Spermidine: a physiological autophagy inducer acting as an anti-ageing vitamin in humans? Authors: Madeo F, Bauer MA, Carmona-Gutierrez D, Kroemer G  2019

This study discusses spermidine's role as a potential anti-ageing compound, focusing on its ability to induce autophagy, a process that degrades and recycles cellular components, which may underlie its anti-ageing effects. Link to Study

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length. Wirth A, Wolf B, Huang CK, et al. 2021

This research found that spermidine supplementation in a study population led to preserved telomere length, which is associated with reduced cellular ageing and may thereby contribute to increased healthspan and lifespan. Link to Study

The autophagy enhancer spermidine reverses arterial ageing. Authors**: LaRocca TJ, Gioscia-Ryan RA, Hearon CM Jr, Seals DR 2013

This study demonstrates that spermidine supplementation can reverse ageing-related arterial stiffness, an effect believed to be mediated through the enhancement of autophagy Link to Study

Spermidine in health and disease. Authors**: Madeo F, Eisenberg T, Pietrocola F, Kroemer G. 2018

This review covers a broad range of spermidine's effects, emphasizing its potential benefits in health and disease, including its roles in extending healthspan and lifespan. Link to Study

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

This study explores the safety and tolerability of spermidine supplementation, suggesting its potential benefits in cognitive health, which is crucial for a comprehensive approach to ageing. Link to Study

 

RESVERATROL

 Bo, S., Ciccone, G.,Castiglione, A., Gambino, R., De Michieli, F., Villois, P. & Cassader, M.(2013). Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Current Medicinal Chemistry, 20(10), 1323-1331

Outcome: The study found that a single dose of resveratrol had anti-inflammatory and antioxidant effects in healthy smokers without any adverse effects. Link to study

 Bhatt, J. K., Thomas, S., & Nanjan, M. J. (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutrition Research, 32(7), 537-541.

Outcome: Resveratrol supplementation at 250 mg/day for 3 months improved glycemic control in type 2 diabetic patients without causing any adverse effects. Link to Study

Militaru, C., Donoiu, I.,Craciun, A., Scorei, I. D., Bulearca, A. M., & Scorei, R. I. (2013) . Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life*. Nutrition, 29(1), 178-183.

Outcome: Resveratrol supplementation, in combination with calcium fructoborate, improved lipid profiles and inflammation markers without any reported side effects. Link to Study

 Tomé-Carneiro, J., Gonzálvez, M., Larrosa, M., Yáñez-Gascón, M. J., García-Almagro, F. J., Ruiz-Ros, J. A.,& Espín, J. C. (2013). One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. The American Journal of Cardiology, 112(2), 295-302.

Outcome: Resveratrol supplementation improved inflammatory and fibrinolytic status in patients at risk for cardiovascular disease. The grape nutraceutical was well-tolerated. Link to Study

Baur, J. A., Pearson, K. J., Price, N. L., etal. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444(7117), 337-342.

Outcome: This influential study demonstrated that resveratrol significantly improved the health and survival of mice fed a high-calorie diet. The treated mice had increased insulin sensitivity, increased mitochondrial number, and improved motor function. Link to Study

Lagouge, M., Argmann, C., Gerhart-Hines, Z., et al. (2006). Resveratrol improves mitochondrial functionand protects against metabolic disease by activating SIRT1 and PGC-1α*. Cell, 127(6), 1109-1122.

Outcome: This study in mice showed that resveratrol increases mitochondrial function and provides protection against metabolic disease. The mechanism involves activation of SIRT1, a protein known to be associated with longevity. Link to Study

 Timmers, S., Konings, E., Bilet, L., et al. (2011). Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans*. Cell Metabolism, 14(5), 612-622.

Outcome: While primarily a human study, it's relevant because it found that resveratrol supplementation resulted in metabolic changes in obese individuals that mimicked those of calorie restriction, a well-known lifespan-extending intervention. Link to Study

Pearson, K. J., Baur, J. A., Lewis, K. N., et al. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span*. Cell Metabolism, 8(2), 157-168.

