Can Caloric Restriction Mimetics Fight Aging and Obesity at the Same Time?

Can Caloric Restriction Mimetics Fight Aging and Obesity at the Same Time?

Aging, at its core, is the process of gradual deterioration of the human body and its components across time. Much to our dismay, aging has long stood as an insurmountable barrier to humanity's pursuit of extended life and vitality. Current aging theories focus on key factors like metabolism, oxidative stress, mitochondrial dysfunction, and epigenetic changes. Modern technological advancements and practices have led to food surpluses across industrialized nations. However, while many of these industrial nations have solved the hunger problem, this excessive food surplus has drastically increased rates of obesity. Excessive weight gain, obesity, and increased fat mass are directly linked to higher disease and cancer rates, often exacerbated by age-related metabolic distress. Despite all of the consequences of modern living, people around the world are growing older than ever before. As a result, populations of all ages seek a wide variety of natural products and alternative approaches in the hope of living a longer and healthier life. This has prompted relentless research efforts to uncover the secrets of longevity and metabolic regulation1.

Caloric Restriction

One of the fundamental theories regarding the aging process revolves around targeting and altering the metabolism. Caloric restriction (CR) is the process by which an organism experiences reduced caloric intake with regards to its normalized caloric requirements and is a fundamental approach in metabolic and aging research2. By reducing caloric intake in various organisms, scientists have discovered a substantial correlation between increased lifespan and caloric reduction in many different organisms (e.g., mice, primates, insects, etc.)2-4. While clinical trials have seen some success regarding CR, problems with adherence plague these studies2, 4. Supportively, humans have evolved to consume and store calories and going against these innate mechanisms to willingly restrict caloric intake is, understandably, unappealing. However, metabolic modulation through caloric restriction and other means may attenuate or cure the symptoms of aging-related diseases while increasing life-span 2. CR is capable of delivering many benefits including, but not limited to; increased glucose homeostasis, decreased oxidative stress, positive changes in gene expression, and increased cell proliferation5. Conversely, the pursuit of compounds capable of mimicking CR, known as either CR mimetics or mimics, has ensued due to the innate difficulties involved in implementing CR in clinical settings5.

CR Mimetics

As an alternative approach to CR, CR mimetics, both synthetic and natural, have been heavily investigated for their potential to mimic the desirable metabolic benefits of CR. Recent research has investigated novel possibilities for nutrition-based caloric restriction mimetics aimed at alleviating the adverse consequences of obesity and aging. In the following, we delve into some of the most up-to-date research and latest advancements in CR mimetics. Over the last decade, research has continually identified the potential for CR mimetics in a wide variety of tissues, organs, and metabolic processes critical to maintaining health and homeostasis across the lifespan, including but not limited to:

  • Obesity/Adipose Tissue6, 7
  • Inflammation/Oxidative Stress8
  • Gut Microbiota Health9
  • Non-Alcoholic Fatty Liver Disease10
  • Skeletal Muscle Function11
  • Glucose Homeostasis12
  • Cardiovascular Health12

Within the following, I will focus on several prominent and well-studied plant-based products and compounds, highlighting their potential as CR mimetics.

Resveratrol

Resveratrol (RSV) is a plant-based polyphenol found in high concentrations in grapes that has been heavily researched for its potential as a CR mimetic13. RSV has continually been shown to activate SIRT1 and other sirtuin proteins, which are associated with increased lifespan and improved metabolic health, similar to the benefits observed with CR14. This activation alone may lead to various benefits, including improved insulin sensitivity, enhanced mitochondrial function, and increased fat metabolism. In direct support of this, one study discovered that RSV could potentially mimic the effects of CR through reducing plasma cytokine levels, promoting lipolysis and fatty acid uptake, and potentially inhibiting the NF-kB pathway in obese rats. This led to decreased body weight and reduced levels of inflammatory biomarkers in the fat tissue7. In another double-blind clinical study, trans-resveratrol supplementation altered adipocyte gene signaling and reduced the size of abdominal fat cells in obese men between the ages of 40 to 656.

