying mechanisms of cellular senescence, immunosenescence, and inflammation, identifying drug intervention targets, and developing targeted interventions can help mitigate aging and aging-related diseases, thereby promoting healthy aging in the elderly. In recent years, based on the establishment of a series of aging-related cellular and animal models (Table 1), the latest research has revealed the molecular mechanisms of cellular senescence and immunosenescence and the body’s regulation of aging from an immune response perspective.
Moreover, based on new mechanisms, strategies targeting the elimination of SCs have become a promising treatment method for alleviating aging and age-related diseases.
Later, it was discovered that some that small-molecule senolytic senolytic drugs target proteins in cell senescent antiapoptotic pathways (SCAPs) can selectively kill SCs (Figure 1).
Currently, effective, safe, and selective immunotherapy selective approaches targeting SCs are becoming promising a treatment method. Some teams research have teams have already already developed senolytic CAR T cells [19], senolytic vaccines [20], and immune checkpoint blockade (ICB) therapies to achieve the clearance of SCs [21].

Figure 1. 1. Cellular Cellular senescence and senolytics. SCs continuously produce numerous pro-inflammatory senescence and senolytics. SCs continuously produce numerous pro-inflammamolecules and tissue-remodeling molecules, known as the SASP, which further accelerates the aging tory molecules and tissue-remodeling molecules, known as the SASP, which further accelerates the process. Senolytics promote the regeneration of new healthy cells by identifying and clearing SCs. Created with BioRender.com (accessed on 10 May 2024).

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Summary and Prospects
The global issue of population aging is becoming increasingly severe, with elderly individuals being more susceptible to infections and age-related diseases, leading to higher morbidity and mortality rates [5]. Cellular senescence and immunosenescence are closely linked to aging; therefore, this review focuses on immunotherapies targeting aging. It revisits significant recent discoveries in the mechanisms of cellular senescence and immunosenescence that have propelled the development of new treatment paradigms for aging and age-related diseases.
Recent Advances in Aging and Immunosenescence: Mechanisms and Therapeutic Strategies. Shuaiqi Wang1 . Cell. 2025
Department of Immunology, CAMS Key Laboratory T-Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China; b2023005058@pumc.edu.cn (S.W.); huotong1998@pumc.edu.cn (T.H.); b2022005055@student.pumc.edu.cn (M.L.); s2022005053@student.pumc.edu.cn (Y.Z.); zhangjianmin@ibms.pumc.edu.cn (J.Z.). https://doi.org/10.3390/cells14070499

3 – Chronic Low-Grade Inflammation and Brain Structure in the Middle-Aged and Elderly Adults. 2024
Abstract: Low-grade inflammation (LGI) mainly acted as the mediator of the association of obesity and inflammatory diet with numerous chronic diseases, including neuropsychiatric diseases. However, the evidence about the effect of LGI on brain structure is limited but important, especially in the context of accelerating aging. This study was then designed to close the gap, and we leveraged a total of 37,699 participants from the UK Biobank and utilized inflammation score (INFLA-score) to measure LGI. We built the longitudinal relationships of INFLA-score with brain imaging phenotypes using multiple linear regression models. We further analyzed the interactive effects of specific covariates. The results showed high level inflammation reduced the volumes of the subcortex and cortex, especially the globus pallidus ( β [95% confidence interval] = −0.062 [−0.083, −0.041]), thalamus (−0.053 [−0.073, −0.033]), insula (−0.052 [−0.072, −0.032]), superior temporal gyrus (−0.049 [−0.069, −0.028]), lateral orbitofrontal cortex (−0.047 [−0.068, −0.027]), and others. Most significant effects were observed among urban residents. Furthermore, males and individuals with physical frailty were susceptive to the associations. The study provided potential insights into pathological changes during disease progression and might aid in the development of preventive and control targets in an age-friendly city to promote great health and well-being for sustainable development goals.

