Stem Cell Exhaustion and Aging -

Following the fecundation of an egg by a sperm, the fertilized egg begins a series of cell divisions that leads to the formation of a mass of cells known as the blastula. This mass contains two types of cell masses, the trophoblast, and the inner cell mass. The trophoblast leads to the formation of the placenta and the inner cell mass to the generation of all cells and tissues in the body [1].

Although most of the cells progress to generate different tissues and organs, few cells conserve stem cell-like characteristics that are committed to the continuous maintenance and repair of tissues and organs throughout the life of an individual [1]. These cells are known as adult stem cells or adult tissue-specific stem cells which exhaustion occurs during aging [2].

What is Stem Cell Exhaustion?

Within tissues and organs of the body, populations of stem cell-like cells known as adult stem cells or adult tissue-specific stem cells maintain and repair tissues and organs throughout the life of an individual.

However, as we age, these populations of cells start to deplete due to several causes that can act individually or collectively such as DNA damage, proteostasis, epigenetics, telomere shortening, mitochondria dysfunction, and cellular senescence [2].

1- What is the Link Between DNA damage and Stem Cell Exhaustion?

During their lifetime within tissues and organs, adult stem cells are the target of genotoxic effects that lead to DNA mutations which result in their functional inactivation or death. These events are enhanced with time and are more pronounced at old age due to the decreased activity of the DNA repair machinery within the cells [3].

2- What is the Link Between the Loss of Proteostasis and Stem Cell Exhaustion?

As products of DNA transcription and RNA translation, proteins are molecules that are involved in all functional activities within the cells. However, when proteins are generated, they must pass a quality control test that relies on checking their synthesis, folding, and degradation. This process is known as protein homeostasis or proteostasis.

Unfortunately, this process is also affected with age leading to abnormal folding, toxic aggregation, and accumulation of damaged proteins, that result in cellular damage and tissue dysfunction [4].

3- What is the Link Between Epigenetics and Stem Cell Exhaustion?

During the process of aging, DNA is subject to epigenetic changes such as acetylation and methylation that control the expression of genes that control longevity. For example, an increase in methylation of lineage-specific gene expression was associated with decreased self-renewal of hematopoietic stem cells (HSCs) [5].

4- What is the Link Between Telomere Shortening and Stem Cell Exhaustion?

During aging, a shortening of telomeres-specialized chromatin structures that are found at the end of chromosomes leads to gene erosion and chromosomal aberrations that result in functional inactivation, death, or senescence of stem cells. A study demonstrated an association between longer telomeres and functional stem cells in hair follicles, intestines, testis, cornea, and the brain [6].

5- What is the Link Between Mitochondria Dysfunction and Stem Cell Exhaustion?

Reactive oxygen species (ROS) that are produced by the mitochondria can induce oxidative damage to the mitochondria’s functions. A theory proposed that elevated ROS are associated with a decline in the integrity of mitochondria [7].

This possibility was tested by a study that showed that hematopoietic stem cells that lack the gene encoding the mitochondrial antioxidant enzyme, superoxide dismutase 2, have oxidative stress-mediated hematopoietic abnormalities [8].

6- What is the Link Between Cellular Senescence and Stem Cell Exhaustion?

Cellular senescence is associated with cells that stopped dividing without entering a programmed cell death. This cellular arrest in growth is associated with DNA damage and/or shortening of the telomeres in senescent cells. A loss of the stem cell pool may be due to a percentage of adult stem cells entering into senescence during aging [9].

How is Stem Cell Exhaustion Slowed down?

To slow down stem cell exhaustion, changes in lifestyle, such as exercise and appropriate diet, can significantly delay this process. Other means are intensively investigated by researchers such as the development of medications that delay stem cell exhaustion and regenerative medicine.

1- How does Lifestyle Slowdown Stem Cell Exhaustion?

Lifestyle changes in diet and exercise were demonstrated to promote longevity.

How Diet Slows Down Stem Cell Exhaustion?

Dietary interventions, including calorie restriction, dietary restriction, protein restriction, and epigenetic diet, promote longevity [10]. Calorie restriction was shown to promote the frequency and function of skeletal muscle stem cells and reduce the severity of aging and aging-related diseases [11][12].

How does Exercise Slow Down Stem Cell Exhaustion?

