In my May 2009 blog post Longevity genes, mTOR and lifespan, I discussed the mTOR signaling pathway in mammals, its role in diseases, the relationship of mTOR to mitochondrial activity and how inhibiting mTOR could conceivably be a strategy for extending longevity. In my Anti-Aging Firewalls treatise I subsequently added ABERRANT mTOR SIGNALLING as one of six additional candidate theories of aging to be considered. Recently-reported research studies concerned with mTOR link up important subjects I have previously discussed in this blog. I focus here on two such sets of links.
mTOR and the hypoxic response
The mTOR pathway is illustrated in this diagram and is seen to be fairly complex even though the diagram leaves some important links out. For example, as illustrated in the diagram a condition of hypoxia activates TSC1/TSC2 which inhibits Rheb which, with AKT, would normally activate mTOR. The net result is that hypoxia inhibits the expression of mTOR, providing a neat linkup of two of the additional candidate theories of aging: the ABERRANT mTOR SIGNALLING theory already mentioned and the THE HYPOXIC RESPONSE theory. See the blog posting Another longevity-related biochemical pathway – the hypoxic response. The hypoxic response is known to lengthen life in primitive organisms and inhibition of mTOR is also thought to be a possible life-extending intervention. The diagram shows a key way in which the two theories weave together.
For those of you interested in delving further, here are links to a few of the research publications linking up hypoxia and mTOR: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex, Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling , and. Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. You may note that a lot of the current interest in controlling and limiting mTOR signaling is using this as an approach for suppressing tumors.
mTOR and the stem cell supply chain
In another important blog post An emerging new view of aging – the stem cell supply chain, I suggested a rather radical new view of aging and what can be done about it. The essence if this view is: A. the 210 different kinds of human cells can be separated into five categories: 1. pluripotent embryonic stem cells, 2. multipotent stem cells, 3. progenitor cells, 4. normal somatic cells and 5. senescent cells. The list is in order of increasing cell-type specificity and decreasing potency to differentiate into other cell types. Starting at conception and throughout life, all cells on this list except the senescent ones will selectively reproduce and differentiate into cells of types further down in the list. Of course all the cells in an individual have the same genome but they acquire additional epigenomic markers as they differentiate. I have referred to this process as the stem cell supply chain which must be kept in good working order if health is to be maintained. B. Understanding aging requires understanding the stem cell supply chain – how and when stem and progenitor cells divide or differentiate and what makes them do that, and how this process can go wrong. C. Effective anti-aging interventions leading to extraordinary longevity will most likely require enhancing the operation of the stem cell supply chain. It is no longer enough that anti-aging science is concerned with the life and death of cells. It must also be concerned with the stem cell supply chain which provides the lifelong stream of cell renewal.
This April 2008 publication mTORC1 signaling governs hematopoietic stem cell quiescence relates mTOR signaling to the fate of an important pool of multipotent stem cells – hematopoietic stem cells (HCSs), the stem cells that give rise to the various blood cell types. “The stringent regulation of hematopoietic stem cell (HSC) quiescence versus cell cycle progression is essential for the preservation of a pool of long-term self-renewing cells and vital for sustaining an adequate supply of all blood lineages throughout life. Cell growth, the process that is mass increase, serves as a trigger for cell cycle progression and is regulated predominantly by mammalian target of rapamycin complex 1 (mTORC1) signaling. Emerging data from various mice models show deletion of several mTORC1 negative regulators, including PTEN, TSC1, PML and Fbxw7 result in similar HSC phenotypes characterized as HSC hyper-proliferation and subsequent exhaustion, and defective repopulating potential(ref).” In other words, unless the negative regulators of mTORC1 are working well, the growth factors loosened by mTORC1 will cause the hematopoietic stem cells to reproduce like crazy exhausting the pool of these valuable cells – a major disruption in the stem cell supply chain.
A second publication highlights the same point. “A balance between quiescence and proliferation of hematopoietic stem cells in interaction with the microenvironment is critical for sustaining long-term hematopoiesis and for protection against stress. — We demonstrated a pivotal role of two downstream effectors of the PI3K/Akt pathway, FoxO3a and mammalian target of rapamycin, as connectors in the SDF-1-/TGF–induced control of the cycling/quiescence switch and proposed a model integrating a dialogue between the two molecules in cell cycle progression(ref).” Essentially the same point is made by a third study December 2008 publication mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. “TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis — Using hematopoietic stem cells (HSCs) as a model system, we demonstrate that somatic deletion of TSC1 produces striking stem cell and derivative effector cell phenotypes characterized by increased HSC cell cycling, mobilization, marked progressive depletion, defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. On the mechanistic level, we further establish that TSC1 regulation of HSC quiescence and long-term repopulating potential and hematopoietic lineage development is mediated through mTORC1 signaling(ref).”
Effective mTORC1 negative regulation is essential for keeping the stem cell supply chain working well, at least insofar as hematopoietic stem cells are concerned.
There is a lot more that can be said about the subjects of this post and I expect I will cover additional key points as time progresses. For example, the AKT and AMPK pathways are interesting and relate to matters discussed both in my treatise and in this blog as well as to mTOR signaling. Perhaps I will take on one of these at some point.