Best Age-Defying Supplements. A Successful Boost to Your Healthy Aging Routine

By Dr. J.E. Williams | 12th April 2023 | Reading Time: 6 minutes

Based on over forty years of clinical practice, I can attest that optimizing nutrition with supplements promotes health and helps slow aging. Recent research suggests age reversal of ten years is possible. But successful aging requires supplementing with specialized age-defying supplements in addition to your daily health-supportive nutrients. 

What to look for when buying age-defying supplements 

An online search provides many options for anti-aging drugs and supplements. However, many products are overly marketed to increase sales. So, it’s good to have an independent guide. Here’s what to look for and some things to avoid: 

• An expert recommendation. Remember, supplement companies often hire doctors or scientists to endorse their products. However, in our age of over-hyped marketing, it’s hard to tell if they have your best interests in mind. Avoid endorsements on paid ads. Look for independent recommendations by a licensed healthcare professional.
• Third-party verification. To ensure the supplement contains what the label claims it provides, look for “GMP” or “USP” on the label. Another reliable resource is ConsumerLab.com, a non-biased, independent testing organization providing reviews of supplements and healthy foods. Avoid unverified claims. 
• Look at the science. What do researchers say in scholarly articles about the main compound in the supplement? Use PubMed or Google Scholar to conduct your online research. Read the abstract and discussion. Avoid misrepresentation by online articles claiming to be scientific.   

The top 6 age-defying supplements in 2023

1. Fisetin 1,500 mg of standard fisetin, or 44.5 mg of bio-fisetin
2. Spermidine 800 mg
3. Oxalocetate 400-800 mg, maximum 1,000 mg 
4. Urolithin A 500 mg
5. Nicotinamide mononucleotide (NMN) 250-500 mg 
6. Crocin 30-60 mg

1. Fisetin

Fisetin is a flavonoid that naturally occurs in strawberries and apples. Researchers found it can improve memory, restore skin health by protecting collagen, and it removes dysfunctional aging cells. It has cancer-preventative effects and protects the brain from degenerative processes. It is considered the most powerful senolytic supplement. Senolytics are molecules that can selectively destroy senescent cells to promote healthy aging. Taking fisetin can reduce the impact of aging. Earlier fisetin supplements required 1,500 mg daily. But newer, bioavailable forms are more absorbable. Take 44.5 mg of bio-fisetin 2-3 times daily.

2. Spermidine

Spermidine may slow aging by stimulating autophagy, a process when the body removes diseased, dead, or aging cells. This assures that the body only has healthy cells. Spermidine supports mitochondria health, assures DNA stability, and manages cell proliferation to help prevent cancer. It is naturally found in soy, green tea, broccoli, and red grapefruit. And it’s particularly high in wheat germ. Human endogenous spermidine levels decline with aging. Researchers found that it is possible to counteract age-associated spermidine deficiency by eating spermidine-rich foods, supplementing with probiotics, and taking a spermidine supplement. Take 800 mg of spermidine from wheat germ extract daily. Those with gluten sensitivity may not tolerate wheat germ extract. 

3. Oxaloacetate

Oxaloacetate is the newest of this group of anti-aging supplements. It’s an antioxidant with mitochondrial DNA protective effects. Though it looks interesting, research evidence is just starting to come in. And it’s been used for ME/CFS patients with reduced oxaloacetate levels. It appears to be without side effects, but safety studies are lacking. Take 200-400 mg daily with a maximum of 800 mg. The study for ME/CFS used 1,000 mg per day, citing impressive improvement in both physical and mental fatigue. It may also have use for Long COVID patients.

4. Urolithin A

Urolithin A is made in the gut from probiotic activity with ellagitannins, bioactive polyphenols from seeds and nuts, tea, and pomegranate. As a supplement, Urolithin A is derived from pomegranate. Urolithin can improve muscle endurance and mitochondrial health during aging. Take 500 mg daily.

5. Nicotinamide mononucleotide (NMN)

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme required by cells to sustain energy production for tissue repair and immune defense. Like the other anti-aging supplements, it plays a role in optimal mitochondrial function. Healthy aging requires a sufficient supply of NAD+. The body makes NAD+ from niacin, niacinamide, and nicotinamide riboside (NR). All three are forms of vitamin B3. Nicotinamide mononucleotide (NMN) is an intermediate molecule that can boost NAD+ levels. However, NMN levels decline with aging. Supplementing with NMN can restore NAD+ levels. Take 250-500 mg of NMN daily. Combinations with vitamin B12, resveratrol, and quercetin have positive synergistic effects.

6. Crocin

Crocin is a carotenoid pigment that makes saffron yellow. It’s an antioxidant that helps protect the brain and improves memory and learning. Crocin boosts brain serotonin levels to brighten the mood. And it helps prevent neurodegenerative conditions like Parkinson’s Disease (PD). It can lower chronic inflammation, restore immune cell balance, and fight cancer. Crocin is an impressive natural compound but expensive. Take 30 mg twice daily of saffron extract containing standardized 2% crocin. 

All these molecules are derived from plants. None are synthetic or repurposed chemical drugs. And they are considered safe. True, most are very new, so the research base is limited. But the combined market of an aging population, plus ME/CFS and Long COVID patients, will drive demand for these natural age-defying nutraceuticals. I’d like to see more studies and a series of interviews with patients who take these supplements, and those will come; for now, I recommend starting with one or two. 

Selected References 

Fisetin 

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.

