Nature's way of promoting longevity - vitamins, polyphenols, and other natural geroprotectors

Highlights:

• Geroprotectors represent a class of nutrients and therapeutic agents that help fight the aging process by promoting autophagy
• There have been several attempts to provide criteria to classify geroprotectors and help translate their value to clinical outcomes
• Vitamins, minerals, polyphenols, and many other compounds are among the naturally occurring geroprotectors

Introduction

Geroprotectors, "protectors against aging”, are therapeutics and nutrients that can target the root causes of aging. These agents target fundamental mechanisms, such as oxidative damage, senescence, and inflammation, which play a role in developing age-related diseases like cardiovascular disorders. The quest for geroprotectors has gained significant momentum in the past decade, where the number of identified agents jumped from 24 in 2009 to 259 during the article's writing. The identified compounds possess properties that slow down the aging process and/or extend the lifespan. Some of these compounds have been tested in preclinical settings, while others tried on humans.    

Selection criteria for geroprotectors

Despite having over 250 compounds and more than 2400 publications in the Geroprotectors.org database, there are no currently marketed geroprotectors (1, 2). There are several reasons behind the latter, including the lack of a unified concept describing the aging mechanisms, the challenges associated with translating findings from animal models to humans, and the reluctance of pharmaceutical companies to pursue research in this domain (1, 3).

To maximize benefits, geroprotectors should increase the lifespan and the healthspan. In other words, they need to promote longevity while maintaining a high quality of life (1). This dictates setting up criteria that help filter potential geroprotectors with the highest return in terms of lifespan and healthspan. . Such standards have been suggested by Moskalev et al., who defined eight criteria that discuss the goals, dose, purpose, result reproducibility, and other factors pertaining to geroprotectors (1, 4).

How are geroprotectors classified?

Currently, there is no universal system to classify geroprotectors. The available approaches classify geroprotectors based on their influence on the lifespan, mechanism of action that acts upon the aging process, and the origin of the active constituent (1). For example, Emanuel and Obukhova suggested classifying geroprotectors by their influence on the survival of a group of individuals (1, 5). Accordingly, geroprotectors might increase the longevity of all members of a population (increase in both average and maximum lifespan), decrease the mortality rate of long-lived individuals (increase in maximum lifespan), and prolong the lifespan of short-lived individuals (increase in average lifespan).  

Another approach was suggested by Anisimov, who proposed dividing geroprotectors based on their mechanism of action into those that prevent accidental damage to nucleic acids, proteins, and lipids and those that slow down the age-related pathologies (1, 6). In addition to the previous, Kapoor et al. classified geroprotectors into natural products, synthetic drugs, and hormone replacement therapies (1). Other approaches were based on the geroprotector's class, like antioxidants, metabolites, and others, while other concepts involved classification based on homeostasis regulation.

Autophagy and longevity

Autophagy is a regulatory process that results from lysosomal (a lysosome is an intracellular organelle that contains digestive enzymes) degradation of intracellular components (7). Autophagy is involved in several physiological processes, where it plays a role in reducing inflammation, eliminating damaged cellular components, preventing genomic damage, and other functions. With aging, the autophagic capacity is reduced, which is associated with numerous conditions like neurogenerative conditions, heart diseases, inflammatory disorders, among others (8-10).

The importance of autophagy as a component of longevity in humans has been thoroughly investigated. In this context, research on healthy centenarians revealed that higher Beclin-1 levels, which are associated with higher autophagy, were linked to a longer lifespan (11).

Vitamins as geroprotectors through promoting autophagy

Natural products, like vitamins and minerals, have been shown to upregulate autophagy. According to literature, these compounds were found to influence both the lifespan and healthspan in the model organisms on which they were tested (7). These molecules have different mechanisms of action that can be utilized to produce therapeutic agents that target these pathways. The following table summarizes the findings from studies that have tested these natural compounds on different model organisms, like mice, rats, and others, in addition to providing natural sources for these compounds (7, 12).

