The mTOR Signaling Pathway and Autophagy: An Anti-aging Secret?

The mTOR signaling pathway is an essential factor in the anabolic and catabolic functions of metabolism in the body. Anabolism uses energy to build or grow molecules. Catabolism creates energy by breaking down tissue or cells. Like any other process in the body, finding a delicate balance of these two pieces of metabolism is critical for your health.

The mammalian target of rapamycin, or mTOR, is a complicated signaling pathway that plays a vital role in the regulation of cellular growth and metabolism[1]. It is supportive of anabolism through the role it plays in protein and fat synthesis and storage.

The mTOR signaling pathway responds to the presence or absence of nutrients and other signaling hormones, especially carbohydrates, insulin, and amino acids from proteins[2]. This response means that when we eat, the food is broken down into nutrients that can send the body a signal that it’s time for growth.

Oppositely, when the body is under nutrient stress (as when calories, protein, or carbohydrates are scarce), inhibition of mTOR occurs.

This inhibition leads to more catabolic or reparative processes in our body (more on this in a minute)[3]. When the body is not in a fed state – whether in a period of time-restricted eating or even just overnight – the body can take a break from creating new cells or muscle tissue, and instead work on breaking down and removing older or damaged cells and tissues.

This process works to keep a healthy balance between growth and repair, but it can be altered negatively in times of illness – or environments of over-nutrition. If the body is in a constant “fed” state with an overabundance of nutrients, the balance is thrown off, and chronic upregulation of mTOR signaling can occur. In this situation, the body is stuck in growth and storage mode, with little room for cleaning and repair.

What does science say about the mTOR signaling pathway and our health?

Understanding the balance between the upregulation and downregulation of the mTOR pathway can help us apply its importance to human health. Metabolic growth is necessary for many reasons. We need mTOR to signal for things like muscle growth and mitochondrial (the energy houses in our cells) formation. The mTOR signaling pathway also promotes the synthesis of proteins, lipids, and cells.

But defects or chronic activation in mTOR signaling are associated with:

• Cognitive and memory disorders[4]
• Cancer[5]
• Epilepsy[6]
• Type 2 diabetes
• Inflammation[7]
• Depression
• Obesity[8]

Inhibition of mTOR using pharmacological drugs supports immune health and anti-aging[9].

In human and animal research, mTOR inhibition is associated with improvements in longevity. It has been shown to push back the onset of diseases typically associated with aging, including cardiac disease, cognitive decline, and decreases in the ability to participate in activities of daily living[10]. One study found that inhibiting mTOR improves the decline of immune function in older adults, enhancing the effectiveness of vaccines, and decreasing the likelihood of getting infections[11].

How can we use what we know about the mTOR signaling pathway to benefit our health?

These outcomes appear to be related to the relationship between mTOR and autophagy. The mTOR signaling pathway is activated primarily by amino acids and insulin, but other hormones such as testosterone, thyroid hormone, ghrelin, and leptin can also enable it[12]. But as mentioned, when nutrients are scarce, mTOR is downregulated. As mTOR is downregulated, autophagy is switched on. As a result, we can support autophagy and the inhibition or activation of mTOR through dietary strategies.

Reminder, autophagy is the body’s way of removing old or damaged cellular debris and organelles.

During autophagy, the body can eliminate cellular waste products as well as pathogens[13]. The process occurs when the body is under nutritional stress, as with fasting. Autophagy helps to promote longevity and inhibit age-related damage to cells. By removing cells with oxidative damage, inflammation in the body is also reduced. Autophagy appears to help mitigate such diseases related to aging cells and inflammation, such as neurodegeneration and cancer.

Autophagy is regulated by mTOR and another signaling pathway known as AMP-activated protein kinase (AMPK).

AMPK also responds to the presence or absence of nutrients in the body[14]. When AMPK senses low glucose as seen with fasting or the keto diet, it responds by turning on autophagy.

Once you start eating as you usually do (whether moving out of ketosis or breaking a fast), the mTOR pathway can resume but will activate the growth of new healthy stem cells. This process is known as stem cell self-renewal. Several studies have suggested that this regeneration cannot happen without autophagy. The mTOR pathway plays a vital role in the proliferation of stem cells, supporting a healthy immune system[15].

Using diet variation to achieve balance

You may be asking yourself – what is the right balance, and how do we find it? We need the mTOR signaling pathway at appropriate levels. For example, we want mTOR signaling to upregulate when we exercise to support muscle growth. So how can we find that happy medium?