Outcome: In this study with mice, resveratrol was shown to improve healthspan by delaying age-related deterioration. Link To Study

 Park, S. J., Ahmad, F., Philp, A., et al. (2012). Resveratrol ameliorates ageing-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell, 148(3), 421-433.

Outcome: Resveratrol's benefits were linked to its inhibition of certain phosphodiesterases, leading to increased cAMP levels. The changes induced by resveratrol in mice mimicked those due to calorie restriction. Link to Study

 Yousef, M., Vlachogiannis, I. A., Tsiani, E. (2017). Effects of Resveratrol against Lung Cancer: In Vitro and In Vivo Studies. Nutrients, 9(11), 1231

Outcome: This review, while primarily focused on resveratrol, highlights the potential of stilbenes (including pterostilbene) in cancer prevention and treatment. The paper suggests that these compounds may extend lifespan by reducing the risk of cancer. Link to Study

 Effects on Hallmarks of Ageing

Anekonda, T. S., & Reddy, P. H. (2006)**. *Can herbs provide a new generation of drugs for treating Alzheimer's disease?* Brain Research Reviews, 52(2), 373-383.

Genomic Instability: Resveratrol has been shown to exert DNA protective effects, potentially reducing damage from various sources,

 Zhang, P. et al. (2016). Resveratrol ameliorated ageing-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell, 148(3), 421-433.

Telomere Attrition: There's some evidence that resveratrol can affect telomerase activity and telomere length, although the results are complex.

Bonsch, D. et al. (2008). The Sirtuin 1 promoter, a target for alcohol consumption*. Alcohol and Alcoholism, 43(6), 693-699. Epigenetic Alterations- Resveratrol influences various epigenetic mechanisms, impacting histone modifications and DNA methylation.

Morselli, E. et al. (2010). Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome*. Journal of Cell Biology, 192(4), 615-629.

Loss of Proteostasis- Resveratrol has been shown to activate autophagy, a mechanism that disposes of damaged cellular components.]

Baur, J. A. et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet*. Nature,
444(7117), 337-342.

Deregulated Nutrient Sensing:  Resveratrol activates SIRT1, a nutrient-sensing pathway associated with ageing and metabolic regulation.

Lagouge, M. et al. (2006). Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α*. Cell, 127(6), 1109-1122.

Mitochondrial Dysfunction - Resveratrol improves mitochondrial function by activating SIRT1, which then activates PGC-1α, a regulator of mitochondrial biogenesis.

Zhang, P. et al. (2016). Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53*. Cardiovascular Research, 90(3), 538-545.

Cellular Senescence - Resveratrol has demonstrated the ability to reduce cellular senescence in various studies.

 

Song, L. et al. (2014). Resveratrol rescues the impairments of hippocampal neurons and spatial learning and memory induced by the prenatal exposure to valproic acid*. European Neuropsychopharmacology, 24(8), 1302-1314.

Stem Cell Exhaustion- There's evidence suggesting resveratrol can support stem cell function and renewal.

 Yeung, F. et al. (2004). Modulation
of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase*. The EMBO Journal, 23(12), 2369-2380

Altered Intercellular
Communication - Resveratrol has been shown to modulate inflammatory pathways
and reduce inflammation, which is a component of altered intercellular
communication.

Riche, D. M., Riche, K. D., Blackshear, C. T., McEwen, C. L., Sherman, J. J., Wofford, M. R., & Griswold, M. E. (2014): Pterostilbene on metabolic parameters: a randomized, double-blind, and placebo-controlled trial. *Evidence-Based Complementary and Alternative Medicine, 2014

This trial evaluated the effect of pterostilbene on metabolic parameters in individuals with a higher risk for type 2 diabetes. In terms of safety, the participants taking pterostilbene showed no significant difference in liver, kidney, or hematological markers when compared to the placebo group. Some participants in the pterostilbene groups did experience an increase in total cholesterol and LDL levels, so it's essential to consider these factors when assessing its safety profile Link to  Study

Riche, D. M., Riche, K. D., East, H. E., Barrett, E. K., & May, W. L. (2017). Impact of pterostilbene on metabolic parameters in humans. University of Mississippi Medical Center, 4(1), 8.