While RSV anti-obesogenic potential is promising, research has also shown that RSV may be capable of targeting the comorbidities of the condition such as nonalcoholic fatty liver disease (NAFLD) and CVD. A double blind randomized control trial found that daily RSV supplementation reduced inflammation and liver cell damage10. Furthermore, the study suggested that resveratrol might be more effective than lifestyle changes as an intervention strategy in patients with NAFLD10. As thoroughly evidenced, RSV supplementation can also provide potential cardioprotective benefits to the aging heart and may mitigate CVD risk factors through its anti-inflammatory, antioxidant, antiplatelet and lipid-lowering properties15. Regarding diabetes and metabolic syndrome, a recent study discovered that RSV may have contributed to a modest improvement in mouse insulin sensitivity, as evidenced by reduced fasting and post-glucose-bolus insulin levels16.

While this evidence strongly supports RSV as a CR mimetic, clinical trials investigating the effects of resveratrol have frequently produced conflicting data, making it challenging to draw definitive conclusions17. These inconsistencies and variations could be attributed to factors such as differences in dosages, the quality of RSV, study populations, and duration of treatment. However, considering the substantial evidence supporting RSV, it is relatively difficult to argue against its potential as a CR mimetic.

Green Tea Extract

Green tea extract is another plant-based supplement that has been heavily investigated for its diverse health benefits. Like RSV, green tea extract and its isolated compounds have been researched for their anti-obesogenic and CR mimetic potential18. Within these studies, evidence has shown that these compounds can reduce adiposity, improve the metabolic profile, and increase fat tissue browning in HFD fed mice18. In further support of this, green tea extract has also been shown to improve insulin sensitivity, reduce oxidative stress and inflammation, promote fat oxidation, activate sirtuin proteins and enhance cellular longevity19, 20. A recent systematic review and meta-analysis of clinical trials revealed that green tea supplementation promoted significant reductions in body weight and BMI21. Moreover, reductions in waist circumference were notable when using green tea at doses ≥800 mg/day for less than 3 months21. Overall, these findings suggest that green tea can be a helpful addition to a balanced diet and exercise regimen for both aging and obese populations.

Quercetin

Quercetin, another natural plant polyphenol, has gained significant attention as a potential CR mimetic due to its unique properties. Similar to RSV, quercetin can potentially promote DNA repair and metabolic regulation through its ability to activate sirtuin proteins22. As evidenced, research has demonstrated the anti-cancer, anti-aging, antioxidant, anti-viral, and neuroprotective benefits of quercetin23. In a most recent study, the therapeutic potential for quercetin against early stage COVID-19 was investigated. Fascinatingly, the study found that quercetin may modulate the hyperinflammatory response and increase the clearance of SARS-CoV-2 in clinical subjects24.

Conclusion

Natural CR mimetics have garnered attention for their potential in addressing both aging and obesity. Compounds like resveratrol, found in grapes, and quercetin, a plant polyphenol, have demonstrated anti-aging effects by activating sirtuin proteins and promoting DNA repair. They also offer anti-obesogenic benefits by improving metabolic health, reducing inflammation, and potentially aiding in weight management. Green tea extract, another CR mimetic, has shown promise in reducing body weight, BMI, and waist circumference, making it a valuable tool for combatting obesity while potentially extending longevity. Beyond the natural CR mimetics mentioned in this article, many other natural and synthetic compounds have shown potential in age and obesity related research.

As described in the following list, you can clearly see the overlapping anti-aging potential between CR and CR mimetics.

  • Metabolic Regulation (Energy Balance, Protein Synthesis, AMPK/mTOR)
    &nsp;- o CR, RSV, Quercetin, Green Tea Extract2, 25, 26
  • Genetic Translation and Genome Function (DNA Repair, Genome Stability, Autophagy, Cell Cycle)
    o CR, RSV, Green Tea Extract27
  • Oxidative Stress and Inflammation
    o CR, RSV, Quercetin, Green Tea Extract12, 28

CR mimetics offer exciting avenues for future research in the quest for extended longevity and holistic approaches to improved metabolic health.