Figure 1. Study workflow.Figure 1. Study workflow. We screened 37,699 UK Biobank participants to explore the effects of
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Conclusions
To sum up, the conceptual and design framework of our investigation is to characterize the associations between LGI and brain imaging phenotypes, thus showing that LGI may lead to subclinical cognitive decline or neuropsychic diseases partly via structural neural pathways. Moreover, our analyses revealed that more significant associations of LGI with the atrophy of brain structure among male or individuals with physical frailty. These findings not only contribute to the evolvement of clinical diagnosis and therapy, but also provide a novel perspective for the development of new preventive strategies, namely, when brain lesions are subclinical and without any apparent clinical sign, inflammatory intervention, such as diet therapy, is an early preventive strategy.
Chronic Low-Grade Inflammation and Brain Structure in the Middle-Aged and Elderly Adults. Yujia Bao et al. School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; bubble-y@sjtu.edu.cn (Y.B.); c.cctx@sjtu.edu.cn (X.C.); melody321@sjtu.edu.cn (Y.L.); scp-173@sjtu.edu.cn (S.Y.). Nutrients 2024, 16, 2313. https:// doi.org/10.3390/nu16142313

Vitamina D e vitamina C favoriscono un invecchiamento sano

by luciano

Panoramica. Sia la vitamina D che la vitamina C contribuiscono alla salute della barriera intestinale supportando la funzione delle giunzioni strette e promuovendone la riparazione. La vitamina D, attraverso il suo recettore (VDR), regola le proteine che formano le giunzioni strette, che mantengono l’integrità della barriera e modulano il sistema immunitario. La vitamina C può anche promuovere la riparazione della barriera, potenzialmente regolando le vie di segnalazione di Notch e influenzando la composizione del microbioma intestinale, che può ulteriormente supportare la barrier

Ruolo della vitamina D
Giunzioni strette:
La forma attiva della vitamina D, 1,25(OH)2D3, regola l’espressione di proteine ​​come le claudine e la ZO all’interno del complesso delle giunzioni strette, che sono cruciali per il mantenimento e la riparazione della barriera intestinale.
Modulazione immunitaria:
La vitamina D si lega ai recettori VDR nelle cellule immunitarie e modula le risposte immunitarie, contribuendo a proteggere da condizioni che possono compromettere la barriera, come le malattie infiammatorie intestinali.
Integrità della barriera:
Legandosi ai recettori VDR e influenzando le cellule immunitarie e le cellule epiteliali, la segnalazione della vitamina D contribuisce a mantenere una barriera intestinale sana e stabile.

Ruolo della vitamina C
Riparazione della barriera:
L’integrazione di vitamina C ha dimostrato effetti benefici sulla barriera intestinale, contribuendo a riparare i danni.
Segnalazione Notch:
In combinazione con la vitamina D, la vitamina C può regolare la via di segnalazione Notch per proteggere la barriera mucosa intestinale, inclusa l’espressione della claudina-2.
Microbioma intestinale:
L’integrazione di vitamina C può aiutare a bilanciare il microbiota intestinale in individui sani con livelli di vitamina C non ottimali, il che può indirettamente giovare alla barriera riducendo la presenza di batteri produttori di LPS potenzialmente dannosi.

Effetti combinati
Protezione sinergica:
La ricerca indica che la combinazione di vitamina C e vitamina D può offrire maggiori effetti protettivi sulla barriera intestinale rispetto all’assunzione di una delle due vitamine da sola, probabilmente attraverso la loro influenza combinata sulla via di segnalazione Notch.
Potenziale terapeutico:
Entrambe le vitamine sono oggetto di studio per il loro potenziale nella gestione delle patologie intestinali, migliorando l’integrità della barriera e modulando la risposta immunitaria nell’intestino.

