The evolution of life in an oxidizing environment led to the development of mechanisms to maintain a balance between oxidation-reduction reactions. This so-called redox homeostasis ensures a healthy physiological state in all living beings by regulating various biological processes such as metabolism, cell death, differentiation, development and aging. Oxidative stress and the failure of antioxidant systems have recently been identified as two major drivers of ferroptosis, an iron-dependent form of cell death caused by massive phospholipid peroxidation. Furthermore, it is widely accepted that a dysregulation of redox balance is a key hallmark of the aging process. Therefore, addressing redox homeostasis might be a suitable strategy to promote health and well-being in an increasingly aging world, where frailty and age-related disorders (especially neurodegeneration) are widespread. To this end, Caenorhabditis elegans has been used as a valuable model to unveil new insights in the role of redox homeostasis in the ferroptosis-aging crosstalk. The progressive loss of the capability to contrast external stressors, the increase in reactive oxygen species and the failure of the antioxidant glutathione system have clearly demonstrated the gradual loss of redox balance in aging wild-type worms. Moreover, selected genes with oxidoreductase activity and potentially involved in regulating ferroptosis were downregulated with age. Among them, only a fatty acil-CoA reductase, fard-1, and a dehydrogenase, dhs-25, causally linked ferroptosis and aging, thus representing promising targets for possible future interventions to improve healthy aging. In this regard, a suitable diet enriched with antioxidant substances has been proved extremely effective in promoting healthy aging and preventing age-related diseases, such as neurodegeneration. Here, a model of Spinocerebellar Ataxia type 3 (SCA3), a neurodegenerative disorder characterized by ataxia as main symptom and amyloid aggregation of the ataxin-3 protein as main hallmark, has been employed. Protective effects of a Cinnamomum cassia buds extract rich of procyanidins were observed under stressful conditions (i.e. exposure to non-permissive temperatures and oxidative agents), although no improvement in survival was seen. On the other hand, neuroprotective properties were demonstrated in SCA3 worms, where both lifespan and ataxic phenotype (i.e. locomotion) improved with chronic extract administration. Additionally, Lavado cocoa flavanols turned out to be effective in ameliorating the ataxic phenotypes due to their ability to affect the ataxin-3 aggregation process, as demonstrated in in vitro studies. In conclusion, this thesis demonstrates the existence of a strict crosstalk between aging and ferroptosis triggered by redox homeostasis, providing new insights into the controversial physiological role of ferroptosis. Novel genes involved in both ferroptosis and aging regulation have been identified and may constitute targets for possible interventions to improve healthy aging. Finally, the importance of a diet enriched with antioxidant molecules (i.e. polyphenols) in enhancing healthy aging and preventing neurodegeneration has been emphasized.

L’evoluzione della vita in un ambiente pro-ossidante ha portato gli organismi viventi a evolvere specifici meccanismi per mantenere un corretto bilanciamento nei processi cellulari di ossido-riduzione. L’ omeostasi redox è essenziale per la salute e regola numerosi processi biologici, tra cui il metabolismo, la morte cellulare, lo sviluppo e l’invecchiamento. È, infatti, generalmente noto e accertato che si va incontro a un progressivo sbilanciamento nell’omeostasi redox durante l’invecchiamento. Inoltre, lo stress ossidativo e il malfunzionamento dei sistemi antiossidanti sono stati recentemente annoverati tra i fattori principali che causano la morte cellulare via ferroptosi. Si tratta di una forma di morte cellulare di recente scoperta, caratterizzata dall’accumulo di perossidazione lipidica a livello dei fosfolipidi di membrana. Ne consegue che agire sull’omeostasi redox potrebbe rappresentare una strategia promettente per garantire salute e benessere anche in età avanzata, nel nostro mondo caratterizzato da un progressivo invecchiamento demografico. Con questo obiettivo, l’utilizzo di Caenorhabditis elegans come organismo modello ha permesso di investigare il ruolo fisiologico della ferroptosi nell’invecchiamento. La progressiva perdita della capacità di contrastare stressogeni esterni, il crescente accumulo di specie reattive dell’ossigeno e la perdita di uno dei principali sistemi antiossidanti, il glutatione, hanno permesso di dimostrare il fallimento dell’omeostasi redox con l’invecchiamento. Inoltre, il livello di espressione di alcune ossidoreduttasi potenzialmente coinvolte nel regolare la ferroptosis è stato visto diminuire con l’età. Particolarmente degne di nota sono l’acil-CoA reduttasi fard-1 e la deidrogenasi dhs-25: la loro delezione comporta una maggiore suscettibilità alla ferroptosi, fornendo una delle prime evidenze di un nesso causa-effetto tra invecchiamento e ferroptosi. Agire su questi geni potrebbe diventare in futuro una delle strategie per promuovere un invecchiamento sano. In questa direzione, è noto che una dieta ricca di sostanze antiossidanti aiuta a mantenere uno stato di salute sano e attivo, prevenendo una serie di patologie legate all’invecchiamento, tra cui la neurodegenerazione. In questo lavoro, è stato impiegato un modello animale di atassia spinocerebellare di tipo 3 (SCA3), una malattia neurodegenerativa caratterizzata da atassia come sintomo principale e dall’aggregazione dell’atassina 3 come hallmark distintivo. L’ estratto di boccioli di cannella, ricco in procianidine, ha mostrato un effetto benefico in nematodi sottoposti a condizioni di stress (es. temperatura non permissiva e esposizione ad agenti ossidanti), senza alcun allungamento della vita. D’altro canto, le sue proprietà neuroprotettive sono state dimostrate in modelli malati di SCA3, dove si è assistito ad un miglioramento sia nella durata della vita che nel fenotipo atassico, il movimento, in seguito alla somministrazione cronica dell’estratto. Anche i flavanoli di cacao Lavado si sono rivelati efficaci nel migliorare i fenotipi di animali atassici, grazie alla loro comprovata capacità di ostacolare il processo di aggregazione dell'atassina-3 in vitro. In conclusione, questa tesi dimostra l'esistenza di una relazione causa-effetto tra invecchiamento e ferroptosi innescata dallo sbilanciamento redox. I nuovi geni identificati, coinvolti nella regolazione sia della ferroptosi che dell’invecchiamento, potrebbero divenire target per eventuali interventi volti a promuovere un invecchiamento sano. Così come una dieta ricca di molecole antiossidanti, come i polifenoli, contribuisce ad assicurare buona salute anche in età avanzata e a prevenire la neurodegenerazione.

