Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology

Simons, Mirre J. P.; Hartshorne, Laura; Trooster, Suzan; Thomson, Jessica L.; Tatar, Marc

doi:10.1101/719096

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…Timing and scheduling of rapamycin treatment can have unpredictable effects and could depend on age. Transient rapamycin treatment [50] and mTor knockdown [51] in early adult life extend lifespan in flies. Similarly, rapamycin during development [52] and a short bout of treatment at middle age [53] extend lifespan in mice.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Phillips

Simons

2022

GeroScience

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Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n = 1223 from 23 studies comprising 46 effect sizes involving DR (n = 17) and rapamycin treatment (n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR = − 0.72; CI = − 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

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Section: Discussionmentioning

confidence: 99%

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Phillips

Simons

2022

GeroScience

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show abstract

“…Timing and scheduling of rapamycin treatment can have unpredictable effects and could depend on age. Transient rapamycin treatment (Juricic et al, 2022) and mTor knockdown (Simons et al, 2019) in early adult life extend lifespan in flies. Similarly, rapamycin during development (Shindyapina et al, 2022) and a short bout of treatment at middle-age (Bitto et al, 2016) extend lifespan in mice.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin not Dietary Restriction improves resilience against pathogens: a meta-analysis

Phillips

Simons

2022

Preprint

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Dietary Restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n=1223 from 23 studies comprising 46 effect sizes involving DR (n=17) and rapamycin treatment (n=29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR=-0.72; CI=-1.17, -0.28; p=0.0015). In contrast, DR reduced post-infection survival (lnHR=0.80; CI=0.08, 1.52; p=0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (P<0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

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Expansion ofDrosophilahaemocytes using a conditionalGeneSwitchdriver affects larval haemocyte function, but does not modulate adult lifespan or survival from infection

Hayman,

Morrin,

Halder

et al. 2024

Preprint

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Macrophages are responsible for diverse and fundamental functions in vertebrates. Fruit flies harbour an innate immune system of which the most populous blood cell (haemocyte) type bears striking homology to the vertebrate macrophage. The importance of these cells has been demonstrated previously, where immune and developmental phenotypes have been observed upon haemocyte ablation using pro-apoptotic transgenes driven by the Hml promoter. Here we show that, as well as ablating Hml-positive cells in vivo using the pro-apoptotic transgene bax, we can also increase Hml-positive cell numbers using a constitutively-active form of ras. However, in adults, compared to larvae, total blood cell numbers were not significantly affected by experimental expansion or ablation. This therefore implies the existence of feedback mechanisms which regulate the number of haemocytes. No effect on lifespan was observed from driving ras and bax in Hml-positive cells using a conditional genetic system (Hml-GeneSwitch). Using a constitutive driver system, we did observe differences in lifespan, however we attribute this to differences in genetic background that could have led to spurious conclusions. Additionally, no effect of either transgene was observed upon infection with two different bacterial species, although a striking pupal lethality phenotype was observed upon expansion of Hml-positive cells in the context of a self-encapsulation mutant genetic background. The latter confirms that the change in Hml-positive cell number does result in a phenotype. The lack of adult phenotypes could be due to the strength of our experimental manipulation or due to compensation via feedback mechanisms that operate to maintain total blood cell numbers. Our study demonstrates the importance of a conditional approach to modulate haemocyte cell numbers in vivo which allows for more precise study of innate immune system function. This approach could be especially fruitful to uncover the mechanisms that regulate total blood cell numbers across development and ageing.

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Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology

Cited by 3 publications

References 47 publications

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Rapamycin not Dietary Restriction improves resilience against pathogens: a meta-analysis

Expansion ofDrosophilahaemocytes using a conditionalGeneSwitchdriver affects larval haemocyte function, but does not modulate adult lifespan or survival from infection

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