Targeting the biology of aging and about TORC1
Inhibition of the mTOR pathway has been observed to extend lifespan and healthspan in multiple animal studies supporting the potential for drugs that target the mTOR pathway to have therapeutic benefits for aging-related diseases in humans.
mTOR is a protein that is activated by eating and inhibited by fasting. When mTOR is activated by eating, cells are stimulated to make proteins and lipids needed for growth. When mTOR is inhibited during periods of fasting, cells activate pathways that protect and repair damage in cells.
Therefore increased mTOR activity is beneficial during years of growth and reproduction, but decreased mTOR activity may be beneficial during post-reproductive years when cells accumulate damage. However, there is evidence that mTOR actually becomes hyperactive in some tissues during aging, which suggests that mTOR inhibition may be of therapeutic benefit during aging because they upregulate protective pathways.
Inhibition of mTOR activity within TORC1 is associated with increased lifespan and improvement in the function of several aging organ systems, including neurologic function. In contrast, TORC2 inhibition has been observed to decrease lifespan and cause unwanted side effects like increased levels of cholesterol and glucose in blood.
Inhibition of mTOR signaling in Parkinson’s Disease prevents L-DOPA-induced dyskinesia.
SCI SIGNALING 2(80), ra36 (2009).
Mitochondrial quality control via the PGC1α-TFEB signaling pathway is compromised by Parkin Q311X mutation but independently restored by rapamycin.
J. NEUROSCI 35(37), 12833-12844 (2015).
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.
PNAS 110(19), E1817-1826 (2013).
Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities.
NEURON 93(5), 1015-1034 (2017).
mTOR is a key modulator of ageing and age-related disease.
Nature. 493, 338-345 (2013).
mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells
Sci. Signal. 2, ra75 (2009)
Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.
Science. 335, 1638-1643 (2012).
Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan
Aging Cell. 13, 911-917 (2014).
Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
PLoS Biol. 7, e1000038 (2009).
NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations.
Cancer Res. 68, 8022-8030 (2008).
RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth.
PLoS One 7, e48548 (2012).
Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.
Elife 5, pii: e16351 (2016).
Relieving autophagy and 4EBP1 from rapamycin resistance.
Mol Cell Biol. 31, 2867-2876 (2011).
TORC1 inhibition enhances immune function and reduces infections in the elderly.
Sci Transl Med, 2018. 10(449).
Medicare Savings Resulting from Reductions in Prevalence of Respiratory Tract Infections among the Elderly.
AMCP Annual Meeting 2019 (San Diego, CA, 25-28 March, 2019)
RTB101 as a potential immunotherapy to reduce the incidence of respiratory tract infections (RTIs) in elderly subjects with asthma.
American Thoracic Society (ATS) International Conference, May 20, 2019