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The Effects of Caloric Restriction on Stem Cells

Reducing calories was shown to combat stem cell exhaustion in multiple ways.

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A review published in The Malaysian Journal of Medical Sciences has outlined what effects caloric restriction (CR) has on the development and differentiation of stem cells.

Stem cells and their exhaustion

The reviewers began by discussing stem cell exhaustion, a hallmark of aging and a common concern of aging research that we have covered extensively. They highlight its place in the hallmarks and the diseases that can arise from it, such as aplastic anemia and failure of the bone marrow.

The researchers highlighted four key areas in which caloric restriction has been shown to have benefits for stem cell potency: muscle tissue, the intestinal lining, the blood, and the skin and hair.

Caloric restriction and muscle tissue

The researchers explain that cells within muscle tissue are replenished from pools of satellite cells, which contain stem cells. Upon injury, these cells become activated in order to repair damaged tissue [1].

The reviewers cite a 2012 study in which both young and old mice were fed a calorically restricted diet and compared to controls [2]. Both young and old mice on CR had stem cells thrice the size of controls, and there were more satellite cells in each gram of muscle. According to that study, this is because the mitochondria receive energy from oxidative processes rather than glycolysis, which promotes energy generation and aids stem cells in their development. On the other hand, other studies suggested the importance of glycolysis in activating these cells, such as during high-intensity exercise [3].

CR also has beneficial effects on signaling, which affects stem cell activity [2]. CR caused more satellite cells to express Sirt1 and Foxo3, two well-known metabolic regulators. These benefits were preserved when the cells were taken outside the mice, and this study found that, if both the recipient and the donor mouse are undergoing caloric restriction, muscle engraftment is four times as effective due to the anti-inflammatory properties of CR and the increase in satellite cells.

Caloric restriction and the intestinal lining

The intestinal lining is consistently maintained through a population of columnar base cells (CBCs) and intestinal stem cells (ISCs) [4]. While CBCs are more active, ISCs are responsible for restoring the intestinal walls after DNA damage, such as from radiation [5].

The primary positive effect of CR on the intestines is its benefit in preserving the population of ISCs [6]. One study found that CR for 4 to 28 weeks increased the intestinal stem cell populations of mice by 35%, compared to a control group, and increased these stem cells’ potency [7].

However, CR also had a negative effect here. The cells were able to better self-renew and maintain their populations under CR, but they were less likely to differentiate. This led to a decrease in the amount of intestinal villi and smaller intestines overall [7].

The reviewers also cite multiple studies outlining the complicated relationship between CR and the well-known metabolic factor mTORC1.

Caloric restriction and hematopoietic stem cells (HSCs)

The term “hematopoietic” refers to the ability of stem cells to create blood cells of all types, and the reviewers point out that stem cell exhaustion in this area leads to blood cell defects and a decreased ability to fight infection [7]. Here, the reviewers hold, CR directly combats the effects of aging.

One strain of mouse, when young, had little effect on its HSCs from CR, but that strain was substantially affected by CR as it aged. The researchers of that study show that CR improves the ability of HSCs to renew themselves and differentiate, thus improving bone marrow function [8]. It also decreases the risk of cancer and reduces p16INK4a, a known marker of senescence.

Caloric restriction and skin stem cells

One study found that by increasing the pool of stem cells, caloric restriction had a substantially beneficial effect on the fur coats of mice; the fur was thicker and less thermally conductive. On the other hand, it also impeded vasoconstriction (which decreases heat loss), and it naturally decreased fat reserves; for small animals such as mice, the ability to burn fat for energy in order to maintain body temperature is important [9]. Here, the benefits seem applicable to human beings, but the downsides are likely to be considerably less so.


While caloric restriction is far from a panacea for any problem, including stem cell exhaustion, its benefits have been shown to be substantial in both human beings and animal models. While not all of the data is positive, the wide variety of studies outlined in this review show how the metabolic effects of CR are largely beneficial towards stem cell proliferation.

By researching this line of inquiry further, it may one day be possible to discover ways to affect the mechanisms of action directly and so develop drugs and therapies that go beyond the effects of simple caloric restriction, directly stimulating stem cells to proliferate and replace losses.

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[1] Wagers, A. J., & Conboy, I. M. (2005). Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell, 122(5), 659-667.

[2] Cerletti, M., Jang, Y. C., Finley, L. W., Haigis, M. C., & Wagers, A. J. (2012). Short-term calorie restriction enhances skeletal muscle stem cell function. Cell stem cell, 10(5), 515-519.

[3] Okabe, K., Mukai, K., Ohmura, H., Takahashi, T., & Miyata, H. (2016). Effect of acute high-intensity exercise in normobaric hypoxia on Thoroughbred skeletal muscle. The Journal of sports medicine and physical fitness, 57(5), 711-719.

[4] Barker, N., Van Es, J. H., Kuipers, J., Kujala, P., Van Den Born, M., Cozijnsen, M., … & Clevers, H. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449(7165), 1003-1007.

[5] Montgomery, R. K., Carlone, D. L., Richmond, C. A., Farilla, L., Kranendonk, M. E., Henderson, D. E., … & Breault, D. T. (2011). Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proceedings of the National Academy of Sciences, 108(1), 179-184.

[6] Yousefi, M., Nakauka-Ddamba, A., Berry, C. T., Li, N., Schoenberger, J., Simeonov, K. P., … & Lengner, C. J. (2018). Calorie restriction governs intestinal epithelial regeneration through cell-autonomous regulation of mTORC1 in reserve stem cells. Stem cell reports, 10(3), 703-711.

[7] Liang, Y., Van Zant, G., & Szilvassy, S. J. (2005). Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood, 106(4), 1479-1487.

[8] Ertl, R. P., Chen, J., Astle, C. M., Duffy, T. M., & Harrison, D. E. (2008). Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated. Blood, The Journal of the American Society of Hematology, 111(3), 1709-1716.

[9] Forni, M. F., Peloggia, J., Braga, T. T., Chinchilla, J. E. O., Shinohara, J., Navas, C. A., … & Kowaltowski, A. J. (2017). Caloric restriction promotes structural and metabolic changes in the skin. Cell reports, 20(11), 2678-2692.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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