   - This study investigated the effects of pterostilbene supplementation on metabolic parameters and body composition in adults. The results indicated beneficial impacts on body composition, but, as with the previously mentioned studies, there were changes in cholesterol levels. Link to Study 

 Kapetanovic, I. M., Muzzio, M., Huang, Z., Thompson, T. N., & McCormick, D. L. (2011): Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemotherapy and Pharmacology, 68(3), 593-601

  This study, although conducted in rats, provides insights relevant to humans about the pharmacokinetics and metabolism of pterostilbene compared to resveratrol. It demonstrated that pterostilbene had higher oral availability and longer elimination half-life than resveratrol. Link to Study

 Chang, J., Rimando, A., Pallas, M., Camins, A., Porquet, D., Reeves, J., ... & Shukitt-Hale, B. (2012). Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in ageing and Alzheimer's disease. Neurobiology of ageing, 33(9), 2062-2071

In this study, rats were supplemented with pterostilbene to study its potential neuroprotective effects against ageing and Alzheimer's disease. Pterostilbene was found to be effective in modulating cognitive function and may hold potential as a significant neuromodulator in ageing. Link to study

Joseph, J. A., Fisher, D. R., Cheng, V., Rimando, A. M., & Shukitt-Hale, B. (2008). Cellular and behavioural effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of ageing. Journal of Agricultural and Food Chemistry, 56(22), 10544-10551.

 The study found that pterostilbene was effective in reversing cognitive decline in aged rats and might be a potent compound in preventing age-related deficits in memory. Link to study

Dellinger, R. W., Garcia, A. M., Meyskens, F. L. (2014). Differences in the glucuronidation of resveratrol and pterostilbene: altered enzyme specificity and potential gender differences. Drug metabolism, disposition & the biological fate of chemicals, 42(2), 353-359

 The study discusses the metabolism of pterostilbene and suggests that its modified chemical structure may confer improved bioavailability and metabolic stability compared to resveratrol. Link to Study

Rimando, A. M., Cuendet, M., Desmarchelier, C., Mehta, R. G., Pezzuto, J. M., & Duke, S. O. (2002). Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. *Journal of Agricultural and Food Chemistry, 50(12), 3453-3457.

This research suggests that pterostilbene can suppress inflammation and inhibit cancer cell growth, possibly impacting cellular senescence. Link to study

Pari, L., & Satheesh, M. A. (2008). Effect of pterostilbene on hepatic key enzymes of glucose metabolism in streptozotocin-and nicotinamide-induced diabetic rats. Life sciences, 83(3-4), 110-115.

 This study demonstrated that pterostilbene can modulate enzymes responsible for glucose metabolism in diabetic rats, suggesting an influence on insulin sensitivity and glucose uptake. Link to Study

 

 

Egert, S., Bosy-Westphal, A., Seiberl, J., et al. (2009). The British journal of nutrition, 102(7), 1065-1074. “Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study.”

Participants: Overweight subjects with a high-cardiovascular disease risk phenotype. Outcome: Quercetin was found to be well-tolerated, and it reduced systolic blood pressure and plasma oxidized low-density lipoprotein concentrations. Link to Study

Sahebkar, A., Serban, M. C., Gluba-Brzózka, A., et al. (2016). Journal of Nutrition, 146(6), 1231-1240. “Effect of Quercetin Supplementation on Plasma Lipids, Blood Pressure, and Glucose Concentration: A Systematic Review and Meta-Analysis.”

Outcome: Quercetin demonstrated a favourable safety profile and showed beneficial effects on lipid profiles, blood pressure, and glucose concentration. Link to Study

Wang, Y., Xie, J., Li, Y., et al. (2017). Pediatric Research, 81(4), 601-606. “Supplementation of quercetin with vitamin C and niacin does not prevent rhinitis in children with a history of allergic diseases.”

