The Role of mTOR Signaling in Aging and Age-Related Diseases: From Cellular Mechanisms to Clinical Applications

The discovery of the mammalian target of rapamycin (mTOR) can be traced back to the late 20th century, with roots in the study of a naturally occurring antifungal and immunosuppressive compound called rapamycin (also known as sirolimus). Rapamycin was first isolated from the bacterium Streptomyces hygroscopicus found in a soil sample collected on Easter Island (Rapa Nui) in 1972 by Suren Sehgal and his colleagues at Ayerst Laboratories¹. The compound exhibited promising antifungal and immunosuppressive properties, which led to further investigation into its cellular target.

In the early 1990s, several research groups independently identified a protein in yeast and mammals that was the cellular target of rapamycin^2-3. This protein was named TOR (Target of Rapamycin) in yeast and mTOR (mammalian Target of Rapamycin) in mammals. The discovery of mTOR provided key insights into the regulation of cell growth, proliferation, and survival, as well as the mechanisms behind the immunosuppressive and antiproliferative properties of rapamycin.

What is mTOR

mTOR is now recognized as a central regulator of cellular processes, including protein synthesis, autophagy, and metabolism, and it plays a critical role in human health and disease, such as cancer, neurodegeneration, and metabolic disorders⁴. The discovery of mTOR has paved the way for the development of mTOR inhibitors, which are used in the treatment of certain types of cancer and to prevent organ transplant rejection⁵.

mTOR is a serine/threonine protein kinase that belongs to the phosphatidylinositol-3-kinase (PI3K)-related kinase family6. It acts as a central regulator of various cellular processes, including cell growth, proliferation, survival, protein synthesis, autophagy, and metabolism⁷. mTOR functions by forming two distinct protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Each complex has unique components and regulates specific cellular processes⁸.

mTORC1 is sensitive to rapamycin and regulates cell growth and proliferation by promoting protein synthesis, ribosome biogenesis, and nutrient uptake. It also inhibits autophagy, a process of cellular self-digestion, which helps cells adapt to nutrient deprivation and maintain cellular homeostasis9. mTORC2, on the other hand, is insensitive to rapamycin and plays a role in regulating cell survival, metabolism, and cytoskeletal organization¹⁰.

Dysregulation of mTOR signaling has been implicated in numerous human diseases, including cancer, neurodegenerative disorders, and metabolic diseases, making it an important target for therapeutic intervention¹¹.

Function of mTOR

mTOR is a protein kinase that plays a central role in regulating a variety of cellular processes, including cell growth, proliferation, survival, protein synthesis, autophagy, and metabolism12. It is not used directly by humans; rather, it is a naturally occurring cellular component that has critical functions within our cells. However, the study and understanding of mTOR signaling have led to several practical applications in medicine and research.

1. Cancer treatment: Dysregulation of mTOR signaling has been implicated in the development and progression of various cancers. mTOR inhibitors, such as rapamycin and its analogs (rapalogs), are used in the treatment of certain types of cancer, including renal cell carcinoma, breast cancer, and pancreatic neuroendocrine tumors¹³.
2. Organ transplant: Due to its immunosuppressive properties, rapamycin and its analogs are used to prevent organ transplant rejection. By inhibiting mTOR, these drugs suppress the immune response, reducing the risk of the recipient’s immune system attacking the transplanted organ¹⁴.
3. Research: mTOR is an important subject of study in basic and applied research, as it helps scientists understand the molecular mechanisms underlying various physiological and pathological conditions. For example, mTOR signaling has been implicated in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, and metabolic disorders, such as diabetes and obesity¹⁵.
4. Anti-aging research: mTOR inhibition has been shown to extend the lifespan of various organisms, including yeast, worms, flies, and mice. This has led to interest in the potential development of therapies targeting mTOR signaling for the promotion of healthy aging and the treatment of age-related diseases¹⁶.