Practicing intermittent fasting and keto can help us control the mTOR pathway, bringing autophagy to our current lifestyles. As intake of carbs (and therefore glucose) drops, AMPK will upregulate while mTOR will stop signaling. Keep in mind that autophagy is catabolic, so while it provides many health benefits, it isn’t a process that you want running full steam all the time.

If you’ve read any of my other pieces on cyclical fasting or keto, you may not be surprised that my answer to the question of how to balance this process is diet variation.

We can affect mTOR signaling activity in the body by appropriate cycling between fasting, keto, and “feasting” days with increases in carbs or nutrients in general. In this way, the body does not become overly adapted, and it will be forced into beneficial nutrient stress.

On feasting days when mTOR turns on, we can trigger cell growth and muscle building. In contrast, during keto or fasting days, autophagy helps balance out the excess fat storage and reducing the risk of chronic disease, as mentioned above.

Diet variation is the sustainable, long-term approach to use to help balance the potentially detrimental effects of chronic stimulation of mTOR signaling. Utilizing this pattern, we can achieve all the benefits of autophagy without overly stressing the body.

References

[1] mTOR signaling at a glance Mathieu Laplante, David M. Sabatini Journal of Cell Science 2009 122: 3589-3594; doi: 10.1242/jcs.051011

[2] Sabatini, David M. “Twenty-Five Years of MTOR: Uncovering the Link from Nutrients to Growth.” Proceedings of the National Academy of Sciences 114, no. 45 (November 7, 2017): 11818. https://doi.org/10.1073/pnas.1716173114.

[3] Zhou, H., Luo, Y., & Huang, S. (2010). Updates of mTOR inhibitors. Anti-cancer agents in medicinal chemistry, 10(7), 571–581. https://doi.org/10.2174/187152010793498663

[4] Kaeberlein, Matt. “MTOR Inhibition: From Aging to Autism and Beyond.” Edited by R. Ria, S.-Y. Shieh, and O. Huber. Scientifica 2013 (November 26, 2013): 849186. https://doi.org/10.1155/2013/849186.

[5] Laplante, Mathieu, and David M. Sabatini. “mTOR Signaling in Growth Control and Disease.” Cell 149, no. 2 (April 13, 2012): 274–93. https://doi.org/10.1016/j.cell.2012.03.017.

[6] IBID

[7] Yang, Kai, and Hongbo Chi. “Tuning MTOR Activity for Immune Balance.” The Journal of Clinical Investigation 123, no. 12 (December 2, 2013): 5001–4. https://doi.org/10.1172/JCI73202.

[8] Kaeberlein, Matt. “MTOR Inhibition: From Aging to Autism and Beyond.” Edited by R. Ria, S.-Y. Shieh, and O. Huber. Scientifica 2013 (November 26, 2013): 849186. https://doi.org/10.1155/2013/849186.

[9] Sabatini, David M. “Twenty-Five Years of MTOR: Uncovering the Link from Nutrients to Growth.” Proceedings of the National Academy of Sciences 114, no. 45 (November 7, 2017): 11818. https://doi.org/10.1073/pnas.1716173114.

[10] Flynn, James M., Monique N. O’Leary, Christopher A. Zambataro, Emmeline C. Academia, Michael P. Presley, Brittany J. Garrett, Artem Zykovich, et al. “Late-Life Rapamycin Treatment Reverses Age-Related Heart Dysfunction.” Aging Cell 12, no. 5 (October 2013): 851–62. https://doi.org/10.1111/acel.12109.

[11] “MTOR Inhibition Improves Immune Function in the Elderly | Science Translational Medicine.” Accessed July 17, 2020. https://stm.sciencemag.org/content/6/268/268ra179?ijkey=1601282de0b3335233a0a6d227abeba015c47c3f&keytype2=tf_ipsecsha.

[12] “Testosterone Signals through MTOR and Androgen Receptor to Induce Muscle Hypertrophy – PubMed.” Accessed July 17, 2020. https://pubmed.ncbi.nlm.nih.gov/23470307/.

[13] White, Eileen, Janice M. Mehnert, and Chang S. Chan. “Autophagy, Metabolism, and Cancer.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 21, no. 22 (November 15, 2015): 5037–46. https://doi.org/10.1158/1078-0432.CCR-15-0490.

[14] Kanchan P., Scarth W. A., Katharina S. A. Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging. Cellular and Molecular Life Sciences. 2013;70(1):89–103. doi: 10.1007/s00018-012-1032-3.

[15] Meng, Delong et al. “mTOR signaling in stem and progenitor cells.” Development (Cambridge, England) vol. 145,1 dev152595. 8 Jan. 2018, doi:10.1242/dev.152595