mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Abstract

Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

“…Modulation of mTOR signaling has been shown to increase lifespan both on the single cell and organism level in yeast 44 , helminths 45 , flies 46 and mammals 29,47 . As a potential mechanism, interference with cell fates controlled by mTOR in response to stress and metabolic cues has been discussed 48 . Autophagy, regulated chiefly by mTORC1, is accorded a central role in the preservation of juvenile cell adaptability 48,49 since it exercises a double function as a survival mechanism in cellular stress conditions: during starvation, when mTORC1 is physiologically inhibited, autophagy regenerates basal metabolic precursors by "self-cannibalism" of cellular structures 24 .…”

“…As a potential mechanism, interference with cell fates controlled by mTOR in response to stress and metabolic cues has been discussed 48 . Autophagy, regulated chiefly by mTORC1, is accorded a central role in the preservation of juvenile cell adaptability 48,49 since it exercises a double function as a survival mechanism in cellular stress conditions: during starvation, when mTORC1 is physiologically inhibited, autophagy regenerates basal metabolic precursors by "self-cannibalism" of cellular structures 24 . On the other hand, cellular debris such as misfolded proteins and dysfunctional organelles that can induce senescence and apoptosis is cleared by autophagy 50 .…”

Optimisation of a screening platform for determining IL-6 inflammatory signalling in the senescence-associated secretory phenotype (SASP)

“…The overall aim of this study was to determine the utility of the assay in a drug screening format. Dysregulation of mTOR signalling and autophagy is observed in multiple ARDs including neurodegenerative diseases, osteoarthritis and cardiovascular diseases (Walters and Cox 2018 ). mTOR inhibitors have therefore been investigated for their potential beneficial effects on ARDs.…”

The Nuclear Lamina: Protein Accumulation and Disease

“…Moreover, when mice modeling HD are treated with the rapamycin ester temsirolimus, there is a decreased aggregation of HTT protein [189], indicating the beneficial effect that rapamycin can provide in these pathologies. In addition, a new generation of rapamycin analogs, called rapalogues (such as Everolimus) [190] exhibit higher specificity with fewer side-effects than rapamycin. Although there are concerns over impacts of immune responsiveness and potential negative effects in the elderly, a growing body of evidence for the benefits of managing cellular energy and stress-sensing pathways through those agents described above is growing and providing tangible strategies to increase health through the clearance of protein accumulations of the nuclear lamina via autophagy.…”