Researches

1 – Gut-interplay: key to mitigating immunosenescence and promoting healthy ageing. 2025
Abstract
Background Immunosenescence is the loss and change of immunological organs, as well as innate and adaptive immune dysfunction with ageing, which can lead to increased sensitivity to infections, age-related diseases, and cancer. Emerging evidence highlights the role of gut-vitamin D axis in the regulation of immune ageing, influencing chronic inflammation and systemic health. This review aims to explore the interplay between the gut microbiota and vitamin D in mitigating immunosenescence and preventing against chronic inflammation and age-related diseases.
Main text
Gut microbiota dysbiosis and vitamin D insufficiency accelerate immunosenescence and risk of chronic diseases. Literature data reveal that vitamin D modulates gut microbiota diversity and composition, enhances immune resilience, and reduce systemic inflammation. Conversely, gut microbiota influences vitamin D metabolism to promote the synthesis of active vitamin D metabolites with implications for immune health.
Conclusions
These findings underscore the potential of targeting gut-vitamin D axis to modulate immune responses, delay the immune ageing, and mitigate age-related diseases. Further research is needed to integrate vitamin D supplementation and microbiome modulation into strategies aimed at promoting healthy ageing.
Keywords Gut microbiota, Vitamin D, Immune ageing, Immunosenescence, Healthy ageing
Gut-vitamin D interplay: key to mitigating immunosenescence and promoting healthy ageing. 2025. Hammad Ullah. https://doi.org/10.1186/s12979-025-00514-y
Hammad Ullah hammadrph@gmail.com 1 School of Pharmacy, University of Management and Technology, Lahore 54000, Pakistan

2 – Perspectives About Ascorbic Acid to Treat Inflammatory Bowel Diseases. Ian Richard Lucena Andriolo et al. 2024.

It is known that reactive oxygen species cause abnormal im- mune responses in the gut during inflammatory bowel dis- eases (IBD). Therefore, oxidative stress has been theorized as an agent of IBD development and antioxidant compounds such as vitamin C (L-ascorbic acid) have been studied as a new tool to treat IBD. Therefore, the potential of vitamin C to treat IBD was reviewed here as a critical discussion about this field and guide future research. Indeed, some preclinical studies have shown the beneficial effects of vitamin C in models of ulcerative colitis in mice and clinical and experimental findings have shown that deficiency in this vitamin is associated with the de- velopment of IBD and its worsening. The main mechanisms that may be involved in the activity of ascorbic acid in IBD in- clude its well-established role as an antioxidant, but also others diversified actions. However, some experimental studies em- ployed high doses of vitamin C and most of them did not per- form dose-response curves and neither determined the mini- mum effective dose nor the ED50. Allometric extrapolations were also not made. Also, clinical studies on the subject are still in their infancy. Therefore, it is suggested that the research agenda in this matter covers experimental studies that assess the effective, safe, and translational doses, as well as the ap- propriate administration route and its action mechanism. After that, robust clinical trials to increase knowledge about the role of ascorbic acid deficiency in IBD patients and the effects of their supplementation in these patients can be encouraged.
Perspectives and conclusion
The pathogenesis of IBD is closely related to oxidative stress due to an intense inflammatory insult and the use of vitamin C in IBD, as well as the role of its deficiency, is currently being investigated. Therefore, this perspective reviewed the pharmacological poten- tial of this vitamin to treat and prevent these diseases. In this ap- proach, Vitamin C may help the integrity of the intestinal barrier under the inflammatory stimulus, and enhance intestinal mucosal barrier function, while reducing oxidative stress.
However, a point that is worthy of attention in non-clinical stud- ies presented here is the dose used, which must be adequate for extrapolation in humans. Studies suggest that a daily intake of vi- tamin C from 100 to 400 mg promotes 100 % of the bioavailability and reaches a maximum serum content of 70–80 µmol/L [33, 34]. In addition, when the intake of vitamin C exceeds 500 mg/day, a further increase in plasma concentration is inhibited and when doses greater than 1,000 mg of ascorbic acid are administered in a single dose the bioavailability can decrease by 30 % [34]. This oc- curs because when 500–1,000 mg of vitamin C are administered orally, the intestinal transporter quickly achieves its maximal satu- ration, while the vitamin is progressively excreted by urine [34, 35].
Another important point, which has not yet been studied, is the impact of the pH of the ascorbic acid solution used in the experi- mental studies. Since the pH of an ascorbic acid solution is very low it is expected that its administration can reduce the pH at the in- jection site, intestine, and colon if an enema was used. So, further studies need to address this bias and evaluate the use of buffered ascorbic acid solutions. Perspectives About Ascorbic Acid to Treat Inflammatory Bowel Diseases. Ian Richard Lucena Andriolo et al. 2024. DOI 10.1055/a-2263-1388. ISSN 2194-9379