Modern Experimental  Longevity Supplements

# 1 Metformin

Metformin is a common and often effective medication for type 2 diabetes, but has recently become of interest to scientists studying aging. It may have anti-aging properties but the scientific evidence that it extends lifespan in humans is not conclusive. It is also known to have side effects which can include abdominal pain, bloating, diarrhea, nausea and vomiting.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: B+

Cost: Reasonable

References

• Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol (Lausanne). 2021 Aug 5;12:718942. doi: 10.3389/fendo.2021.718942. PMID: 34421827; PMCID: PMC8374068.
• Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair and Mathew LaPlante, ‎Atria Books; Illustrated edition 2019

# 2 EGCG and L-theanine

EGCG (epigallocatechin gallate) and L-theanine are natural antioxidants that are present in green tea. Research has shown anti-cancer, anti-obesity, anti-diabetes, anti-inflammatory, as well as neuroprotective effects, and benefits such as improving cardiovascular health and protecting against diabetes. The most obvious way to take these supplements is by drinking green tea.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: B+

Cost: Reasonable

References

• Pervin M, Unno K, Takagaki A, Isemura M, Nakamura Y. Function of Green Tea Catechins in the Brain: Epigallocatechin Gallate and its Metabolites. Int J Mol Sci. 2019 Jul 25;20(15):3630. doi: 10.3390/ijms20153630. PMID: 31349535; PMCID: PMC6696481.

# 3 Omega-3s

Omega-3 fatty acids have been studied extensively with conflicting results. Recent reviews have attributed these discrepancies to a number of factors, including dose. Omega-3s are currently believed to offer anti-aging benefits such as reducing chronic inflammation, and a lowered risk for heart attack and death from coronary heart disease.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: B

Cost: Reasonable

References

• DiNicolantonio JJ, O’Keefe JH. The Importance of Marine Omega-3s for Brain Development and the Prevention and Treatment of Behavior, Mood, and Other Brain Disorders. Nutrients. 2020 Aug 4;12(8):2333. doi: 10.3390/nu12082333. PMID: 32759851; PMCID: PMC7468918.
• Bischoff-Ferrari HA, Vellas B, Rizzoli R, Kressig RW, da Silva JAP, Blauth M, Felson DT, McCloskey EV, Watzl B, Hofbauer LC, Felsenberg D, Willett WC, Dawson-Hughes B, Manson JE, Siebert U, Theiler R, Staehelin HB, de Godoi Rezende Costa Molino C, Chocano-Bedoya PO, Abderhalden LA, Egli A, Kanis JA, Orav EJ; DO-HEALTH Research Group. Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial. JAMA. 2020 Nov 10;324(18):1855-1868. doi: 10.1001/jama.2020.16909. PMID: 33170239; PMCID: PMC7656284.
• Rauch, B.; Schiele, R.; Schneider, S.; Diller, F.; Victor, N.; Gohlke, H.; Gottwik, M.; Steinbeck, G.; Del Castillo, U.; Sack, R.; et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010, 122, 2152–2159.
• Mccarty, M.F.; DiNicolantonio, J.J.; Lavie, C.J.; O’Keefe, J.H. Omega-3 and prostate cancer: Examining the pertinent evidence. Mayo Clin. Proc. 2014, 89, 444–450.
• DiNicolantonio, J.J.; Mccarty, M.F.; Lavie, C.J.; O’Keefe, J.H. Do omega-3 fatty acids cause prostate cancer? MO Med. 2013,110, 293–294.
• Hu Y, Hu FB, Manson JE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J Am Heart Assoc. 2019 Oct;8(19):e013543. doi: 10.1161/JAHA.119.013543. Epub 2019 Sep 30. PMID: 31567003; PMCID: PMC6806028.

# 4 Curcumin

Curcumin (diferuloylmethane) is both modern and ancient. It is the active ingredient in the Ayurvedic herb turmeric. Research on curcumin is more extensive than on almost any other natural product. Studies on curcumin have also shown it affects the expression of SIRT1 protein, suggesting a positive role in the treatment of diabetes, heart disease, and aging. While numerous benefits in animals have been verified in thousands of published papers, human studies are limited by the bioavailability of this active ingredient. A 2017 study points out that no double-blind, placebo controlled clinical trials of curcumin have ever been successful. It further states that when curcumin is isolated, it is unstable, reactive, and difficult to assimilate in humans. Is isolating an active ingredient, the best approach when there could be other beneficial substances in turmeric that could interact synergistically to enhance its absorption and overall effects?