Caloric Restriction

mTOR signaling has emerged as a key player in the regulation of aging and lifespan, partly due to its role in nutrient sensing and cellular growth. Studies have demonstrated that inhibition of mTOR signaling can extend the lifespan of various organisms, including yeast, worms, flies, and mice¹⁷. This has led to a growing interest in understanding the potential of mTOR-targeted interventions for promoting healthy aging and treating age-related diseases.

Caloric restriction (CR) or reduced calorie intake without malnutrition is a well-established intervention that has been shown to extend lifespan and delay the onset of age-related diseases in a variety of organisms, from yeast to mammals¹⁸. One of the mechanisms by which CR exerts its beneficial effects on lifespan is through the modulation of mTOR signaling.

Under conditions of nutrient abundance, mTOR signaling is active, promoting cell growth and proliferation while inhibiting autophagy, a process of cellular self-digestion that helps maintain cellular homeostasis¹⁸. However, when nutrient availability is limited, as in the case of CR, mTOR signaling is suppressed, which in turn activates autophagy and other stress-response pathways that contribute to increased cellular maintenance and overall organismal health.¹⁹

The connection between mTOR signaling, CR, and aging has been demonstrated in various studies. For example, in yeast, inhibition of TOR signaling has been shown to mimic the effects of CR, leading to extended lifespan. Similarly, in mice, pharmacological inhibition of mTOR with rapamycin has been shown to extend lifespan, even when administered late in life²⁰.

These findings suggest that targeting mTOR signaling may be a promising strategy for developing interventions that mimic the beneficial effects of CR on aging and age-related diseases.

Current and Future Therapies

Current and future therapies targeting mTOR signaling are aimed at treating various diseases, including cancer, neurodegenerative disorders, and metabolic conditions. Additionally, there is interest in developing therapies to promote healthy aging. Here are some of the current and potential future therapies:

1. Cancer treatments: Rapamycin and its analogs (rapalogs), such as temsirolimus, everolimus, and ridaforolimus, are used to treat specific types of cancer, including renal cell carcinoma, breast cancer, and pancreatic neuroendocrine tumors₂₂. Researchers are also investigating the use of mTOR inhibitors in combination with other targeted therapies or chemotherapy to enhance treatment efficacy and overcome drug resistance.
2. Neurodegenerative disorders: Preclinical studies have shown that mTOR inhibition can promote neuronal survival, reduce protein aggregation, and alleviate cognitive deficits in animal models of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s²³. This has spurred interest in developing mTOR-targeted therapies for these conditions, but more research is needed before they can be translated to clinical settings.
3. Metabolic disorders: Dysregulation of mTOR signaling has been implicated in metabolic diseases, such as type 2 diabetes and obesity. Some studies suggest that mTOR inhibitors might improve insulin sensitivity and glucose homeostasis, providing a potential therapeutic approach for these conditions24. However, further research is needed to determine the safety and efficacy of such interventions in humans.
4. Healthy aging: Given the link between mTOR signaling, caloric restriction, and lifespan extension, there is interest in developing interventions that target mTOR to promote healthy aging and reduce the risk of age-related diseases. Rapamycin has been shown to extend lifespan in mice, even when administered late in life²⁴. Future research may focus on developing more specific and safer mTOR inhibitors or modulators to harness these potential benefits in humans.

Overall, mTOR-targeted therapies hold promise for treating a range of diseases and promoting healthy aging. However, more research is needed to fully understand the safety and long-term effects of these interventions, as well as to optimize their therapeutic potential.

Glossary of Terms

Autophagy: A cellular self-digestion process that helps maintain cellular homeostasis by recycling damaged organelles and proteins.

Caloric Restriction: A dietary intervention that involves reducing calorie intake without causing malnutrition, known to extend lifespan and delay the onset of age-related diseases in various organisms.

Cancer: A group of diseases characterized by the uncontrolled growth and spread of abnormal cells, which can lead to the formation of tumors and invasion of surrounding tissues.

