Dietary and pharmacological interventions to improve mammalian healthspan and lifespan

Advances in the field of ageing over recent years have led to the discovery that pharmacological and dietary interventions can slow the ageing process. Genetic alterations to the insulin/insulin-like growth factor (IGF) signalling (IIS) and mechanistic target of rapamycin (mTOR) network in multiple organisms have provided promising targets for pharmacological interventions. mTOR inhibition by rapamycin robustly extends lifespan and is associated with marked health improvements in multiple model organisms. Similarly, pharmacological manipulation of Ras signalling by trametinib prolongs lifespan in flies, and treatment with a combination of trametinib, rapamycin and lithium induced an additive increase in fly lifespan. However, whether trametinib alone or in combination with rapamycin can also extend mouse lifespan is currently unknown. Although combinatorial drug treatments hold great promise to maximise longevity, and potentially to reduce drug dosage and hence side-effects, to date, the most effective environmental intervention known to extend healthy lifespan in various animal species is Dietary Restriction (DR). DR alleviates a plethora of age-related pathologies, including immune dysregulation with age. The adaptive immune system is highly sensitive to DR feeding and DR delays age-associated T-cell immune senescence. Nevertheless, the impact of DR on B-cell immune responses, and whether the improved health and lifespan of DR mice can be attributed to some extent to enhanced B-cell immunity under DR, remain largely unexplored. My PhD thesis first explores the potential of a novel pharmacological intervention to promote mouse healthy ageing. Second, the work elucidates the role of adaptive immunity as a contributor to the benefits of a robust dietary intervention on mouse health and longevity. Specifically the thesis work addresses the following: (I) Does trametinib administration extend lifespan in mice and is there an additive effect by combining trametinib and rapamycin on mouse health and/or longevity. (II) Does B-cell immunity change in response to DR and could these changes contribute to the increased health and lifespan under DR

Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity

Aging impairs the capacity to respond to novel antigens, reducing immune protection against pathogens and vaccine efficacy. Dietary restriction (DR) extends life- and health span in diverse animals. However, little is known about the capacity of DR to combat the decline in immune function. Here, we study the changes in B cell receptor (BCR) repertoire during aging in DR and control mice. By sequencing the variable region of the BCR heavy chain in the spleen, we show that DR preserves diversity and attenuates the increase in clonal expansions throughout aging. Remarkably, mice starting DR in mid-life have repertoire diversity and clonal expansion rates indistinguishable from chronic DR mice. In contrast, in the intestine, these traits are unaffected by either age or DR. Reduced within-individual B cell repertoire diversity and increased clonal expansions are correlated with higher morbidity, suggesting a potential contribution of B cell repertoire dynamics to health during aging

Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity

Aging impairs the capacity to respond to novel antigens, reducing immune protection against pathogens and vaccine efficacy. Dietary restriction (DR) extends life- and health span in diverse animals. However, little is known about the capacity of DR to combat the decline in immune function. Here, we study the changes in B cell receptor (BCR) repertoire during aging in DR and control mice. By sequencing the variable region of the BCR heavy chain in the spleen, we show that DR preserves diversity and attenuates the increase in clonal expansions throughout aging. Remarkably, mice starting DR in mid-life have repertoire diversity and clonal expansion rates indistinguishable from chronic DR mice. In contrast, in the intestine, these traits are unaffected by either age or DR. Reduced within-individual B cell repertoire diversity and increased clonal expansions are correlated with higher morbidity, suggesting a potential contribution of B cell repertoire dynamics to health during aging