6/20/2021
 

Intermittent fasting, or caloric restriction, if done in a way that will not cause malnutrition, has been highlighted through research in a range of species to have a range of health benefits and lifespan extending effects. However, most people do not incorporate fasting into their lifestyle because many consider it uncomfortable.

From previous research, we have elucidated the molecular mechanisms within the body activated from fasting which could lead to the lifespan increase, and now we have identified a handful of compounds that activate these same pathways, mimicking caloric restriction, hence their name, caloric restriction mimetics (CRM’s) (1, 17).

More specifically, caloric restriction induces a form of cellular recycling, called autophagy. Autophagy is the removal of dysfunctional proteins and cellular materials, which optimizes functionality and longevity (1, 17).

The CRM’s which are most often discussed are SGLT2 inhibitors (dapagliflozin, empagliflozin), metformin, turmeric (curcumin), resveratrol, spermidine, hydroxycitric acid, nicotinamide mononucleotide, and nicotinamide riboside.

Because these medications are already available as prescription medications for diabetes, they have already been thoroughly investigated with regards to their safety and side effects. They also target lifespan extension in a wide variety of ways, making this one of the most promising candidates (2, 16).

Like the SGLT2 inhibitors, this is a prescription diabetes medication and therefore has been thoroughly tested. It improves cellular longevity in a few ways, and there are certain pathways that it may act on but have not yet been proven. It has shown health benefits in many areas including Alzheimer’s Disease, metabolic syndrome, cardiovascular disease, and cancer (1, 17).

Curcumin(turmeric) has displayed a plethora of health benefits on the brain, cancers, and diabetes. It has prolonged the lifespan of mice, and other species (1). Its mechanism of action for extending life is not fully understood at this time. This compound has not been as rigorously tested; some studies have shown that it appears to be safe to use for short periods of time (less 3 months) (3,4). More research is needed at this time.

The evidence for health and life span benefits from resveratrol is conflicting. In mice, the life span extension was only seen if the mice were on a high fat diet (1). There is evidence that resveratrol acts sometimes as a pro-oxidizing agent, and at other times it acts as an antioxidant (its oxidation mechanism is complex) (18). It has shown negative and positive effects on metabolic syndrome (1). It has also shown a number of positive health effects on cardiovascular disease, brain health, diabetes longevity and cancer (1, 18). Some studies showed that resveratrol is safe when taken in low amounts and for shorter periods of time in certain populations (less than a few months) (22,23,24). More research is needed for us to know if it will benefit longevity in humans or be used long term (18).

Spermidine is found in foods and naturally in the human body (1). Studies have shown that it can cause autophagy, extend lifespan and has benefits on brain, heart, immune and muscle tissue in rodents (1). Research correlations have been found showing positive and negative possibilities, more research is needed to fully understand how this substance could benefit the human lifespan. One small study in 30 elderly participants demonstrated tolerability (20). There is currently not enough information at this time regarding spermidine supplementation for lifespan extension in the general population (20, 21).

Hydroxycitric acid is currently used in OTC weight loss products (1, 11). Studies have shown that this substance can have benefits in cancer, oxidation, insulin resistance, and weight loss (1). Hydroxycitric acid inhibits an enzyme called ATP citrate lyase, which depletes the cells of acetyl CoA, mimicking human fasting (1, 12, 13). More research is needed on this substance’s effectiveness as a CRM and there have been instances reported of liver, reproductive and central nervous system toxicity (11, 12, 13, 19).

Many supplements currently available claim to promote our longevity by increasing the amount of NAD+ within our cells. Our NAD+ levels do decrease as we age, and substances such as nicotinamide mononucleotide and nicotinamide riboside, which are metabolized info NAD+, have been shown to increase NAD+ levels and to extend lifespan in mice in most studies (1, 7, 8, 9, 10). Benefits have been shown in brain, heart, vascular and liver tissues (1). There is not enough toxicological and clinical data for us to know if these substances should be used in humans for this purpose at this time, but trials are ongoing which will provide us more information. Some preliminary studies are showing positive safety data from ribosome mononucleotide in animals (14, 15). In some short-term (less than a few months) studies, nicotinamide riboside did not show any safety concerns in humans (5, 6, 9, 10).

Substances that may extend human life span in the general population are creating a new area of research with exciting developments. It is helpful for everyone to be cognizant of this to look out for prospects, apply this knowledge into decision making of current prescription regimens, and to consult with their doctors about if a CRM will be right for them.

Always consult with your doctor before beginning any supplements to ensure your safety.

Sources:

1. Frank Madeo,1,2, * Didac Carmona-Gutierrez,1 Sebastian J. Hofer,1 and Guido Kroemer. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. 2019;Cell Metabolism:29: 592-610. link.

2. Caroline W S Hoong, Marvin W J Chua, SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases, Endocrinology, 2021;, bqab079 link.

3. Zeng L, Yu G, Hao W, Yang K, Chen H. The efficacy and safety of Curcuma longa extract and curcumin supplements on osteoarthritis: a systematic review and meta-analysis. Biosci Rep. 2021 Jun 25;41(6):BSR20210817. doi: 10.1042/BSR20210817. PMID: 34017975. link.

