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.

[12] Piper, M.D. and Bartke, A., 2008. Diet and aging. Cell metabolism, 8(2), pp.99-104.

[13] Seri, B., Garcıa-Verdugo, J.M., McEwen, B.S. and Alvarez-Buylla, A., 2001. Astrocytes give rise to new neurons in the adult mammalian hippocampus. Journal of Neuroscience, 21(18), pp.7153-7160.

[14] Kim, K., Sung, Y.H., Seo, J.H., Lee, S.W., Lim, B.V., Lee, C.Y. and Chung, Y.R., 2015. Effects of treadmill exercise-intensity on short-term memory in the rats born of the lipopolysaccharide-exposed maternal rats. Journal of exercise rehabilitation, 11(6), p.296.

[15] Gomes, A.P., Price, N.L., Ling, A.J., Moslehi, J.J., Montgomery, M.K., Rajman, L., White, J.P., Teodoro, J.S., Wrann, C.D., Hubbard, B.P. and Mercken, E.M., 2013. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), pp.1624-1638.

[16] Chen, C., Liu, Y., Liu, Y. and Zheng, P., 2009. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Science signaling, 2(98), pp.ra75-ra75.

[17] Kirkland, J.L. and Tchkonia, T., 2020. Senolytic drugs: From discovery to translation. Journal of internal medicine, 288(5), pp.518-536.

[18] Atala, A., Lanza, R., Mikos, T. and Nerem, R. eds., 2018. Principles of regenerative medicine. Academic press.

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During the process of aging, the function of beneficial microbes, that provide necessary nutrients for the body tissues, are severely affected, while harmful microbes, that contribute to the process, such as chronic inflammation and cancer, flourish [1][2][3][4][5].

What Evidence Supports the Role of the Gut Flora in Longevity?

Several in vivo studies demonstrated that fecal microbiota transplantation from younger mice (Donor) to older (Recipient) enhanced their health and lifespan. This procedure led to the restoration of healthy microbiota in the recipient suggesting its potential application in the field of longevity.

These conclusions are reinforced through the study of progeria mice, a model characterized by an advanced aging process and that has dysfunctional gut flora (Dysbiosis), like that of progeria patients. The researchers demonstrated that fecal microbiota transplantation from wild-type mice enhanced health span and lifespan in progeroid mouse models [6].

What Bacteria Are found in the Gut?

The gut contains about 1000 species of bacteria and the most dominant species are Bacteroides, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, Bifidobacterium, and Clostridium.

What Are the Good Bacteria in the Gut?

The gut’s most known “good bacteria” are Lactobacillus and Bifidobacterium, also known as probiotics. These bacteria help other gut bacteria by providing them with nutrients that are commonly known as prebiotics [7].

What Are the Health Benefits of Good Bacteria?

Probiotics have been shown to prevent symptoms of allergies, diabetes type 2 (Diabetes Miletus), autoimmune diseases, rheumatoid arthritis, cancer, diarrhea, constipation, irritable bowel syndrome, Crohn’s disease, and obesity.

Because they produce lactic acid, Lactobacillus and Bifidobacterium also suppress pathogens in healthy individuals through induction of immunomodulatory molecules with antagonistic effects [8].

What food Help Good Bacteria in the Gut?

To help the growth of good bacteria in the gut, you can consume products that contain probiotics, prebiotics, or both:

1- Probiotics Food

Probiotics are found in yogurt, lactobacillus milk, some cheeses such as Gouda, cheddar, cottage cheese, mozzarella, pickles, sauerkraut, kefir, kimchi, tempeh, kombucha, and miso.

2- Prebiotic food

Prebiotics are found in carrots, quinoa, radishes, onions, chicory roots, konjac roots, oats, yams, garlic, barley, wheat bran, berries, apples, asparagus, bananas, leeks, chia seeds, flax seeds, cocoa, coconut, jicama root, and dandelion greens.

How Does Prebiotics Help Good Bacteria in the Gut?

The most common prebiotics are fructooligosaccharides, galactooligosaccharides, and trans-galactooligosaccharides, but other prebiotics plays important roles in health and aging such as insulin enriched-oligofructose, lactulose, and oligofructose.

They are indigestible carbohydrates that are fermented and broken down by probiotics to obtain survival energy, and short-chain fatty acids such as lactic acid, butyric acid, and propionic acid [8].