Several studies demonstrated that exercise promotes the survival and proliferation of stem cells. For example, exercise has been shown to increase the size of the hippocampus in human adults [6], and in rodent models, it has been shown to increase the proliferation and survival of the progenitor cells as they differentiated and matured into granule neurons in the dentate gyrus (DG) [13] [14].

2- How do NAD⁺ Precursors Slowdown Stem Cell Exhaustion?

Nicotinamide adenine dinucleotide (NAD⁺) is an essential mitochondrial cofactor in the redox pathway that contributes to the generation of ATP. When NAD⁺is in the nucleus, it promotes the balance between nuclear and mitochondria encoded respiratory chain subunits.

In a model of aged mice and Drosophila, a decline in nuclear NAD⁺ was reported to disrupt oxidative phosphorylation leading to mitochondria dysfunction suggesting a potential role of nuclear NAD⁺ in the maintenance of the stem cell pool [15].

3- How does Rapamycin Slowdown Stem Cell Exhaustion?

Rapamycin is a bacterial compound that has immunosuppressant activities towards T and B cells. Rapamycin has been reported to restore the self-renewal and hematopoietic potential of aged hematopoietic stem cells through the inhibition of the mTOR pathway. The inhibition of this pathway results in increased glycolysis and removal of dysfunctional proteins by autophagy [16].

4- How do Senolytics Slowdown Stem Cell Exhaustion?

To eradicate senescent cells from the body and restore the dysfunction of stem cells, several drugs have been developed such as Dasatinib, Quercetin, Fisetin, and Navitoclax. Although the exact mechanism of action is not provided, these drugs appear to act by inactivating anti‐apoptotic pathways [17].

5- How Can Regenerative Medicine Slowdown Stem Cell Exhaustion?

Regenerative medicine is a therapeutic medical field that focuses on developing technologies that use stem cells to replace, engineer, or regenerate human or animal cells, tissues, or organs to restore or establish normal function [18].

Although this approach encounters many technical challenges, non-embryonic and mature cells can be reprogrammed back into stem cells using cloning methods that promote the expression of a core of transcriptional network involving cell factors such as OCT4, SOX2, KLF4, and C-Myc [1]. These reprogrammed cells can then be differentiated into tissue-specific stem cells before transplantation into patients.

Conclusion

During aging, stem cell exhaustion is due to several causes that can act individually or collectively such as DNA damage, proteostasis, epigenetics, telomere shortening, mitochondria dysfunction, and cellular senescence.

However, many studies on aging and longevity indicate the importance of diet and exercise in these processes and future medical advances will certainly contribute to this effort in preventing or slowing down aging.

References

[1] Regad, T., Sayers, T. and Rees, R., 2015. Principles of stem cell biology and cancer: future applications and therapeutics. John Wiley & Sons.

[2] Oh, J., Lee, Y.D. and Wagers, A.J., 2014. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature medicine, 20(8), pp.870-880.

[3] Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J. and Weissman, I.L., 2007. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 447(7145), pp.725-729.

[4] Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C.M. and Stefani, M., 2002. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. nature, 416(6880), pp.507-511.

[5] Beerman, I., Bock, C., Garrison, B.S., Smith, Z.D., Gu, H., Meissner, A. and Rossi, D.J., 2013. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell stem cell, 12(4), pp.413-425.

[6] Flores, I., Canela, A., Vera, E., Tejera, A., Cotsarelis, G. and Blasco, M.A., 2008. The longest telomeres: a general signature of adult stem cell compartments. Genes & development, 22(5), pp.654-667.

[7] Harman, D., 1972. Free radical theory of aging: dietary implications. The American journal of clinical nutrition, 25(8), pp.839-843.

[8] Ahmad, K.A., CLEMENT, M.V. and Pervaiz, S., 2003. Pro‐oxidant Activity of Low Doses of Resveratrol Inhibits Hydrogen Peroxide—Induced Apoptosis. Annals of the New York Academy of Sciences, 1010(1), pp.365-373.

[9] Geiger, H., De Haan, G. and Florian, M.C., 2013. The ageing haematopoietic stem cell compartment. Nature Reviews Immunology, 13(5), pp.376-389.

[10] Kitada, M., Ogura, Y., Monno, I. and Koya, D., 2019. The impact of dietary protein intake on longevity and metabolic health. EBioMedicine, 43, pp.632-640.

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