The mTOR–lysosome axis at the centre of ageing

Abstract

Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

Rejuvenation of Senescent Cells, in vitro and in vivo, by Low-frequency Ultrasound without Senolysis

“…If LFU was acting by activating autophagy as suggested in our working model (Figure 3D), then rapamycin, which is known to activate autophagy by inhibiting mTORC1, should be synergistic with ultrasound 22 . As predicted, addition of rapamycin increased rejuvenation of LFU-treated cells (Figure S3E).…”

“…The senescent cell state has been extensively studied but the molecular bases for the changes are not fully understood. There are major roles for changes in autophagy and mitochondria in senescence 22, 38 . Accordingly, most models of the senescence process postulate major roles for changes in autophagy and mitochondria function with changes in the communication between lysosomes, mitochondria and other cellular organelles.…”

Innovation and renovation: FEBS Open Bio in 2023

“…These disease states include cancer and neurodegeneration, as reviewed by Janko Kos and co‐authors in the same issue [ 2 ]. Lysosomes are also implicated in ageing‐related diseases through cross‐talk between the autophagy‐lysosome pathway and mTORC1 activity; Timothy J. Sargeant and colleagues explored this interaction and whether targeting this pathway might slow the ageing process [ 3 ]. Thomas Reinheckel and Martina Tholen reviewed how the release of cathepsin proteases from lysosomes may not be a death sentence for the cell, and that cathepsins have other cellular functions compatible with cell survival [ 4 ].…”

Targeting Immune Senescence in Atherosclerosis

“…Another study has also reported high SA-βgal activity within the mature macrophages and aged cardiomyocytes [ 121 , 122 ]. A combination of both SA-βgal activity and lipofuscin can be markers [ 64 ].…”