How Does Prebiotics Maintain health and protect against Diseases?

1- Prebiotics’ Effects on Gastrointestinal Disorders

The administration of the prebiotic fructo-oligosaccharides to patients diagnosed with irritable bowel syndrome (IBS) or Crohn’s disease (CD) has been shown to significantly improve the symptoms of the two disorders in randomized double-blind, and placebo-controlled clinical trials [9][10].

Additionally, symbiotic therapy using Lactobacillus and Bifidobacterium has been shown to reduce the risk of colorectal cancer by inhibiting the proliferation of colorectal cancer cells [11].

2- Prebiotics’ Effects on the Immune System

Prebiotics induce the expression of cytokines that promote communication between immune cells leading to improved immune response and protection against infections and other diseases such as cancer and neurodegenerative diseases.

Several studies showed that the administration of fructo-oligosaccharides improves antibody response to viral vaccines [12][13], upregulates toll-like receptor 2-mediated immune response [14], and increased phagocytosis, and the levels of NK cells and the anti-inflammatory IL-10 [15].

3- Prebiotics’ Effects on the Nervous System

The administration of prebiotics such as non-starch polysaccharides was shown to improve the performance of working and recognition memory and cognitive functions [16][17], while another prebiotic known as insulin enriched-oligofructose enhances mood and immediate memory [18]. Lactulose was also shown to improve cognitive function and health-related quality of life [19].

4- Prebiotics’ Effects on the Cardio-vascular System

The prebiotics inulin has been shown to reduce cardiovascular diseases by reducing the levels of HDL-cholesterol, triglycerides, and lipoprotein A [20], while lactulose reduces the concentrations of free fatty acids that are originated from colon absorption [21].

5- Prebiotics’ Effects on the Skin

The administration of galactooligosaccharides with and without probiotics was shown to prevent the reduction in water and keratin caused by phenols that denatures proteins and disrupt disulfide bridges in the skin keratin [22]. 

Conclusion

The gut flora is essential for health, aging, and longevity and its unbalance (Dysbiosis) can lead to severe health consequences through the lack of availability of quality nutrients that are necessary for preventing diseases such as infections, cardiovascular diseases, nervous system, gastrointestinal, skin, and immune disorders that significantly promote aging, reduces the quality of life, and shorten longevity.

Therefore, the consumption of probiotics and prebiotics can considerably prevent these consequences and ensure a longer and high quality of life.

References

[1] Leulier, F. et al. Integrative physiology: at the crossroads of nutrition, microbiota, animal physiology and human health. Cell Metab. 25, 522–534 (2017).

[2] Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

[3] Loomba, R. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 25, 1054–1062 (2017).

[4] Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

[5] Zitvogel, L., Daillere, R., Roberti, M. P., Routy, B. & Kroemer, G. Anticancer effects of the microbiome and its products. Nat. Rev. Microbiol. 15, 465–478 (2017).

[6] Bárcena, Clea, et al. “Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice.” Nature medicine 25.8 (2019): 1234-1242.

[7] Wang, H., Wei, C.X., Min, L. and Zhu, L.Y., 2018. Good or bad: gut bacteria in human health and diseases. Biotechnology & Biotechnological Equipment, 32(5), pp.1075-1080.

[8] Davani-Davari, D., Negahdaripour, M., Karimzadeh, I., Seifan, M., Mohkam, M., Masoumi, S.J., Berenjian, A. and Ghasemi, Y., 2019. Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods, 8(3), p.92.

[9] Lindsay, J.O., Whelan, K., Stagg, A.J., Gobin, P., Al-Hassi, H.O., Rayment, N., Kamm, M.A., Knight, S.C. and Forbes, A., 2006. Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn’s disease. Gut, 55(3), pp.348-355.

[10] Silk, D.B.A., Davis, A., Vulevic, J., Tzortzis, G. and Gibson, G.R., 2009. Clinical trial: the effects of a trans‐galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome. Alimentary pharmacology & therapeutics, 29(5), pp.508-518.

[11] Rafter, J., Bennett, M., Caderni, G., Clune, Y., Hughes, R., Karlsson, P.C., Klinder, A., O’Riordan, M., O’Sullivan, G.C., Pool-Zobel, B. and Rechkemmer, G., 2007. Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. The American journal of clinical nutrition, 85(2), pp.488-496.

