Biohack Longevity Supplements:
Modern Science and Ancient Ayurveda
Robert Keith Wallace, PhD
What is it that determines how long we live and how healthy we are? Most researchers estimate that our individual genetic heritage contributes about 20 to 40% to our chances of living longer. Ashkenazi Jews, however, may have won the sweepstakes when it comes to longevity genes. Apparently, a number of them can smoke and indulge in other bad habits, remaining healthy while they live to be 95 or older. For the rest of us, our longevity depends a great deal on how we are able to live our lives from early childhood on. The field of epigenetics explains that practically everything we do turns our genes either on or off. Fortunately, there are certain things we can do that seem to activate our longevity genes, improving our chance of living a longer healthier life.
One of the best-known theories of aging concerns free radicals, which postulated that aging is caused by cumulative oxidative damage to cells and tissues. Free radicals are generated by normal biological processes, resulting in the splitting of oxygen molecules into unstable oxygen atoms. In this unstable state they are reactive and cause damage to various parts of the body. This can occur as a result of UV radiation, the presence of toxins, or just wear and tear. The good news is that we’re not totally defenseless against the ravages of these free radicals since our bodies naturally produce free radical scavengers which can counteract and quiet down reactive oxygen molecules.
The theory proposes that as we age we become less effective in producing free radical scavengers and a billion-dollar anti-oxidant supplement industry is burgeoning in spite of the many studies showing that antioxidant supplements do not, in fact, extend lifespan. This and other research has made the free radical theory of aging is more limited in scope and less popular.
Reduction of Caloric Intake
The most conclusive research on extending lifespan so far, shows that by reducing the calories animals eat regularly, extends their longevity. Hundreds of studies have reproduced these findings in animals, but very few have been done in humans. This is not surprising because, as you might guess, it is very hard to get people to voluntarily eat less for a long period of time. Studies do reveal that caloric restriction acts as an epigenetic challenge, causing certain genes and pathways to be more strongly expressed while others are silenced.
The potential list of relevant genes and pathways is quite long, so we’ll focus on only one important gene family, the sirtuin, and the pathways that are affected by them. There are seven sirtuin genes, each producing specific signaling proteins with different metabolic functions including DNA repair, stress resistance, and inflammation.
Harvard geneticist, David Sinclair, has studied sirtuin genes extensively. In his book Lifespan, he identifies several survival pathways that he believes are crucial to maintaining health and extending life. He also discusses specific supplements, which he thinks can epigenetically modify these pathways.
Sinclair describes the overall function of the sirtuin proteins or enzymes, which is to remove a particular chemical group, the acetyl group, from histones. Histones are special proteins in our chromosomes around which our DNA is wound. When the acetyl group is removed, the histones can pack the DNA more tightly and by doing so, silence the expression of certain genes.
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).
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). It is also unclear if resveratrol taken orally is capable of directly activating sirtuins.
Another possible anti-aging candidate with many potential uses, is quercetin, a plant flavonoid found in many fruits and vegetables. The English word “quercetin” is derived from the Latin “quercetum” which means oak forest. Quercetin has been observed to increase SIRT1 activity by fivetimes, 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.
Quercetin and other supplements have been found to act on another longevity pathway, the “mammalian target of rapamycin” or “mTOR.” Discovered in an expedition to Easter Island, which collected soil samples among the large standing stones, a bacteria was found that produced an antifungal compound, later resulting 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.
The mTOR pathway regulates cell division and participates in multiple signaling pathways involved in such diseases as cancer, arthritis, insulin resistance, and osteoporosis. By inhibiting the mTOR pathway with caloric restriction, more energy is available for self-repair, thus extending an animal’s life. One of these self-repair processes is autophagy, during which dysfunctional cell components are broken down, removed, or recycled.
Metformin, much promoted by anti-aging enthusiasts, is a common type 2 diabetes drug that also inhibits the mTOR pathway. It affects a third longevity pathway as well, the AMP-activated protein kinase (AMPK). The AMPK pathway coordinates cell growth, autophagy, and metabolism. In addition, it regulates the body’s energy metabolism by directing cells to store or use existing energy reserves. When activated, it increases levels of NAD, and enlivens SIRT1 enzymes. Caloric restriction and vigorous exercise also stimulate the AMPK pathway, causing the reduction of fat stores, and producing beneficial effects that increase animal lifespan.
