Table 1. Overview of supplements claimed for longevity

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a natural lipophilic molecule, needed in many enzymatic reactions in live organisms. In humans and other mammals, it is mainly localized within the mitochondria, where its main role is the transport of electrons through the electron transport chain which produces energy (1).

CoQ10 is chemically composed of two parts, one benzoquinone ring, and a longer polyisoprenoid lipid chain. CoQ10 serves as an antioxidant that reduces reactive oxygen species that can cause damage in mitochondria and in the rest of the cell. The less oxidative damage there is in the cell, the possibility of disease development is lower. Therefore, the main idea behind CoQ10 and longevity is the indirect connection between life prolongation because of less overall cell damage. The damage that represents the biggest problem would be DNA damage, which CoQ10 successfully prevents, even though the mechanism of how it’s done remains unclear (2).

So far, CoQ10 has been tested as a damage-preventative and anti-aging supplement many times. Studies done on model organisms such as yeast, worms, and rodents, showed that CoQ10 supplementation increased resistance against oxidative damage and extended lifespan in correlation. Several studies on mice also showed that the levels of CoQ proteins decrease with aging and that CoQ10 supplementation was able to increase its levels in plasma, liver, heart, kidney, and skeletal muscle (1). Moreover, in rodents, CoQ10 supplementation (up to 12 mg/kg body weight) showed no long-term accumulation in those tissues or interference with the normal biological production of CoQ10. This was also proven for human patients, which tolerated up to 3000 mg/day, even though the suggested dose is up to 1200 mg (3). Some studies did report mild nausea and gastrointestinal troubles after taking the supplement. 

Several studies on the effect of CoQ10 supplementation in human trials have discovered the following:

• 1200 mg of CoQ10 per day has reduced oxidative damage markers in 65 patients undergoing hemodialysis (4),
• CoQ10 can enhance and improve sperm count and motility, and improve male fertility, which also declines in aging (5),
• CoQ10 can improve diabetic and obesity markers (6, 7),
• Supplementation with CoQ10 and selenium combined can improve health span and cardiovascular mortality in the elderly (8).

So far, human studies show CoQ10 supplementation might improve longevity by improving the overall health of patients suffering from diabetes, obesity, and cardiovascular diseases. Fertility might also be improved, which prolongs life through generations. 

Literature:

1. Díaz-Casado ME, Quiles JL, Barriocanal-Casado E, González-García P, Battino M, López LC, Varela-López A. The Paradox of Coenzyme Q10 in Aging. Nutrients. 2019 Sep 14;11(9):2221. doi: 10.3390/nu11092221. 
2. Tomasetti M, Alleva R, Borghi B, Collins AR. In vivo supplementation with coenzyme Q10 enhances the recovery of human lymphocytes from oxidative DNA damage. FASEB J. 2001 Jun;15(8):1425-7. doi: 10.1096/fj.00-0694fje. 
3. Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors. 2008;32(1-4):199-208. doi: 10.1002/biof.5520320124.
4.  Rivara MB, Yeung CK, Robinson-Cohen C, Phillips BR, Ruzinski J, Rock D, Linke L, Shen DD, Ikizler TA, Himmelfarb J. Effect of Coenzyme Q10 on Biomarkers of Oxidative Stress and Cardiac Function in Hemodialysis Patients: The CoQ10 Biomarker Trial. Am J Kidney Dis. 2017 Mar;69(3):389-399. doi: 10.1053/j.ajkd.2016.08.041. 
5. Salas-Huetos A, Rosique-Esteban N, Becerra-Tomás N, Vizmanos B, Bulló M, Salas-Salvadó J. The Effect of Nutrients and Dietary Supplements on Sperm Quality Parameters: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Adv Nutr. 2018 Nov 1;9(6):833-848. doi: 10.1093/advances/nmy057.
6. Moradi M, Haghighatdoost F, Feizi A, Larijani B, Azadbakht L. Effect of Coenzyme Q10 Supplementation on Diabetes Biomarkers: a Systematic Review and Meta-analysis of Randomized Controlled Clinical Trials. Arch Iran Med. 2016 Aug;19(8):588-96. PMID: 27544369.
7. Raygan F, Rezavandi Z, Dadkhah Tehrani S, Farrokhian A, Asemi Z. The effects of coenzyme Q10 administration on glucose homeostasis parameters, lipid profiles, biomarkers of inflammation and oxidative stress in patients with metabolic syndrome. Eur J Nutr. 2016 Dec;55(8):2357-2364. doi: 10.1007/s00394-015-1042-7. 
8. Johansson P, Dahlström Ö, Dahlström U, Alehagen U. Improved Health-Related Quality of Life, and More Days out of Hospital with Supplementation with Selenium and Coenzyme Q10 Combined. Results from a Double-Blind, Placebo-Controlled Prospective Study. J Nutr Health Aging. 2015 Nov;19(9):870-7. doi: 10.1007/s12603-015-0509-9.