[12] Langkamp‐henken, B., Bender, B.S., Gardner, E.M., Herrlinger‐garcia, K.A., Kelley, M.J., Murasko, D.M., Schaller, J.P., Stechmiller, J.K., Thomas, D.J. and Wood, S.M., 2004. Nutritional formula enhanced immune function and reduced days of symptoms of upper respiratory tract infection in seniors. Journal of the American Geriatrics Society, 52(1), pp.3-12.

[13] Lomax, A.R., Cheung, L.V., Noakes, P.S., Miles, E.A. and Calder, P.C., 2015. Inulin-type β2-1 fructans have some effect on the antibody response to seasonal influenza vaccination in healthy middle-aged humans. Frontiers in immunology, 6, p.490.

[14] Clarke, S.T., Green-Johnson, J.M., Brooks, S.P., Ramdath, D.D., Bercik, P., Avila, C., Inglis, G.D., Green, J., Yanke, L.J., Selinger, L.B. and Kalmokoff, M., 2016. β2-1 Fructan supplementation alters host immune responses in a manner consistent with increased exposure to microbial components: results from a double-blinded, randomised, cross-over study in healthy adults. British journal of nutrition, 115(10), pp.1748-1759.

[15] Vulevic, J., Drakoularakou, A., Yaqoob, P., Tzortzis, G. and Gibson, G.R., 2008. Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. The American journal of clinical nutrition, 88(5), pp.1438-1446.

[16] Best, T., Howe, P., Bryan, J., Buckley, J. and Scholey, A., 2015. Acute effects of a dietary non-starch polysaccharide supplement on cognitive performance in healthy middle-aged adults. Nutritional neuroscience, 18(2), pp.76-86.

[17] Best, T., Kemps, E. and Bryan, J., 2009. Saccharide effects on cognition and well-being in middle-aged adults: a randomized controlled trial. Developmental neuropsychology, 35(1), pp.66-80.

[18] Smith, A.P., Sutherland, D. and Hewlett, P., 2015. An investigation of the acute effects of oligofructose-enriched inulin on subjective wellbeing, mood and cognitive performance. Nutrients, 7(11), pp.8887-8896.

[19] Prasad, S., Dhiman, R.K., Duseja, A., Chawla, Y.K., Sharma, A. and Agarwal, R., 2007. Lactulose improves cognitive functions and health‐related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology, 45(3), pp.549-559.

[20] Russo, F., Chimienti, G., Riezzo, G., Pepe, G., Petrosillo, G., Chiloiro, M. and Marconi, E., 2008. Inulin-enriched pasta affects lipid profile and Lp (a) concentrations in Italian young healthy male volunteers. European journal of nutrition, 47(8), pp.453-459.

[21] Brighenti, F., Vuksan, V., Rao, A.V., Cunnane, S.C., Ocana, A., Corey, P. and Vezina, C., 1991. Specific types of colonic fermentation may raise low-density-lipoprotein-cholesterol concentrations. The American journal of clinical nutrition, 54(1), pp.141-147.

[22] Kano, M., Masuoka, N., Kaga, C., Sugimoto, S., Iizuka, R., Manabe, K., Sone, T., Oeda, K., Nonaka, C., Miyazaki, K. and Ishikawa, F., 2013. Consecutive intake of fermented milk containing Bifidobacterium breve strain Yakult and galacto-oligosaccharides benefits skin condition in healthy adult women. Bioscience of microbiota, food and health, 32(1), pp.33-39.

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What Is the Epigenome?

The epigenome is a set of chemical modifications of the DNA and DNA-related proteins that are involved in regulating gene expression in physiological and pathological conditions, including age-related diseases.

Environmental and dietary factors, such as nutritional factors and chemicals have been directly implicated in altering the epigenome through mechanisms involving DNA methylation and histone modification, leading to the development of abnormalities that affect health and longevity [2].

How do Bioactive Compounds Affect the Epigenome?

Interestingly, several studies have demonstrated that several bioactive compounds, such as the ones found in fruit, vegetables, and plants, can positively affect the epigenome, contributing to improvements in longevity.

