Dietary and pharmacological interventions to improve mammalian healthspan and lifespan (Dissertation)

This from a person in the Pattridge lab at the University of Cologne:

Lisonia Gkioni

This is a dissertation accepted by the Faculty of Mathematics and Natural Sciences
of the University of Cologne

Date of thesis defense: 03.02.2023

Gutachter: Prof. Dr. Linda Partridge

Prof. Dr. Matteo Bergami

3. Double treatment with trametinib and rapamycin maximises longevity in mice 31

3.1. Introduction 33

3.1.1 Ageing 33 Definition of ageing and hallmarks of ageing 33 Controlling the rate of ageing through genetic and pharmacological

interventions 34 Genetic interventions 34 Pharmacological interventions 35

3.2. Results 37

3.2.1. Trametinib effects on mouse lifespan and healthspan 37 Lifespan assessment under trametinib administration 37 Trametinib administration extends mouse lifespan 37 Healthspan assessment under trametinib administration 39 Trametinib maintains heart rate with age 39 Trametinib administration induces mild improvement in motor

coordination at middle and old age 41 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 Lifespan assessment under joint treatment with trametinib and rapamycin 45 Joint treatment with trametinib and rapamycin increases lifespan more

than does treatment with either drug singly 45 Healthspan assessment under joint treatment with trametinib and rapamycin

46 Rapamycin alone and in combination with trametinib maintains cardiac

function with age and rapamycin mildly improves motor function at old age 46 Trametinib and rapamycin combination enhances exploratory behaviour

in old females 47 Pathology assessment under joint treatment with trametinib and rapamycin 48 Trametinib and rapamycin combination reduces non-neoplastic and

neoplastic pathologies in old mice 48

6 Trametinib and rapamycin combination slows spleen tumour progression

52 Combined treatment with rapamycin and trametinib attenuates the agerelated

increase in glucose uptake in the brain 54 Combined trametinib and rapamycin treatment reduces age-related brain

inflammation 56 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

KUPS_Thesis_LG_editted_final_version_SM.pdf (5.2 MB)


And from that thread… good to note:

Do not take trametinib for longevity purposes. I worked on synthetic lethal chemo combinations in cancer at a startup for years. We tested this compound and it is not a good idea. The Erk pathway is very important for most epithelial cells. Stick to low risk acarbose and rapamycin combinations and do not consider trametinib. If you have melanoma or another type of solid tumor type then you could consider trametinib. Just trying to prevent you from causing long term damage.

Source Post: Anyone taking Trametinib? - #25 by Livin


Page 46.

Males (mice) median and maximum lifespan: c: 716 days (median); r: 835 days (median) and 1044 days (maximum); t-low: 752 days (median) and 1015 days (maximum); t-high: 789 days (median); rt: 912 (median). Log rank test: Females: r vs c p-value<0.0001; rt vs c p-value<0.0001; t-low vs c p-value= 0.0255; t-high vs c p-value=0.0430. Males: r vs cl p-value<0.0001; rt vs c p-value<0.0001; t-high vs c p-value<0.0001. Data are expressed as *P < 0.05 and ****P < 0.0001.

If I remember correctly, rapamycin + acarbose provides similar max life extension. (Hunting down the source). If my recollection is correct, there would be no justification for rapa + trametinib, when rapa + some other supplement would provide the same max life extension.

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