Essay: Intervening in the mTOR pathway: a promising anti-ageing therapy for humans?

Dijkstra, D.J. (2015) Essay: Intervening in the mTOR pathway: a promising anti-ageing therapy for humans? Master's Thesis / Essay, Biology.

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Abstract

Life expectancy at birth is increasing every year, resulting in more humans reaching a high age. However, ageing comes with a risk of developing age-related diseases, including cancer and metabolic diseases. Targeting the mTOR pathway might be a way to promote healthy ageing and increase life span. mTOR is the catalytic subunit of two distinct multiprotein complexes: mTORC1 and mTORC2. Little is known about mTORC2 signaling. mTORC1 is activated by amino acids, insulin and insulin-like growth factor and high energy levels, while it is repressed by cellular stress, including energy deprivation, hypoxia and DNA damage. When activated, mTORC1 promotes the transcription of SREBP1, PPARγ, STAT3, HIF1α, YY1 and PCG1α, which result in cellular survival, growth, and proliferation. Furthermore, mTORC1 promotes transcription and represses autophagy. Overactivation of mTORC1 can lead to age-related diseases, including cancer, autoimmune disorders, diabetes and obesity. Furthermore, mTORC1 accelerates ageing on cell and tissue level. On cell level, mTORC1 activation decreases autophagy and increases the amount of reactive oxygen species, which leads to increased levels of damaged and aggregated proteins and organelles in the cell, a hallmark of ageing. On tissue level, mTORC1 stimulates proliferation, which can lead to exhaustion or senescence of stem cells and thereby to an increasing amount of aged cells. Low mTORC1 or TOR1 activity, achieved by caloric restriction, genetic manipulation or drugs, has been shown to decline ageing in yeast, fruit flies, nematodes and mice. Caloric restriction seems to decline ageing in non-human primates as well and this is possibly mediated by decreased mTOR signaling. Since high levels of caloric restriction would be hard to achieve for humans, mTOR-inhibiting drugs are of great interest. The drug rapamycin inhibits mTORC1 directly, which results in declined ageing in several animal models, but comes with severe side effects in humans, including immunosuppression and insulin resistance. Metformin simulates a state of energy deprivation. It decreases mTORC1 activity by activating AMPK, but it seems to have no effect on aged mice. Since directly inhibiting mTORC1 leads to severe side effects, new anti-ageing drug should either mimic an mTORC1-repressive status or target downstream effectors of mTORC1.

Item Type:	Thesis (Master's Thesis / Essay)
Degree programme:	Biology
Thesis type:	Master's Thesis / Essay
Language:	English
Date Deposited:	15 Feb 2018 08:08
Last Modified:	15 Feb 2018 08:08
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/13309

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