This is a dissertation accepted by the Faculty of Mathematics and Natural Sciences
of the University of Cologne
3. Double treatment with trametinib and rapamycin maximises longevity in mice 31
3.1. Introduction 33
3.1.1 Ageing 33
3.1.1.1 Definition of ageing and hallmarks of ageing 33
3.1.1.2 Controlling the rate of ageing through genetic and pharmacological
interventions 34
3.1.1.2.1 Genetic interventions 34
3.1.1.2.2 Pharmacological interventions 35
3.2. Results 37
3.2.1. Trametinib effects on mouse lifespan and healthspan 37
3.2.1.1. Lifespan assessment under trametinib administration 37
3.2.1.1.1. Trametinib administration extends mouse lifespan 37
3.2.1.2. Healthspan assessment under trametinib administration 39
3.2.1.2.1. Trametinib maintains heart rate with age 39
3.2.1.2.2. Trametinib administration induces mild improvement in motor
coordination at middle and old age 41
3.2.1.2.3. Trametinib has no effect on mouse exploratory drive, anxiety or
endurance at old age 43
3.2.2. Effects of combined trametinib and rapamycin treatment on mouse lifespan and
healthspan 45
3.2.2.1. Lifespan assessment under joint treatment with trametinib and rapamycin 45
3.2.2.1.1. Joint treatment with trametinib and rapamycin increases lifespan more
than does treatment with either drug singly 45
3.2.2.2. Healthspan assessment under joint treatment with trametinib and rapamycin
46
3.2.2.2.1. Rapamycin alone and in combination with trametinib maintains cardiac
function with age and rapamycin mildly improves motor function at old age 46
3.2.2.2.2. Trametinib and rapamycin combination enhances exploratory behaviour
in old females 47
3.2.2.3. Pathology assessment under joint treatment with trametinib and rapamycin 48
3.2.2.3.1. Trametinib and rapamycin combination reduces non-neoplastic and
neoplastic pathologies in old mice 48
6
3.2.2.3.2. Trametinib and rapamycin combination slows spleen tumour progression
52
3.2.2.3.3. Combined treatment with rapamycin and trametinib attenuates the agerelated
increase in glucose uptake in the brain 54
3.2.2.3.4. Combined trametinib and rapamycin treatment reduces age-related brain
inflammation 56
3.2.2.3.5. Combined rapamycin and trametinib treatment reduces inflammation in
the kidney 58
3.3. Discussion 61
3.4. Supplementary figures 71
4. Dietary restriction attenuates the age-related decline in mouse B cell receptor
repertoire diversity 90
4.1. Introduction 92
4.1.1 Dietary interventions to delay ageing 92
4.1.2 The immune system as an effector of DR 93
4.2. Results 96
4.2.1 DR slows the age-associated decline of BCR repertoire diversity in the spleen 96
4.2.2 DR attenuates clonal expansions with age in the spleen 99
4.2.3 DR maintains the somatic hypermutation rate and CDR3 length distribution at old
age in the spleen 100
4.2.4 Midlife onset of DR has more positive effects on the BCR repertoire of the spleen
than late-life onset DR 101
4.2.5 Effects of DR and ageing on the intestinal BCR repertoire 103
4.2.6 Late-onset DR has no effect on the intestinal BCR repertoire 106
4.2.7 The ageing microbiome responds to late-onset DR 107
4.2.8 DR-related BCR metrics are associated with healthier phenotypes 108
4.3. Discussion 110
4.4. Supplementary figures 114