References

  1. Steele CB, Thomas CC, Henley SJ, Massetti GM, Galuska DA, Agurs-Collins T, et al. Vital Signs: Trends in Incidence of Cancers Associated with Overweight and Obesity - United States, 2005-2014. MMWR Morbidity and mortality weekly report 2017; 66: 1052-1058, doi:10.15585/mmwr.mm6639e1.
  2. Balasubramanian P, Howell PR, Anderson RM. Aging and Caloric Restriction Research: A Biological Perspective With Translational Potential. EBioMedicine 2017; 21: 37-44, doi:10.1016/j.ebiom.2017.06.015.
  3. Whitaker R, Faulkner S, Miyokawa R, Burhenn L, Henriksen M, Wood JG, et al. Increased expression of Drosophila Sir 2 extends life span in a dose-dependent manner. Aging (Albany NY) 2013; 5: 682-691, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808700/.
  4. Lees H, Walters H, Cox LS. Animal and human models to understand ageing. Maturitas 2016; 93: 18-27, doi:https://doi.org/10.1016/j.maturitas.2016.06.008.
  5. Gillespie ZE, Pickering J, Eskiw CH. Better Living through Chemistry: Caloric Restriction (CR) and CR Mimetics Alter Genome Function to Promote Increased Health and Lifespan. Frontiers in Genetics 2016; 7: 142, doi:10.3389/fgene.2016.00142.
  6. Konings E, Timmers S, Boekschoten MV, Goossens GH, Jocken JW, Afman LA, et al. The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. International Journal of Obesity 2013; 38: 470, doi:10.1038/ijo.2013.155.
  7. Gómez-Zorita S, Fernández-Quintela A, Lasa A, Hijona E, Bujanda L, Portillo MP. Effects of resveratrol on obesity-related inflammation markers in adipose tissue of genetically obese rats. Nutrition 2013; 29: 1374-1380, doi:https://doi.org/10.1016/j.nut.2013.04.014.
  8. Gabandé-Rodríguez E, Gómez de Las Heras MM, Mittelbrunn M. Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria. Cells 2019; 9, doi:10.3390/cells9010082.
  9. Shintani T, Shintani H, Sato M, Ashida H. Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension. Geroscience 2023, doi:10.1007/s11357-023-00851-0.
  10. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutrition Research 2014; 34: 837-843, doi:10.1016/j.nutres.2014.09.005.
  11. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of clinical investigation 2001; 108: 1167-1174, doi:10.1172/jci13505.
  12. Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metabolism 2019; 29: 592-610, doi:https://doi.org/10.1016/j.cmet.2019.01.018.
  13. Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 2012; 22: 546-554, doi:10.1016/j.tcb.2012.07.004.
  14. Iside C, Scafuro M, Nebbioso A, Altucci L. SIRT1 Activation by Natural Phytochemicals: An Overview. Front Pharmacol 2020; 11: 1225, doi:10.3389/fphar.2020.01225.
  15. Pang L, Jiang X, Lian X, Chen J, Song E-F, Jin L-G, et al. Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences. Military Medical Research 2022; 9: 33, doi:10.1186/s40779-022-00389-w.
  16. Günther I, Rimbach G, Mack CI, Weinert CH, Danylec N, Lüersen K, et al. The Putative Caloric Restriction Mimetic Resveratrol has Moderate Impact on Insulin Sensitivity, Body Composition, and the Metabolome in Mice. Mol Nutr Food Res 2020; 64: e1901116, doi:10.1002/mnfr.201901116.
  17. Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: a review of clinical trials. npj Precision Oncology 2017; 1: 35, doi:10.1038/s41698-017-0038-6.
  18. Lee MS, Kim CT, Kim Y. Green tea (-)-epigallocatechin-3-gallate reduces body weight with regulation of multiple genes expression in adipose tissue of diet-induced obese mice. Annals of nutrition & metabolism 2009; 54: 151-157, doi:10.1159/000214834.
  19. Chacko SM, Thambi PT, Kuttan R, Nishigaki I. Beneficial effects of green tea: a literature review. Chin Med 2010; 5: 13, doi:10.1186/1749-8546-5-13.
  20. Vilella R, Izzo S, Naponelli V, Savi M, Bocchi L, Dallabona C, et al. In Vivo Treatment with a Standardized Green Tea Extract Restores Cardiomyocyte Contractility in Diabetic Rats by Improving Mitochondrial Function through SIRT1 Activation. Pharmaceuticals (Basel) 2022; 15, doi:10.3390/ph15111337.
  21. Lin Y, Shi D, Su B, Wei J, Găman MA, Sedanur Macit M, et al. The effect of green tea supplementation on obesity: A systematic review and dose-response meta-analysis of randomized controlled trials. Phytother Res 2020; 34: 2459-2470, doi:10.1002/ptr.6697.
  22. Iside C, Scafuro M, Nebbioso A, Altucci L. SIRT1 Activation by Natural Phytochemicals: An Overview [Review]. Frontiers in Pharmacology 2020; 11, doi:10.3389/fphar.2020.01225.
  23. Yessenkyzy A, Saliev T, Zhanaliyeva M, Masoud AR, Umbayev B, Sergazy S, et al. Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research. Nutrients 2020; 12, doi:10.3390/nu12051344.
  24. Di Pierro F, Khan A, Iqtadar S, Mumtaz SU, Chaudhry MNA, Bertuccioli A, et al. Quercetin as a possible complementary agent for early-stage COVID-19: Concluding results of a randomized clinical trial. Front Pharmacol 2022; 13: 1096853, doi:10.3389/fphar.2022.1096853.
  25. Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun 2008; 373: 545-549, doi:10.1016/j.bbrc.2008.06.077.
  26. Mousavi A, Vafa M, Neyestani T, Khamseh M, Hoseini F. The effects of green tea consumption on metabolic and anthropometric indices in patients with Type 2 diabetes. J Res Med Sci 2013; 18: 1080-1086.
  27. Gillespie ZE, Pickering J, Eskiw CH. Better Living through Chemistry: Caloric Restriction (CR) and CR Mimetics Alter Genome Function to Promote Increased Health and Lifespan. Front Genet 2016; 7: 142, doi:10.3389/fgene.2016.00142.
  28. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. Quercetin, Inflammation and Immunity. Nutrients 2016; 8: 167, doi:10.3390/nu8030167.
Zurück zum Blog