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C-

Cost: Reasonable

References

• Tomeh MA, Hadianamrei R, Zhao X. A Review of Curcumin and Its Derivatives as Anticancer Agents. Int J Mol Sci. 2019 Feb 27;20(5):1033. doi: 10.3390/ijms20051033. PMID: 30818786; PMCID: PMC6429287.
• Salehi B, Stojanović-Radić Z, Matejić J, Sharifi-Rad M, Anil Kumar NV, Martins N, Sharifi-Rad J. The therapeutic potential of curcumin: A review of clinical trials. Eur J Med Chem. 2019 Feb 1;163:527-545. doi: 10.1016/j.ejmech.2018.12.016. Epub 2018 Dec 7. PMID: 30553144.
• Lang A, Salomon N, Wu JC, Kopylov U, Lahat A, Har‑Noy O, et al. Curcumin in combination with mesalamine induces remission in patients with mild‑to‑moderate ulcerative colitis in a randomized controlled trial. Clin Gastroenterol Hepatol 2015;13:1444‑9.e1.
• Sudheeran SP, Jacob D, Mulakal JN, Nair GG, Maliakel A, Maliakel B, et al. Safety, tolerance, and enhanced efficacy of a bioavailable formulation of curcumin with fenugreek dietary fiber on occupational stress a randomized, double‑blind, placebo‑controlled pilot study. J Clin Psychopharmacol 2016;36:236‑43.
• Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti‑inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic Int J Biochem Cell Biol 2009;41:40‑59.
• Venigalla M, Sonego S, Gyengesi E, Sharman MJ, Münch G. Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer’s disease. Neurochem Int 2016;95:63‑74.
• Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. The Essential Medicinal Chemistry of Curcumin. J Med Chem. 2017 Mar 9;60(5):1620-1637. doi: 10.1021/acs.jmedchem.6b00975. Epub 2017 Jan 11. PMID: 28074653; PMCID: PMC5346970.

# 5 Resveratrol

Resveratrol, derived from grape skins, stimulates the SIRT1 protein. As it is present in red wine, experts have suggested that this is what explains the so called “French Paradox,” referring to the low incidence of heart attacks in the French population despite their high per capita consumption of saturated fats in butter and meats.

Studies have shown that the combination of resveratrol and caloric restriction can markedly extend the lifespan of animals. But resveratrol is not assimilated very well in humans and, like many other anti-aging substances it isn’t always effective. A much higher dose would have to be consumed (the equivalent of many bottles of wine).

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C-

Cost: Reasonable

References

• Li J, Zhang CX, Liu YM, Chen KL, Chen G. A comparative study of anti-aging properties and mechanism: resveratrol and caloric restriction. Oncotarget. 2017 Aug 9;8(39):65717-65729. doi: 10.18632/oncotarget.20084. PMID: 29029466; PMCID: PMC5630366.
• Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair and Mathew LaPlante, ‎Atria Books; Illustrated edition 2019

# 6 Quercetin

Another possible anti-aging candidate with many potential uses, is quercetin, a plant flavonoid found in fruits and vegetables. Quercetin has been observed to increase SIRT1 activity by five times, and is found to act as a senolytic, a compound that can eliminate old or senescent cells whose presence adversely affects other cells and actually accelerates the aging process. Again, however, its therapeutic value is reduced by its limited ability to reach body tissues.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C-

Cost: Reasonable

References

• Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016 Dec 29;5:e47. doi: 10.1017/jns.2016.41. PMID: 28620474; PMCID: PMC5465813.
• Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008 May 13;585(2-3):325-37. doi: 10.1016/j.ejphar.2008.03.008. Epub 2008 Mar 18. PMID: 18417116.
• Bischoff SC. Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):733-40. doi: 10.1097/MCO.0b013e32831394b8. PMID: 18827577.
• Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair and Mathew LaPlante, ‎Atria Books; Illustrated edition 2019