These natural compounds can influence a relaxed or closed chromatin form that determines the DNA accessibility of transcription factors that are involved in transcriptional and functional processes involved in aging and longevity (Lifespan).

What Are the Bioactive Compounds That Affect the Epigenome?

Resveratrol, sulforaphane, and curcumin can act on relaxed and closed forms of the chromatin, while others, such as Genistein can promote a relaxed form of chromatin, and Epigallocatechin-3-gallate can act oppositely by promoting a closed-form of chromatin [3] [4].

How Does Resveratrol Prolong Longevity?

Resveratrol is a polyphenol found in red wine that has antiaging and anti-diabetic properties and is used as a nutritional supplement. Resveratrol has been shown to increase the levels of the NAD-dependent deacetylase sirtuin-1 (SIRT-1), a protein that is involved in the cellular response to inflammatory, metabolic, and oxidative stressors.

Resveratrol metabolic activity appears to be mediated through the inhibition of the cAMP-degrading phosphodiesterase that results in increased levels of SIRT-1 and NAD+ leading to histones deacetylation and chromatin relaxation [5].

How Does Sulforaphane Prolong Longevity?

Sulforaphane (SFN) is an isothiocyanate that is present in cruciferous vegetables such as cauliflower, cabbage, kale, garden cress, bok choy, broccoli, and Brussels sprouts. In addition to its epigenetic effect through the inhibition of HDAC and DNA methyltransferases which relaxes the chromatin [6], Sulforaphane also inhibits inflammation by inhibiting NFkB and promotes antioxidation via the induction of NrF2, a master regulator of detoxification, anti-inflammation, and antioxidation processes within the cells. 

How Does Curcumin Prolong Longevity?

Curcumin is a bioactive polyphenolic extract of turmeric that is used as a spice, food additive, and herbal medicine. Although curcumin increases longevity through the induction of the activity of the antioxidant superoxide dismutase (SOD), but also through other pathways, it also significantly inhibits histone acetylation which promotes chromatin relaxation promoting DNA accessibility to longevity and anti-aging transcription factors [7].

How Does Genistein Prolong Longevity?

Genistein is an isoflavone that is found in plants such as soybeans and fava beans and is used as a dietary supplement. Genistein has been shown to have anti-cancer and antiaging properties. It functions by increasing histone acetylation through the induction of histone acetyltransferases which relaxes the chromatin allowing access for transcriptional regulatory factors [8].

How Does Epigallocatechin-3-gallate Prolong Longevity?

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol component of green tea that has been shown to have benefits for health and longevity. EGCG promotes chromatin relaxation by affecting the expression and activity of epigenome modulators such as HDAC5 and 7, p300, CREBP, LSD1, or KMT2A [9].

How Does Garlic Prolong Longevity?

Garlic through its organosulfur compounds such as diallyl sulfide, diallyl disulfide, and diallyl trisulfide, have been shown to alter the activity of histone deacetylases (HDACs) which derepresses epigenetically silenced genes that may be involved in anti-aging and longevity [11].

How Do Environmental Exposures Affect the Epigenome?

Many studies investigated the changes in the epigenome following exposures to chemicals and air pollution. For instance, air pollution through particulate matter (PM) exposure results in gene-specific methylation in workers of steel plants. Benzene exposure was also shown to alter DNA methylation resulting in aberrations similar to the ones observed in cancer cells.

Exposure to the environmental contaminants, Trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic acid (TCA) was reported to prevent DNA hypomethylation. Other types of exposure such to the metals nickel, cadmium, lead, and arsenic are also involved in Oxidative DNA damage which can interfere with the ability of methyltransferases to interact with DNA [10].

Interestingly some environmental pollutants such as alloxan, cyclophosphamide, orthoaminoasotoluol, benzopyrene, diethylstilbestrol (DES), and vinclozolin have been reported to induce transgenerational phenotypic effects that cause abnormalities in the offspring for at least three generations [10]. 

Conclusion

Considering that these bioactive compounds play different roles in regulating the longevity-related epigenome, perhaps, determining the right dietary amounts may further improve their longevity benefits. On the other hand, some chemicals and air pollutants would have reverse effects on health and longevity.

References

[1]Booth, Lauren N., and Anne Brunet. “The aging epigenome.” Molecular cell 62.5 (2016): 728-744.