Hinterlasse einen Kommentar

Bitte beachte, dass Kommentare vor der Veröffentlichung freigegeben werden müssen.

Featured collection

  • Breaking the Aging Barrier: Marathons as an Anti-Aging Strategy

    Breaking the Aging Barrier: Marathons as an Ant...

    Does running marathons and long lifetime expectancy have any connection? As society continues to grapple with the challenges posed by an aging population, the quest for effective anti-aging strategies intensifies....

    Breaking the Aging Barrier: Marathons as an Ant...

    Does running marathons and long lifetime expectancy have any connection? As society continues to grapple with the challenges posed by an aging population, the quest for effective anti-aging strategies intensifies....

  • Finding  the Right Dose: How Much Collagen Do I Need?

    Finding the Right Dose: How Much Collagen Do I...

    Collagen, the most abundant protein in our bodies, plays a vital role in maintaining skin elasticity, joint health, and overall well-being. As collagen supplements gain popularity, the question arises: How much...

    Finding the Right Dose: How Much Collagen Do I...

    Collagen, the most abundant protein in our bodies, plays a vital role in maintaining skin elasticity, joint health, and overall well-being. As collagen supplements gain popularity, the question arises: How much...

  • Finding the Right Dose: How Much Quercetin Do I Need?

    Finding the Right Dose: How Much Quercetin Do I...

    Quercetin, a powerful antioxidant found in various fruits, vegetables, and supplements, has gained attention for its potential health benefits. However, determining the right dosage can be a challenge. In this article, we...

    Finding the Right Dose: How Much Quercetin Do I...

    Quercetin, a powerful antioxidant found in various fruits, vegetables, and supplements, has gained attention for its potential health benefits. However, determining the right dosage can be a challenge. In this article, we...

1 von 3