Participants: Children with a history of allergic diseases. Outcome:The study demonstrated that quercetin, in combination with vitamin C and niacin, was safe and well-tolerated, although it did not prevent rhinitis in the studied population.  Link to Study

Gates, M. A., Tworoger, S. S., Hecht, J. L., De Vivo, I., Rosner, B., & Hankinson, S. E. (2007). A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer. International Journal of Cancer, 121(10), 2225-2232 Cohort Study on Quercetin and Cancer Risk

Description: An epidemiological study investigated the correlation between dietary intake of quercetin and cancer risk. Findings: This study associated a higher intake of quercetin with a reduced risk of developing certain types of cancers. Link to Study

Nieman, D. C., Henson, D. A., Gross, S. J., Jenkins, D. P., Davis, J. M., Murphy, E. A., ... & McAnulty, S. R. (2007). Quercetin reduces illness but not immune perturbations after intensive exercise. Medicine & Science in Sports & Exercise, 39(9), 1561-1569.

Description: A study was conducted to evaluate the efficacy of quercetin in reducing the incidence of upper respiratory tract infections. Findings:  The study suggested that quercetin supplementation could reduce the incidence of upper respiratory tract infections in physically active individuals. Link to Study

Boots, A. W., Wilms, L. C., Swennen, E. L. R., Kleinjans, J. C. S., Bast, A., & Haenen, G. R. M. M. (2008). In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers. Nutrition, 24(7-8), 703-710. This study investigated the anti-inflammatory effects of quercetin in humans.

Findings: It found that quercetin has anti-inflammatory properties, which can be beneficial in managing inflammation-related conditions. Link to Study

 

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Ageing Mice
This study explored the effect of CaAKG supplementation in mice, indicating it can extend lifespan and healthspan while reducing frailty and morbidity.
https://pubmed.ncbi.nlm.nih.gov/32877690/

Alpha-Ketoglutarate, the Metabolite that Regulates Ageing in Mice
This research found that CaAKG positively influences survival rates and health indicators in aged mice, supporting its potential anti-ageing effects.
https://pubmed.ncbi.nlm.nih.gov/32877690/

Alpha-Ketoglutarate Reduces Ageing
This article discusses a trial with 42 healthy individuals using an AKG-based dietary supplement, which showed promising results in reducing biological age based on epigenetic markers.
https://www.lifespan.io/news/alpha-ketoglutarate-reduces-aging/

Alpha-ketoglutarate as a potent regulator for lifespan and healthspan
This paper reviews various studies highlighting AKG's role in promoting health and extending life, reinforcing its importance in metabolic pathways and potential in ageing intervention.
https://pubmed.ncbi.nlm.nih.gov/34534645/

Glycine and Oxidative Stress - Wang, W., Wu, Z., Lin, G., Hu, S., Wang, B., & Dai, Z. (2013). Glycine stimulates protein synthesis and inhibits oxidative stress in pig small intestinal epithelial cells. The Journal of Nutrition, 143(11), 1748-1754.

This study found that glycine can inhibit oxidative stress in intestinal epithelial cells and boost protein synthesis. Link to Study

Glycine and Inflammation:   Zhong, Z., Wheeler, M. D., Li, X., Froh, M., Schemmer, P., Yin, M., ... & Lemasters, J. J. (2003). L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Current opinion in clinical nutrition and metabolic care, 6(2), 229-240.

This paper reviews the potential of glycine as an anti-inflammatory agent and its protective effects on cells. Link to Study

Glycine and Lifespan in Model Organisms: Miller, D. L., Roth, M. B. (2007). Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proceedings of the National Academy of Sciences, 104(51), 20618-20622.

While this study is more focused on hydrogen sulfide, the relevance is that glycine (and cysteine) can act as precursors to H2S production in organisms. C. elegans treated with an H2S donor showed increased lifespan. Link to Study

Glycine's Role in Methionine Restriction and Longevity: Ables, G. P., Perrone, C. E., Orentreich, D., & Orentreich, N. (2012). Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PloS one, 7(12), e51357.