(2025). Studies on Caenorhabditis elegans aging provide insights into the physiological role of ferroptosis and on the impact of nutrition on health and neurodegeneration. (Tesi di dottorato, , 2025).

Studies on Caenorhabditis elegans aging provide insights into the physiological role of ferroptosis and on the impact of nutrition on health and neurodegeneration

PENSOTTI, ROBERTA
2025

Abstract

The evolution of life in an oxidizing environment led to the development of mechanisms to maintain a balance between oxidation-reduction reactions. This so-called redox homeostasis ensures a healthy physiological state in all living beings by regulating various biological processes such as metabolism, cell death, differentiation, development and aging. Oxidative stress and the failure of antioxidant systems have recently been identified as two major drivers of ferroptosis, an iron-dependent form of cell death caused by massive phospholipid peroxidation. Furthermore, it is widely accepted that a dysregulation of redox balance is a key hallmark of the aging process. Therefore, addressing redox homeostasis might be a suitable strategy to promote health and well-being in an increasingly aging world, where frailty and age-related disorders (especially neurodegeneration) are widespread. To this end, Caenorhabditis elegans has been used as a valuable model to unveil new insights in the role of redox homeostasis in the ferroptosis-aging crosstalk. The progressive loss of the capability to contrast external stressors, the increase in reactive oxygen species and the failure of the antioxidant glutathione system have clearly demonstrated the gradual loss of redox balance in aging wild-type worms. Moreover, selected genes with oxidoreductase activity and potentially involved in regulating ferroptosis were downregulated with age. Among them, only a fatty acil-CoA reductase, fard-1, and a dehydrogenase, dhs-25, causally linked ferroptosis and aging, thus representing promising targets for possible future interventions to improve healthy aging. In this regard, a suitable diet enriched with antioxidant substances has been proved extremely effective in promoting healthy aging and preventing age-related diseases, such as neurodegeneration. Here, a model of Spinocerebellar Ataxia type 3 (SCA3), a neurodegenerative disorder characterized by ataxia as main symptom and amyloid aggregation of the ataxin-3 protein as main hallmark, has been employed. Protective effects of a Cinnamomum cassia buds extract rich of procyanidins were observed under stressful conditions (i.e. exposure to non-permissive temperatures and oxidative agents), although no improvement in survival was seen. On the other hand, neuroprotective properties were demonstrated in SCA3 worms, where both lifespan and ataxic phenotype (i.e. locomotion) improved with chronic extract administration. Additionally, Lavado cocoa flavanols turned out to be effective in ameliorating the ataxic phenotypes due to their ability to affect the ataxin-3 aggregation process, as demonstrated in in vitro studies. In conclusion, this thesis demonstrates the existence of a strict crosstalk between aging and ferroptosis triggered by redox homeostasis, providing new insights into the controversial physiological role of ferroptosis. Novel genes involved in both ferroptosis and aging regulation have been identified and may constitute targets for possible interventions to improve healthy aging. Finally, the importance of a diet enriched with antioxidant molecules (i.e. polyphenols) in enhancing healthy aging and preventing neurodegeneration has been emphasized.
LA FERLA, BARBARA
REGONESI, MARIA ELENA
Invecchiamento; Omeostasi redox; C. elegans; Nutrizione; Ferroptosi
Aging; Redox homeostasis; C. elegans; Nutrition; Ferroptosis
BIO/10 - BIOCHIMICA
English
11-feb-2025
37
2023/2024
embargoed_20280211
(2025). Studies on Caenorhabditis elegans aging provide insights into the physiological role of ferroptosis and on the impact of nutrition on health and neurodegeneration. (Tesi di dottorato, , 2025).
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Descrizione: PhD thesis Roberta Pensotti
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/542922
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