Alpha-Lipoic acid / R-Lipoic acid

Alpha or R-lipoic acid is a metabolite naturally produced by mitochondria in our cells, but of course, in small quantities. Physiologically, it is soluble in both lipid and water environments, and it functions as an antioxidant. By catching and neutralizing reactive oxygen species, R-lipoic acid protects the body from their harmful actions, like damaging the DNA or destabilizing signaling molecules. Alpha-lipoic acid also regenerates vitamins C and E, which are important antioxidants too (1). 

R-lipoic acid has recently become very popular as a dietary supplement that can help improve health and prolong lifespan. Research performed on human patients does show R-lipoic acid shows excellent potential and good results in the following areas:

• Diabetes - alpha-lipoic acid can help alleviate typical symptoms and consequences of diabetes, such as impaired vision, where 300 mg of alpha-lipoic acid supplementation helped after 3 months of administration (2)
• Alzheimer’s disease - taking 600 mg of alpha-lipoic acid over the course of a year slowed down Alzheimer’s progression in 48 patients (3),
• weight loss - human trials showed alpha-lipoic acid can slightly improve weight loss (1.6 kg loss after 1200 mg supplementation for a couple of weeks) (4),
• metabolic syndrome - a number of studies done on human subjects showed supplementation with R-lipoic acid can decrease the levels of fasting glucose, triglycerides, and insulin resistance (5, 6),
• skincare - applying creams that contain alpha-lipoic acid provided UV protection and reduced the appearance of aging skin in human trials (7).

Generally, the maximum dose of R-lipoic acid a human body can take well is 2400 mg (6), but the average amounts supplemented daily were between 300-600 mg per day. In some cases, people who took R-lipoic acid were slightly nauseous or developed a rash. Studies did not show an increased amount of R-lipoic acid supplementation exhibited more positive effects. The correct dose for a specific purpose should be determined by a healthcare provider. 

Literature:

1. Nguyen, H., Gupta, V. (2022) Alpha-Lipoic Acid. StatPearls. Treasure Island (FL): StatPearls Publishing. 
2. Gębka A, Serkies-Minuth E, Raczyńska D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators Inflamm. 2014;2014:131538. doi: 10.1155/2014/131538.
3. Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1463-70. doi: 10.1016/j.addr.2008.04.015.
4. Namazi N, Larijani B, Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr. 2018 Apr;37(2):419-428. doi: 10.1016/j.clnu.2017.06.002.
5. Akbari M, Ostadmohammadi V, Lankarani KB, Tabrizi R, Kolahdooz F, Khatibi SR, Asemi Z. The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials. Metabolism. 2018 Oct;87:56-69. doi: 10.1016/j.metabol.2018.07.002. 
6. Mendoza-Núñez VM, García-Martínez BI, Rosado-Pérez J, Santiago-Osorio E, Pedraza-Chaverri J, Hernández-Abad VJ. The Effect of 600 mg Alpha-lipoic Acid Supplementation on Oxidative Stress, Inflammation, and RAGE in Older Adults with Type 2 Diabetes Mellitus. Oxid Med Cell Longev. 2019 Jun 12;2019:3276958. doi: 10.1155/2019/3276958.
7. Cremer DR, Rabeler R, Roberts A, Lynch B. Safety evaluation of alpha-lipoic acid (ALA). Regul Toxicol Pharmacol. 2006 Oct;46(1):29-41. doi: 10.1016/j.yrtph.2006.06.004. 