4. Thanawala S, Shah R, Somepalli V, Alluri KV, Desomayanandam P, Bhuvanendran A. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Assessing Efficacy and Safety of a Novel Low-Dose Turmeric Extract Formulation in Healthy Adults with Chronic Knee Pain. Clin Pharmacol. 2021 May 21;13:91-100. doi: 10.2147/CPAA.S307464. PMID: 34045905; PMCID: PMC8149286. link.

5. Mehmel M, Jovanović N, Spitz U. Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Nutrients. 2020;12(6):1616. Published 2020 May 31. doi:10.3390/nu12061616. link.

6. Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep. 2019 Jul 5;9(1):9772. doi: 10.1038/s41598-019-46120-z. PMID: 31278280; PMCID: PMC6611812. link.

7. Harrison DE, Strong R, Reifsnyder P, et al. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell. 2021;20(5):e13328. doi:10.1111/acel.13328 link.

8. Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. PMID: 29211728; PMCID: PMC5718430. link.

9. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. Published 2018 Mar 29. doi:10.1038/s41467-018-03421-7 link.

10. Conze, D., Brenner, C. & Kruger, C.L. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep 9, 9772 (2019). https://doi.org/10.1038/s41598-019-46120-z link.

11. Andueza N, Giner RM, Portillo MP. Risks Associated with the Use of Garcinia as a Nutritional Complement to Lose Weight. Nutrients. 2021 Jan 29;13(2):450. doi: 10.3390/nu13020450. PMID: 33572973; PMCID: PMC7911601. link.

12. Márquez F, Babio N, Bulló M, Salas-Salvadó J. Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans. Crit Rev Food Sci Nutr. 2012;52(7):585-94. doi: 10.1080/10408398.2010.500551. PMID: 22530711. link.

13. Preuss HG, Rao CV, Garis R, Bramble JD, Ohia SE, Bagchi M, Bagchi D. An overview of the safety and efficacy of a novel, natural(-)-hydroxycitric acid extract (HCA-SX) for weight management. J Med. 2004;35(1-6):33-48. PMID: 18084863. link.

14. Cros C, Cannelle H, Laganier L, Grozio A, Canault M. Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. Food Chem Toxicol. 2021 Apr;150:112060. doi: 10.1016/j.fct.2021.112060. Epub 2021 Feb 12. PMID: 33587977. link.

15. You Y, Gao Y, Wang H, Li J, Zhang X, Zhu Z, Liu N. Subacute Toxicity Study of Nicotinamide Mononucleotide via Oral Administration. Front Pharmacol. 2020 Dec 15;11:604404. doi: 10.3389/fphar.2020.604404. PMID: 33384603; PMCID: PMC7770224. link.

16. Hoong CWS, Chua MWJ. SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases. Endocrinology. 2021 Apr 15:bqab079. doi: 10.1210/endocr/bqab079. Epub ahead of print. PMID: 33857309.

17. Son DH, Park WJ, Lee YJ. Recent Advances in Anti-Aging Medicine. Korean J Fam Med. 2019;40(5):289-296. doi:10.4082/kjfm.19.0087 link.

18. Salehi B, Mishra AP, Nigam M, et al. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines. 2018;6(3):91. Published 2018 Sep 9. doi:10.3390/biomedicines6030091 link.

19. Li Oon Chuah, Swee Keong Yeap, Wan Yong Ho, Boon Kee Beh, Noorjahan Banu Alitheen, "In Vitro and In Vivo Toxicity of Garcinia or Hydroxycitric Acid: A Review", Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 197920, 12 pages, 2012. https://doi.org/10.1155/2012/197920 link.

20. Schwarz C, Stekovic S, Wirth M, et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging (Albany NY). 2018;10(1):19-33. doi:10.18632/aging.101354

21. Wirth, M., Schwarz, C., Benson, G. et al. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial. Alz Res Therapy 11, 36 (2019). https://doi.org/10.1186/s13195-019-0484-1.

22. Jeyaraman MM, Al-Yousif NSH, Singh Mann A, Dolinsky VW, Rabbani R, Zarychanski R, Abou-Setta AM. Resveratrol for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Jan 17;1(1):CD011919. doi: 10.1002/14651858.CD011919.pub2. PMID: 31978258; PMCID: PMC6984411. link.

23. Hausenblas HA, Schoulda JA, Smoliga JM. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Mol Nutr Food Res. 2015 Jan;59(1):147-59. doi: 10.1002/mnfr.201400173. Epub 2014 Oct 9. PMID: 25138371. link.

24. Movahed A, Raj P, Nabipour I, Mahmoodi M, Ostovar A, Kalantarhormozi M, Netticadan T. Efficacy and Safety of Resveratrol in Type 1 Diabetes Patients: A Two-Month Preliminary Exploratory Trial. Nutrients. 2020; 12(1):161. https://doi.org/10.3390/nu12010161. link.

By: Evan Redmond, Pharm.D.