What if we just eat less and trigger these pathways naturally? Many people have tried intermittent fasting or other variations in which, instead of limiting the number of calories, the overall time period for eating is limited to about 8 to 10 hours. Typically, the participants don’t eat for 14 to 16 hours every day, often limiting themselves to two meals by skipping either dinner or breakfast. Reviews of research on intermittent fasting have provided evidence of improvements in such factors as blood glucose levels and lipid profile, suggesting its value for health. It has also been shown to activate sirtuin pathways. Other researchers, however, feel that it is limited in its use for weight loss and is not significantly better than other approaches, such as continuous energy restriction (CER), which could typically involve taking in 500 calories less each day.
Ayurveda and Rasayanas
Eating less and fasting are cornerstones of all traditional natural health systems, including Ayurveda, except of course in conditions of malnutrition or undernourishment. There are also a large number of time-tested herbal supplements used in Ayurveda for the prevention and treatment of disease—with an entire class of anti-aging compounds called rasayanas. One of these, called Maharishi Amrit Kalash, has been extensively studied, and chemical analysis shows that it contains plant phytochemicals with strong antioxidant properties. These include polyphenols, bioflavonoids, vitamins C and E, beta carotene, catechin, tannic acid, and resveratrol. Maharishi Amrit Kalash is a combination of two separate compounds, “Nectar” (M-4), and “Ambrosia” (M-5) and is composed of 23 herbs.
There has been extensive scientific research at institutions such as the National Institutes of Health, the National Cancer Institute, the Niwa Institute of Immunology in Japan, Ohio State University College of Medicine, Loyola University Medical School, University of Kansas Medical Center, South Dakota State University, University of Colorado, Indiana University, SRI International, and the University of California at Irvine.
The studies have clearly shown the rasayana Maharishi Amrit Kalash to have important potential benefits:
- inhibiting tumor growth
- scavenging free radicals
- positively influencing known cardiovascular risk factors
- inhibiting degenerative processes, including abnormal platelet aggregation (clotting leading to cardiovascular disease) and the aging process
- enhanced immune response
According to Ayurveda, this herbal preparation helps to reset the proper sequential unfoldment of the inner intelligence of the body, and automatically corrects imbalances that may lead to disease.
Turmeric and Curcumin
In Ayurveda, even common spices such as ginger, cumin, and coriander have been found to benefit health. One of the most extensively studied is the active ingredient in turmeric, curcumin (diferuloylmethane). Research on curcumin is more extensive than on almost any other natural product. In one study curcumin was found to affect SIRT1 expression, suggesting a positive role in the treatment of diabetes and heart disease. While numerous benefits in animals have been found in thousands of published papers, human studies are once again limited by the bioavailability of this active ingredient. We wonder how desirable isolating one active ingredient, curcumin, really is as there may very well be other beneficial substances in turmeric that could interact synergistically to enhance its absorption and overall effects.
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. This is valuable information, yet most people are unaware of it and still continue to use the supplement (and since the data about its results is both limited and confusing this is understandable). Clearly, more long-term human research is needed, and this is a common problem with almost all supplements. Although they show promising result in animals, very few well-controlled clinical studies have proven their effectiveness in humans. Another enormous obstacle to good human studies is high cost.
For any medication or supplement to be legally advertised or promoted for the diagnosis or treatment of disease, Food and Drug Administration (FDA) approval is necessary. This requires a rigorous series of tests and clinical trials that can take ten or more years to complete at an estimated cost of $2 to 4 billion per approved medication. Pharma companies make the enormous investment for these development programs based on the expectation that when one of them is successful, it will produce enough revenue to pay for all those that weren’t. If the substance is a natural product that cannot be patented, and therefore sold by anyone else once approved, there is no incentive to make such an investment. It is ironic that the system created to protect us from adverse side effects of modern drugs, makes FDA approval of natural products grossly unaffordable.
- Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair and Mathew LaPlante, Atria Books; Illustrated edition 2019
- Curry AM, White DS, Donu D, Cen Y. Human Sirtuin Regulators: The “Success” Stories. Front Physiol. 2021 Oct 21;12:752117. doi: 10.3389/fphys.2021.752117. PMID: 34744791; PMCID: PMC8568457.
- Ren BC, Zhang YF, Liu SS, Cheng XJ, Yang X, Cui XG, Zhao XR, Zhao H, Hao MF, Li MD, Tie YY, Qu L, Li XY. Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways. J Cell Mol Med. 2020 Nov;24(21):12355-12367. doi: 10.1111/jcmm.15725. Epub 2020 Sep 22. PMID: 32961025; PMCID: PMC7687015.
- Carling D. AMPK signalling in health and disease. Curr Opin Cell Biol. 2017 Apr;45:31-37. doi: 10.1016/j.ceb.2017.01.005. Epub 2017 Feb 21. PMID: 28232179.
- Inaba R, Mirbod SM, Sugiura H. Effects of Maharishi Amrit Kalash 5 as an Ayurvedic herbal food supplement on immune functions in aged mice. BMC Complement Altern Med. 2005 Mar 25;5:8. doi: 10.1186/1472-6882-5-8. PMID: 15790423; PMCID: PMC1084244.
- Vohra BP, Sharma SP, Kansal VK. Effect of Maharishi Amrit Kalash on age dependent variations in mitochondrial antioxidant enzymes, lipid peroxidation and mitochondrial population in different regions of the central nervous system of guinea-pigs. Drug Metabol Drug Interact. 2001;18(1):57-68. doi: 10.1515/dmdi.2001.18.1.57. PMID: 11522125.
- 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.
- Cho Y, Hong N, Kim KW, Cho SJ, Lee M, Lee YH, Lee YH, Kang ES, Cha BS, Lee BW. The Effectiveness of Intermittent Fasting to Reduce Body Mass Index and Glucose Metabolism: A Systematic Review and Meta-Analysis. J Clin Med. 2019 Oct 9;8(10):1645. doi: 10.3390/jcm8101645. PMID: 31601019; PMCID: PMC6832593.
- Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014 Feb 4;19(2):181-92. doi: 10.1016/j.cmet.2013.12.008. Epub 2014 Jan 16. PMID: 24440038; PMCID: PMC3946160
- Welton S, Minty R, O’Driscoll T, Willms H, Poirier D, Madden S, Kelly L. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020 Feb;66(2):117-125. PMID: 32060194; PMCID: PMC7021351.
- Allaf M, Elghazaly H, Mohamed OG, Fareen MFK, Zaman S, Salmasi AM, Tsilidis K, Dehghan A. Intermittent fasting for the prevention of cardiovascular disease. Cochrane Database Syst Rev. 2021 Jan 29;1(1):CD013496. doi: 10.1002/14651858.CD013496.pub2. PMID: 33512717; PMCID: PMC8092432.
- Hammer SS, Vieira CP, McFarland D, Sandler M, Levitsky Y, Dorweiler TF, Lydic TA, Asare-Bediako B, Adu-Agyeiwaah Y, Sielski MS, Dupont M, Longhini AL, Li Calzi S, Chakraborty D, Seigel GM, Proshlyakov DA, Grant MB, Busik JV. Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction. Diabetologia. 2021 Jul;64(7):1674-1689. doi: 10.1007/s00125-021-05431-5. Epub 2021 Mar 26. PMID: 33770194; PMCID: PMC8236268.
- Lingappa N, Mayrovitz H N (September 04, 2022) Role of Sirtuins in Diabetes and Age-Related Processes. Cureus 14(9): e28774. doi:10.7759/cureus.28774
- Gut Crisis: How Diet, Probiotics, and Friendly Bacteria Help You Lose Weight and Heal Your Body and Mind by Robert Keith Wallace, PhD, and Samantha Wallace, Dharma Publications, 2017
- The Rest And Repair Diet: Heal Your Gut, Improve Your Physical and Mental Health, and Lose Weight by Robert Keith Wallace, PhD, Samantha Wallace, Andrew Stenberg, MA, Jim Davis, DO, and Alexis Farley, Dharma Publications, 2019