Trimethylglycine (Betaine)

Betaine or trimethylglycine (TMG) is a natural compound produced by our bodies. It is also present in plants (like beets), animals, and microorganisms. Chemically, it has a glycine base with three methyl groups attached. TMG is an important metabolite in our cells, which takes part in DNA methylation by donating its methyl groups and converting homocysteine to methionine (1).

As a supplement, TMG has shown positive results in the following areas (human studies):

• lowers levels of homocysteine in healthy people (2),
• decreases insulin resistance and prevents the development of diabetes (3).

Most studies done on humans have tested up to 10 or 15 grams of TMG daily and found it safe, with possible milder side effects. Taking higher doses of TMG (10 g daily) will result in some gastrointestinal side effects, such as:

• nausea,
• vomiting,
• diarrhea,
• cramping. 

In rare cases, taking higher doses of TMG can result in fluid build-up around the brain, which can cause cerebral edema (4).

People who take NMN as a supplement sometimes also take TMG, because high production of NAD+ from NMN can exhaust methyl groups in the cells. Therefore, TMG taken additionally can provide replacement of those methyl groups. 

Literature:

1. Arumugam MK, Paal MC, Donohue TM Jr, Ganesan M, Osna NA, Kharbanda KK. Beneficial Effects of Betaine: A Comprehensive Review. Biology (Basel). 2021 May 22;10(6):456. doi: 10.3390/biology10060456.
2. McRae MP. Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis. J Chiropr Med. 2013 Mar;12(1):20-5. doi: 10.1016/j.jcm.2012.11.001.
3. Gao X, Wang Y, Sun G. High dietary choline and betaine intake is associated with low insulin resistance in the Newfoundland population. Nutrition. 2017 Jan;33:28-34. doi: 10.1016/j.nut.2016.08.005.
4. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Betaine.

Spermidine

Spermidine is a fairly new supplement that quickly became famous for its apparent ability to prolong the human lifespan. It is a naturally produced amide compound present in all living organisms but in small concentrations, which continue to deplete even further as we age. Research showed that people who live over a hundred years present with spermidine concentrations similar to those of young healthy people. 

The role of spermidine in the physiological processes in our bodies is complex. It is involved in DNA and RNA stabilization, cell growth and division, and regulation of gene expression. One of the most important processes it plays a role in is autophagy, a controlled process in which a body removes old and damaged cells or cell parts, or reuses them for other purposes, making less way for disease development or complete degradation (1). This could possibly be one of the ways in which spermidine reverses aging in humans, even though that hasn’t been cleared yet. 

So far, research done on human subjects shows that daily supplementation of spermidine helps improve longevity. One trial performed on 829 participants (ages 45-84), with a 13-year-later follow-up study, showed that nutrition rich in spermidine improved longevity among participants. However, in this study, the exact concentration of spermidine was not tested in the laboratory (2). 

A study done on 30 participants, ages 60 to 80, showed a daily intake of 1.2 mg of spermidine over a period of 3 months had no adverse effects, was well tolerated, and was overall safe (3). 

Literature:

1. Madeo F, Bauer MA, Carmona-Gutierrez D, Kroemer G. Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? Autophagy. 2019 Jan;15(1):165-168. doi: 10.1080/15548627.2018.1530929.
2. Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, Werner P, Ruckenstuhl C, Iglseder B, Weger S, Mairhofer B, Gartner M, Kedenko L, Chmelikova M, Stekovic S, Stuppner H, Oberhollenzer F, Kroemer G, Mayr M, Eisenberg T, Tilg H, Madeo F, Willeit J. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018 Aug 1;108(2):371-380. doi: 10.1093/ajcn/nqy102.
3. Schwarz C, Stekovic S, Wirth M, Benson G, Royer P, Sigrist SJ, Pieber T, Dammbrueck C, Magnes C, Eisenberg T, Pendl T, Bohlken J, Köbe T, Madeo F, Flöel A. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging (Albany NY). 2018 Jan 8;10(1):19-33. doi: 10.18632/aging.101354.