Li W, Qin L, Feng R, Hu G, Sun H, He Y, Zhang R. Emerging senolytic agents derived from natural products. Mech Ageing Dev. 2019 Jul;181:1-6. doi: 10.1016/j.mad.2019.05.001. Epub 2019 May 8. PMID: 31077707.

Elsallabi O, Patruno A, Pesce M, Cataldi A, Carradori S, Gallorini M. Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection. Molecules. 2022 Jan 23;27(3):738. doi: 10.3390/molecules27030738. PMID: 35164003; PMCID: PMC8839434.

Spermidine

Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788. doi: 10.1126/science.aan2788. PMID: 29371440.

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. Epub 2018 Oct 11. PMID: 30306826; PMCID: PMC6287690

Sagar NA, Tarafdar S, Agarwal S, Tarafdar A, Sharma S. Polyamines: Functions, Metabolism, and Role in Human Disease Management. Med Sci (Basel). 2021 Jun 9;9(2):44. 

doi: 10.3390/medsci9020044. PMID: 34207607; PMCID: PMC8293435. 

Stefan Kiechl, Raimund Pechlaner, Peter Willeit, Marlene Notdurfter, Bernhard Paulweber, Karin Willeit, Philipp Werner, Christoph Ruckenstuhl, Bernhard Iglseder, Siegfried Weger, Barbara Mairhofer, Markus Gartner, Ludmilla Kedenko, Monika Chmelikova, Slaven Stekovic, Hermann Stuppner, Friedrich Oberhollenzer, Guido Kroemer, Manuel Mayr, Tobias Eisenberg, Herbert Tilg, Frank Madeo, Johann Willeit, Higher spermidine intake is linked to lower mortality: a prospective population-based study, The American Journal of Clinical Nutrition, Volume 108, Issue 2, August 2018, Pages 371–380, https://doi.org/10.1093/ajcn/nqy102

Zou D, Zhao Z, Li L, Min Y, Zhang D, Ji A, Jiang C, Wei X, Wu X. A comprehensive review of spermidine: Safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing. Compr Rev Food Sci Food Saf. 2022 May;21(3):2820-2842. Epub 2022 Apr 27. PMID: 35478379. 

https://doi: 10.1111/1541-4337.12963   

Oxaloacetate

Cash, A., Kaufman, D.L. Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial. J Transl Med 20, 295 (2022). https://doi.org/10.1186/s12967-022-03488-3

Gupte, R., Keselman, P.L., Christian, S.K., Hu, J., Swerdlow, R.H. and Harris, J.L. (2020), Does oxaloacetate preserve mitochondrial function in the aged brain?. Alzheimer’s Dement., 16: e037386. https://doi.org/10.1002/alz.037386

Urolithin A

Singh, A., D’Amico, D., Andreux, P.A. et al. Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. Eur J Clin Nutr 76, 297–308 (2022). https://doi.org/10.1038/s41430-021-00950-1

Andreux, P.A., Blanco-Bose, W., Ryu, D. et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab 1, 595–603 (2019). https://doi.org/10.1038/s42255-019-0073-4 

Mary, A., Eysert, F., Checler, F. et al. Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches. Mol Psychiatry 28, 202–216 (2023). https://doi.org/10.1038/s41380-022-01631-6 

Liu S, D’Amico D, Shankland E, et al. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(1):e2144279. doi:10.1001/jamanetworkopen.2021.44279 

Nicotinamide mononucleotide NMN 

Shade C. The Science Behind NMN-A Stable, Reliable NAD+Activator and Anti-Aging Molecule. Integr Med (Encinitas). 2020 Feb;19(1):12-14. PMID: 32549859; PMCID: PMC7238909.

Shade C. The Science Behind NMN-A Stable, Reliable NAD+Activator and Anti-Aging Molecule. Integr Med (Encinitas). 2020 Feb;19(1):12-14. PMID: 32549859; PMCID: PMC7238909.

Yi, L., Maier, A.B., Tao, R. et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience 45, 29–43 (2023). https://doi.org/10.1007/s11357-022-00705-1

Crocin

Siddiqui SA, Ali Redha A, Snoeck ER, Singh S, Simal-Gandara J, Ibrahim SA, Jafari SM. Anti-Depressant Properties of Crocin Molecules in Saffron. Molecules. 2022 Mar 23;27(7):2076. 

doi: 10.3390/molecules27072076. PMID: 35408474; PMCID: PMC9000812. 

Wang C, Cai X, Hu W, Li Z, Kong F, Chen X, Wang D. Investigation of the neuroprotective effects of crocin via antioxidant activities in HT22 cells and in mice with Alzheimer’s disease. Int J Mol Med. 2019 Feb;43(2):956-966. 

doi: 10.3892/ijmm.2018.4032. Epub 2018 Dec 18. PMID: 30569175; PMCID: PMC6317678.

Bastani S, Vahedian V, Rashidi M, Mir A, Mirzaei S, Alipourfard I, Pouremamali F, Nejabati H, Kadkhoda J, Maroufi NF, Akbarzadeh M. An evaluation on potential antioxidant and anti-inflammatory effects of Crocin. Biomed Pharmacother. 2022 Sep;153:113297. 

doi: 10.1016/j.biopha.2022.113297. Epub 2022 Jun 20. PMID: 35738178.

Abdi H, Aganj Z, Hosseinzadeh H, Mosaffa F. Crocin restores the balance of Th1/Th2 immune cell response in ConA-treated human lymphocytes. Pharmacol Rep. 2022 Jun;74(3):513-522. doi: 10.1007/s43440-022-00362-3. Epub 2022 Mar 16. PMID: 35294736.