[2]Gallou-Kabani, Catherine, et al. “Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond.” Clinical Chemistry and Laboratory Medicine (CCLM) 45.3 (2007): 321-327.

[3]Cosentino, Claudia, and Raul Mostoslavsky. “Metabolism, longevity and epigenetics.” Cellular and Molecular Life Sciences 70.9 (2013): 1525-1541.

[4]Hardy, Tabitha M., and Trygve O. Tollefsbol. “Epigenetic diet: impact on the epigenome and cancer.” Epigenomics 3.4 (2011): 503-518.

[5] Park, S.J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A.L. and Kim, M.K., 2012. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell, 148(3), pp.421-433.

[6] Santín-Márquez, R., Alarcón-Aguilar, A., López-Diazguerrero, N.E., Chondrogianni, N. and Königsberg, M., 2019. Sulforaphane-role in aging and neurodegeneration. GeroScience, 41(5), pp.655-670.

[7] Mohammadi-Bardbori, A., Akbarizadeh, A.R., Delju, F. and Rannug, A., 2016. Chromatin remodeling by curcumin alters endogenous aryl hydrocarbon receptor signaling. Chemico-biological interactions, 252, pp.19-27.

[8] Shen, L.R., Parnell, L.D., Ordovas, J.M. and Lai, C.Q., 2013. Curcumin and aging. Biofactors, 39(1), pp.133-140.

[9] Ciesielski, O., Biesiekierska, M. and Balcerczyk, A., 2020. Epigallocatechin-3-gallate (EGCG) alters histone acetylation and methylation and impacts chromatin architecture profile in human endothelial cells. Molecules, 25(10), p.2326.

[10] Baccarelli, A. and Bollati, V., 2009. Epigenetics and environmental chemicals. Current opinion in pediatrics, 21(2), p.243.

[11] Nian, H., Delage, B., Pinto, J.T. and Dashwood, R.H., 2008. Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. Carcinogenesis, 29(9), pp.1816-1824.

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These diseases are the main causes of bad quality of life, and death, and therefore, significantly reduce individuals’ lifespan. A group of genes named Conserved Transcriptional Response to Adversity (CTRA) appears to play a key role in linking chronic inflammation and longevity.

What is the Conserved Transcription Response to Adversity (CTRA)?

The Conserved Transcriptional Response to Adversity (CTRA) gene expression pattern involves the expression of a group of genes (e.g., IL1B, IL6, IL8/CXCL8, COX2/PTGS2, and TNF) that are involved in promoting chronic inflammation through the activation of pro-inflammatory cytokines ^[2].

How is CTRA Activated?

CTRA gene expression appears to be induced by a signaling pathway named the “social transduction pathway” that is controlled by evolutionary treats response systems in the central nervous system (CNS) and that are triggered by adverse environmental conditions, such as poverty, stress, loss, trauma, and instability.

What is the Mechanism of CTRA induction?

Mechanistically, adverse environmental conditions create chronic and uncertain conditions that prompt the peripheral neural signaling to secrete norepinephrine, which induces the beta-adrenergic receptor/cAMP/PKA signaling pathway, resulting in the activation of transcription factors, such as CREB, NF-kB, and AP1, that induce the expression of CTRA genes [2].

What is the Relation Between Stress and CTRA Activation?

Stress is a key activator of CTRA leading to chronic inflammation and potentially to reduced longevity. A study evaluated the correlation between stress, CTRA gene-expression profile, and survival in treated Breast cancer patients. Based on predicted statistical analysis, the researchers found that stress increases the expression of CTRA genes which may result in a shorter 11-year disease-free survival (DFS) in the treated breast cancer patients. They also show that cognitive-behavioral stress management (CBSM) can limit this effect [3].

What Is the Relation Between Anxiety and CTRA Activation?

Several studies demonstrated that stress is one of the main triggers of anxiety [4] and that video gaming reduces anxiety [5][6]. A study has shown that gamers with a strong social connection have a reduced CTRA expression profile compared to gamers with low-social well-being [7].

What Is the Relation Between Low Socioeconomic Status and CTRA Activation?

It has been shown that low socioeconomic status (SES) has negative effects on long-term health and longevity. By analyzing pilot data on 120 older adults from the health and retirement study in the United States (2002-2010), a study showed an association between increased CTRA expression in individuals from low socioeconomic status who had extended periods of threat, uncertainty, or adverse life circumstances, when compared with individuals from higher socioeconomic groups [8].