Apigenin

Apigenin is a flavone compound naturally found in plants like parsley, chamomile, and celery. It is one of the most known and potent antioxidants which we can only consume in small amounts through food. For that reason, apigenin became a popular dietary supplement with many potential health uses. Unfortunately, apigenin is hardly soluble in water environments, so its application needs to be through nanobodies, liposomes, or micelles (1).

Clinical studies performed on human subjects showed that apigenin:

• improves cognitive function of Alzheimer’s patients after a year of double daily application (unknown dosage, only abstract available in English) (2),
• improves daytime functioning and insomnia (270 mg of chamomile tablets supplementation) (3),
• reduced anxiety and depression symptoms (500 mg of chamomile extract that contains apigenin 3x a day) (4),
• reduces the need for analgesics for knee osteoarthritis (applying apigenin-rich chamomile oil to knees 3x a day for 3 weeks) (5).

Other studies that were performed on animal models, like mice and rats, showed great potential in the application against diabetes, obesity, and cancer. Several studies done on mice also showed the application of apigenin can prolong the lifespan, by inhibiting the activity of an enzyme called CD38. Mice that had less expression of CD38 lived longer than their counterparts and were more resistant to high-fat diets (6).

CD38 uses NAD+, a molecule critical for proper cell functioning and energy synthesis, which gets more and more depleted as we get older. CD38 also uses more of the NAD+ as we get older as well. Therefore, by inhibiting its function, apigenin could ensure there is enough NAD+ left in the cell for other crucial processes, like supplying energy and stopping mitochondrial dysfunction. This effect, however, was not tested on humans yet. 

Regarding dosage, there are also not enough data, especially for pure apigenin. It was mostly administered through chamomile extract, which is rich in apigenin. Dried chamomile contains approximately 3.5 mg of apigenin per gram of dried chamomile flowers (7). In the studies mentioned above, all subjects tolerated apigenin/chamomile extract/oil well, with no adverse effects. 

Literature:

1. Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, Lucarini M, Santini A, Souto EB, Novellino E, Antolak H, Azzini E, Setzer WN, Martins N. The Therapeutic Potential of Apigenin. Int J Mol Sci. 2019 Mar 15;20(6):1305. doi: 10.3390/ijms20061305.
2. de Font-Réaulx Rojas E, Dorazco-Barragan G. Estabilización clínica en enfermedades neurodegenerativas: estudio clínico en fase II [Clinical stabilisation in neurodegenerative diseases: clinical study in phase II]. Rev Neurol. 2010 May 1;50(9):520-8. Spanish. PMID: 20443170.
3. Zick SM, Wright BD, Sen A, Arnedt JT. Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: a randomized placebo-controlled pilot study. BMC Complement Altern Med. 2011 Sep 22;11:78. doi: 10.1186/1472-6882-11-78.
4. Amsterdam JD, Shults J, Soeller I, Mao JJ, Rockwell K, Newberg AB. Chamomile (Matricaria recutita) may provide antidepressant activity in anxious, depressed humans: an exploratory study. Altern Ther Health Med. 2012 Sep-Oct;18(5):44-9. PMID: 22894890.
5. Shoara R, Hashempur MH, Ashraf A, Salehi A, Dehshahri S, Habibagahi Z. Efficacy and safety of topical Matricaria chamomilla L. (chamomile) oil for knee osteoarthritis: A randomized controlled clinical trial. Complement Ther Clin Pract. 2015 Aug;21(3):181-7. doi: 10.1016/j.ctcp.2015.06.003.
6. Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, O'Neil L, White TA, Sinclair DA, Chini EN. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes. 2013 Apr;62(4):1084-93. doi: 10.2337/db12-1139.
7. Shankar E, Goel A, Gupta K, Gupta S. Plant flavone apigenin: An emerging anticancer agent. Curr Pharmacol Rep. 2017 Dec;3(6):423-446. doi: 10.1007/s40495-017-0113-2.