Kinase: A type of enzyme that catalyzes the transfer of a phosphate group from a high-energy molecule, such as adenosine triphosphate (ATP), to a specific target molecule or substrate. This process, known as phosphorylation, results in the addition of a phosphate group to the target molecule, which can lead to changes in its activity, function, or location within the cell. Phosphorylation is a crucial regulatory mechanism in many cellular processes, including signal transduction, cell division, metabolism, and apoptosis.

Metabolic Disorders: A group of conditions that affect the body’s ability to metabolize nutrients, including glucose, lipids, and amino acids, often resulting in imbalances that can lead to diseases such as diabetes and obesity.

mTOR (mammalian target of rapamycin): A serine/threonine protein kinase that plays a central role in regulating cell growth, proliferation, survival, protein synthesis, autophagy, and metabolism.

mTORC1 (mTOR Complex 1): A protein complex formed by mTOR that is sensitive to rapamycin and regulates cell growth and proliferation by promoting protein synthesis, ribosome biogenesis, and nutrient uptake, while inhibiting autophagy.

mTORC2 (mTOR Complex 2): A protein complex formed by mTOR that is insensitive to rapamycin and plays a role in regulating cell survival, metabolism, and cytoskeletal organization.

Neurodegenerative Disorders: A group of diseases that primarily affect the neurons in the human brain, leading to their progressive degeneration and loss of function, resulting in conditions such as Alzheimer’s, Parkinson’s, and Huntington’s disease.

Phosphatidylinositol-3-kinase (PI3K): A family of lipid kinases involved in the regulation of various cellular processes, including cell growth, proliferation, differentiation, motility, and survival.

Protein Kinase: An enzyme that modifies other proteins by chemically adding phosphate groups to them, which can result in the activation or deactivation of target proteins and play a crucial role in various cellular processes.

Rapamycin: A bacterial product that acts as a potent inhibitor of mTOR signaling, originally discovered for its immunosuppressive and antifungal properties, and later found to have anticancer and anti-aging effects.

Serine/Threonine Kinase: A type of protein kinase that specifically phosphorylates the hydroxyl group of serine or threonine amino acid residues in target proteins, playing a role in the regulation of various cellular processes.

Footnotes

1. Sehgal, S. N., Baker, H., & Vézina, C. (1975). Rapamycin (AY-22,989), a new antifungal antibiotic. The Journal of Antibiotics, 28(10), 727-732.
2. Heitman, J., Movva, N. R., & Hall, M. N. (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 253(5022), 905-909.
3. Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P., & Snyder, S. H. (1994). RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell, 78(1), 35-43.
4. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274-293.
5. Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 168(6), 960-976.
6. Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124(3), 471-484.
7. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274-293.
8. Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 168(6), 960-976.
9. Kim, J., Kundu, M., Viollet, B., & Guan, K. L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology, 13(2), 132-141.
10. Sarbassov, D. D., Ali, S. M., & Sabatini, D. M. (2005). Growing roles for the mTOR pathway. Current Opinion in Cell Biology, 17(6), 596-603.
11. Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011). mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Reviews Molecular Cell Biology, 12(1), 21-35.
12. Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124(3), 471-484.
13. Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011). Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Reviews Drug Discovery, 10(11), 868-880.
14. Shapiro, R., & Young, J. B. (2006). Renal transplantation. The New England Journal of Medicine, 355(12), 1257-1260.
15. Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature, 493(7432), 338-345.
16. Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature, 493(7432), 338-345.
17. Fontana, L., & Partridge, L. (2015). Promoting health and longevity through diet: from model organisms to humans. Cell, 161(1), 106-118.
18. Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011). Autophagy and aging. Cell, 146(5), 682-695.
19. Kaeberlein, M., Powers III, R. W., Steffen, K. K., Westman, E. A., Hu, D., Dang, N., … & Kennedy, B. K. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science, 310(5751), 1193-1196.
20. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., … & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395.
21. Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011). Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Reviews Drug Discovery, 10(11), 868-880.
22. Perluigi, M., Di Domenico, F., & Butterfield, D. A. (2015). mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiology of Disease, 84, 39-49.
23. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274-293.
24. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., … & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395.