What Is the Relation Between Grief and CTRA Activation?

The relationship between widowhood and CTRA expression was evaluated by bioinformatics analyses of data from 36 widows and 27 nonbereaved married women (controls). The results showed an increased expression of some CTRA genes in widowed women compared to controls [9].

What Is the Relation Between Happiness and CTRA?

By studying the correlation between happiness and CTRA gene expression in a sample of 22 women who survived breast cancer, a study showed that eudaimonic well–being, a state of being happy and feeling healthy reduces the CTRA proinflammatory gene expression and increases the expression of the antiviral/antibody-related CTRA immune subcomponent [10].

What Is the Relation Between Cancer and CTRA?

It has been shown that beta-adrenergic receptor activates transcription factors, such as CREB, NF-kB, and AP1, through the cAMP/PKA signaling pathway leading to the expression of CTRA genes. A study reported that the inhibition of the beta-adrenergic receptor using the beta-adrenergic antagonist, propranolol, decreases CTRA gene expression in individuals that received autologous hematopoietic cell transplant for multiple myeloma [11].

Conclusion

Increasing longevity may rely on multi-layers interventions that could include lifestyle changes via improving living conditions, reducing stress, promoting positive attitudes and behaviors, but may also involve pharmacological approaches that can interfere with the pathways that trigger the CTRA gene expression.

References

[1]Zhong, Jixin, and Guixiu Shi. “Regulation of inflammation in chronic disease.” Frontiers in Immunology 10 (2019): 737.

[2]Furman, David, et al. “Chronic inflammation in the etiology of disease across the life span.” Nature medicine 25.12 (2019): 1822-1832.

[3] Antoni, M.H., Bouchard, L.C., Jacobs, J.M., Lechner, S.C., Jutagir, D.R., Gudenkauf, L.M., Carver, C.S., Lutgendorf, S., Cole, S.W., Lippman, M. and Blomberg, B.B., 2016. Stress management, leukocyte transcriptional changes and breast cancer recurrence in a randomized trial: an exploratory analysis. Psychoneuroendocrinology, 74, pp.269-277.

[4] McEwen, B.S., Eiland, L., Hunter, R.G. and Miller, M.M., 2012. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology, 62(1), pp.3-12.

[5] Zayeni, D., Raynaud, J.P. and Revet, A., 2020. Therapeutic and preventive use of video games in child and adolescent psychiatry: a systematic review. Frontiers in psychiatry, 11, p.36.

[6] Viana, R.B. and de Lira, C.A.B., 2020. Exergames as coping strategies for anxiety disorders during the COVID-19 quarantine period. Games for health journal, 9(3), pp.147-149.

[7] McEwen, B.S., Eiland, L., Hunter, R.G. and Miller, M.M., 2012. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology, 62(1), pp.3-12.

[8] Levine, M.E., Crimmins, E.M., Weir, D.R. and Cole, S.W., 2017. Contemporaneous social environment and the architecture of late-life gene expression profiles. American journal of epidemiology, 186(5), pp.503-509.

[9] O’Connor, M.F., Schultze-Florey, C.R., Irwin, M.R., Arevalo, J.M. and Cole, S.W., 2014. Divergent gene expression responses to complicated grief and non-complicated grief. Brain, behavior, and immunity, 37, pp.78-83.

[10] Boyle, C.C., Cole, S.W., Dutcher, J.M., Eisenberger, N.I. and Bower, J.E., 2019. Changes in eudaimonic well-being and the conserved transcriptional response to adversity in younger breast cancer survivors. Psychoneuroendocrinology, 103, pp.173-179.

[11] Knight, J.M., Rizzo, J.D., Hari, P., Giles, K.E., Pasquini, M.C., D’Souza, A., Logan, B.R., Hamadani, M., Chhabra, S., Dhaka, B. and Shah, N., 2019. Abstract# 2055 Beta-adrenergic blockade inhibits stress-related transcriptome profiles associated with worse cancer outcomes: A randomized controlled study of propranolol in hematopoietic cell transplantation recipients. Brain, Behavior, and Immunity, 76, p.e4.

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