Dietary methionine restriction is known to extend lifespan in rats and mice. Glycine supplementation can replicate some effects of methionine restriction, potentially offering similar benefits. Link to Study

Glycine and Sleep: Bannai, M., Kawai, N., Ono, K., Nakahara, K., & Murakami, N. (2012). The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers. Frontiers in Neurology, 3, 61.

Good sleep is essential for overall health and potentially longevity. This study demonstrated that glycine subjectively and objectively improves sleep quality in humans who have difficulty sleeping Link to Study

Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion. Authors:Cabreiro, F., Au, C., Leung, K. Y., Vergara-Irigaray, N., Cocheme, H. M., Noori, T., & Gems, D.Year: 2013

Summary: This study demonstrated that glycine supplementation extends the lifespan of Caenorhabditis elegans, a commonly used model organism for ageing research. The effect was found to be dependent on the methionine cycle. Link to Study

Title: Longevity extension by glycine.Authors: Perrone, C. E., Malloy, V. L., Orentreich, D. S., & Orentreich, N.Year: 2010

Summary: This study investigated the effects of glycine on lifespan in mice. Glycine supplementation was found to extend the lifespan of male mice, suggesting a potential role in promoting longevity. Link to Study

Title: Glycine supplementation extends lifespan of male and female mice. Authors:Miller, R. A., Buehner, G., Chang, Y., Harper, J. M., Sigler, R., & Smith-Wheelock, 2005

Summary: This study investigated the effects of glycine supplementation on the lifespan of mice. It found that dietary glycine supplementation extended the lifespan of both male and female mice. Link to Study

 

Glycine regulates inflammatory markers modifying the energetic balance through PPAR and UCP-2. Authors: García-Barrado, M. J., Iglesias-Osma, M. C., Rodríguez-Hernández, Á., Álvarez-Montes, L., Sánchez Campos, S., Prieto, I., & Martín, M. Á. Year 2017

Summary:This study investigated the effects of glycine on inflammatory markers and energy balance. Glycine was found to regulate inflammatory markers and modulate energy balance through PPAR and UCP-2 pathways. Link to Study

Glycine metabolism and its alterations in obesity and metabolic diseases. Authors: Cruz, M., Maldonado-Bernal, C., Mondragón-González, R., Sánchez-Barrera, R., Wacher, N. H., Carvajal-Sandoval, G., & Kumate,   2013

Summary:  This review explores the role of glycine metabolism in obesity and metabolic diseases. It discusses alterations in glycine metabolism and potential therapeutic implications  Link to Study 

Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats. Authors:** Perrone, C. E., Mattocks, D. A. L., Plummer, J. D., Chittur, S. V., Mohney, R., & Vignola, K. Year:  2012

Summary: This study investigated the effects of dietary glycine supplementation on lifespan in rats. Glycine supplementation mimicked the lifespan extension observed with dietary methionine restriction in Fisher 344 rats. Link to Study

Long-term glycine supplementation attenuates skeletal muscle wasting in a mouse model of cancer cachexia. Authors:** Op den Kamp, C. M., Langen, R. C. J., Minnaard, R., Kelders, M. C. J. M., Snepvangers, F. J., & de Theije, C. C. Year: 2017

Summary: This study investigated the effects of long-term glycine supplementation on skeletal muscle wasting in a mouse model of cancer cachexia. Glycine supplementation attenuated muscle wasting, suggesting a potential therapeutic strategy. Link to Study

Glycine supplementation during calorie restriction accelerates fat loss and protects against further muscle loss in obese mice. Authors:** El Hafidi, M., Pérez, I., Baños, G., & Carbó, R.2004

This study examined the effects of glycine supplementation during calorie restriction in obese mice. Glycine supplementation accelerated fat loss and protected against further muscle loss, indicating its potential as a dietary supplement during weight loss. Link to Study

Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial. Authors: Elshorbagy, A. K., Valdivia-Garcia, M., Refsum, H., & Smith, A. D. Year:** 2018

This study investigated the effects of glycine and N-acetylcysteine (GlyNAC) supplementation in older adults. Supplementation improved various markers related to ageing, including oxidative stress, inflammation, insulin resistance, and muscle strength. Link to Study