# 7 Rapamycin

In an expedition to Easter Island, which collected soil samples among the large standing stones, a bacteria was found that produced an antifungal compound. This later resulted in the development of the drug rapamycin, which is now an important immune suppressant used in cancer treatment and organ transplant. It was named to acknowledge its discovery on Easter Island, originally known by the Polynesian name Rapa Nui. It is an effective drug but as an anti-aging supplement its uses may be limited because of its many side-effects. There is research showing benefical effects on aging skin.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C-

Cost: High

References

• Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY). 2019;11(19):8048-8067. doi:10.18632/aging.102355
• Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair and Mathew LaPlante, ‎Atria Books; Illustrated edition 2019
• Blagosklonny MV. Rapamycin for the aging skin. Aging (Albany NY). 2019 Dec 27;11(24):12822-12826. doi: 10.18632/aging.102664. Epub 2019 Dec 27. PMID: 31895693; PMCID: PMC6949048

# 8 Fisetin

Fisetin is an anti-oxidant bioactive flavonoid compound found in fruits and vegetables that acts as a senolytic, killing senescent cells. Animal studies suggest that it may reduce the number of senescent cells in tissues, extend life span, and improving cognitive and behavior performance.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C

Cost: Reasonable

References

• Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PMID: 30279143; PMCID: PMC6197652.
• Das J, Singh R, Ladol S, Nayak SK, Sharma D. Fisetin prevents the aging-associated decline in relative spectral power of α, β and linked MUA in the cortex and behavioral alterations. Exp Gerontol. 2020 Sep;138:111006. doi: 10.1016/j.exger.2020.111006. Epub 2020 Jun 24. PMID: 32592831.
• Kashyap D, Garg VK, Tuli HS, Yerer MB, Sak K, Sharma AK, Kumar M, Aggarwal V, Sandhu SS. Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules. 2019 May 6;9(5):174. doi: 10.3390/biom9050174. PMID: 31064104; PMCID: PMC6572624.

# 9 NAD+

The longevity supplement NAD+, or nicotinamide adenine dinucleotide, is known to energize the sirtuin pathway and boost the activity of all 7 sirtuin proteins (SIRT1 through SIRT7). It is involved in metabolic processes, including energy production, DNA repair, and gene expression. With age, NAD+ levels decline. The reasoning for its use as a longevity supplement is to create more NAD+ in the body that could be beneficial to promote healthier aging. To do this supplements often contain precursor compounds such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) that help synthesize more NAD+. There have been many studies in animals showing beneficial effects. Clinical trials have shown its safety and the effectiveness of precursor vitamin, nicotinamide riboside (NR), in stimulating NAD+ metabolism in healthy middle-aged and older adults, with some of the studies showing no effects for certain conditions such as abnormal pancreatic function. Further human studies are eagerly awaited.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C-

Cost: High

References

• Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair and Mathew LaPlante, ‎Atria Books; Illustrated edition 2019
• Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD⁺ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7. PMID: 29599478; PMCID: PMC5876407.
• Dollerup OL, Trammell SAJ, Hartmann B, Holst JJ, Christensen B, Møller N, Gillum MP, Treebak JT, Jessen N. Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity. J Clin Endocrinol Metab. 2019 Nov 1;104(11):5703-5714. doi: 10.1210/jc.2019-01081. PMID: 31390002
• Wang K, Liu H, Hu Q, Wang L, Liu J, Zheng Z, Zhang W, Ren J, Zhu F, Liu GH. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct Target Ther. 2022 Nov 7;7(1):374. doi: 10.1038/s41392-022-01211-8. PMID: 36336680; PMCID: PMC9637765.

# 10 CoQ10

CoQ10 is an antioxidant produced naturally by your body, which declines with age. It is involved in the growth and maintenance of cells, and has been suggested to help with congestive heart failure and a variety of other conditions. Supplements are often made with ubiquinone, an already-oxidized form of CoQ10 that is difficult for your body to absorb. Other formulations are attempting to improve bioavailability.

Scientific Evidence in Animals: A

Scientific Evidence in Humans: C-

Cost: Reasonable

References

• Pravst I, Rodríguez Aguilera JC, Cortes Rodriguez AB, Jazbar J, Locatelli I, Hristov H, Žmitek K. Comparative Bioavailability of Different Coenzyme Q10 Formulations in Healthy Elderly Individuals. Nutrients. 2020 Mar 16;12(3):784. doi: 10.3390/nu12030784. PMID: 32188111; PMCID: PMC7146408.