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 therapies that effectively 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 is a regulatory nexus 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.

The quest to slow ageing through drug discovery

“…The reasons for the different findings are not clear. In addition to cancer, rapamycin has also proved protective in a wide range of mouse models of age-related disease, including metabolic diseases such as type II diabetes 63 ; neurological diseases 64,65 including AD [66][67][68][69] , Parkinson's disease (PD) 70 , Huntington's 71,72 , and Leigh Syndrome 73 ; lung diseases 74 , cardiovascular syndromes 75 and many others 76 .…”

Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan

“…Currently, there are no drugs that specifically and effectively target RICTOR or mTORC2 with precision (39,40,43,44). Therefore, to inhibit mTORC2 signaling activity in SMAD4-negative colon cancer in our proof of principle experiments, we opted to block its downstream effector target AKT using MK2206, a commercially available, most clinically advanced, and well-tolerated allosteric inhibitor of AKT, which blocks S473 phosphorylation of AKT, the primary target of mTORC2 pathway (41).…”

The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19

“…Studies investigating the mechanistic target of rapamycin (mTOR) pathway have shown that immunosenescence can be reversed by targeting biological ageing. 13,14 The mTOR protein is a nutrient-responsive and stressresponsive kinase that functions as a conserved regulator of ageing in eukaryotes. 14,15 Activation of mTOR promotes development and growth, 16,17 whereas genetic inhibition of mTOR increases lifespan in yeast, 18,19 nema todes, 20 fruit flies, 21 and mice.…”

“…9 The collective outcome is a compromised immune response and an increased incidence of inflammatory comorbidities-eg, cancers and age-related neuro degeneration, which further weaken the immune system. [10][11][12][13] The innate immune system, which is primarily involved in the response to new infections, is also compromised due to a reduction in clonal diversity. 14 This reciprocal relationship between inflam maging and immuno senescence is believed to underlie the adaptive processes, which exacerbates the severity of symptoms in older individuals who tend to exhibit an enhanced susceptibility towards infections along with a dimin ished response to vaccines.…”