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Examples of other natural geroprotectives and their role in autophagy

In addition to vitamins, other bioactive compounds like polyphenols, minerals, among others, have been found to play a role in autophagy across numerous age-related conditions (7, 12). The following table contains a diverse selection of natural bioactive compounds that promote longevity through influencing autophagy, in addition to providing natural sources for these compounds (12-16).

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*A compound belonging to flavonols, a subclass of flavonoids, which are polyphenolic compounds.

**A compound belonging to isoflavones, a subclass of flavonoids, which are polyphenolic compounds.

***A compound belonging to flavanols, a subclass of flavonoids, which are polyphenolic compounds.

In addition to the compounds included in the table, there are other bioactive molecules, like urolithin A (UA), a metabolite derived from the gut microbiota. This metabolite has been found to promote longevity in C. elegans and improve physical functioning in mice models (17). In addition, it has been found to modulate autophagy by influencing the mTOR pathway (18). Another example produced by the gut microbiota is spermidine – a compound which can also be obtained by dietary means. Its supplementation has been linked with cardioprotective and neuroprotective effects (19). According to research, its impact could be attributed to its role as calorie-restriction mimetic and/or autophagy-inducing properties.

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Tips

• Explain to your clients/patients what geroprotectors are and how they influence their lifespan.
• Encourage your clients to consume foods rich in the compounds mentioned above, like cheese, eggs, milk, mango, oily fish, and others.
• Highlight to clients the benefits they may attain from using UA or spermidine supplements, although you explain that the available data are from animal models.
• Tell them how the field of geroprotectors is advancing and encourage them to always remain updated with the latest information by checking Geroprotectors.org.

Conclusions

Geroprotectors are a class of therapeutic and nutritional compounds that help slow down the aging process or reverse their effect. Over the years, numerous techniques have been developed to discover and classify them. Geroprotectors mainly perform their action by influencing autophagy, which is rooted in many pathways related to the lifespan. Many naturally occurring compounds can be labeled as geroprotectors, many of which have been highlighted in this article. It is important to note that geroprotectors are still being researched; therefore, there is no current solid, evidence-based data to elucidate their full role, function, and influence on the aging process.

References

1.            Moskalev A, Chernyagina E, Kudryavtseva A, Shaposhnikov M. Geroprotectors: A Unified Concept and Screening Approaches. Aging and disease. 2017;8(3):354-63.

2.            CURATED DATABASE OF GEROPROTECTORS Online: Geroprotectors.org; 2022 [cited 2022 14 March].

3.            Zhavoronkov A, Moskalev A. Editorial: Should We Treat Aging as a Disease? Academic, Pharmaceutical, Healthcare Policy, and Pension Fund Perspectives. Front Genet. 2016;7:17.

4.            Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut'ko V, et al. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell. 2016;15(3):407-15.

5.            Emanuel NM, Obukhova LK. Types of experimental delay in aging patterns. Exp Gerontol. 1978;13(1-2):25-9.

6.            Anisimov VN. Life span extension and cancer risk: myths and reality. Exp Gerontol. 2001;36(7):1101-36.

7.            Raj SD, Fann DY, Wong E, Kennedy BK. Natural products as geroprotectors: An autophagy perspective. Medicinal Research Reviews. 2021;41(6):3118-55.

8.            Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell. 2011;146(5):682-95.

9.            Cuervo AM. Autophagy and aging: keeping that old broom working. Trends Genet. 2008;24(12):604-12.

10.          Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27-42.

11.          Emanuele E, Minoretti P, Sanchis-Gomar F, Pareja-Galeano H, Yilmaz Y, Garatachea N, et al. Can enhanced autophagy be associated with human longevity? Serum levels of the autophagy biomarker beclin-1 are increased in healthy centenarians. Rejuvenation Res. 2014;17(6):518-24.

12.          Wilson T, Temple NJ, Bray GA. Nutrition Guide for Physicians and Related Healthcare Professions: Springer; 2021.

13.          Cione E, La Torre C, Cannataro R, Caroleo MC, Plastina P, Gallelli L. Quercetin, epigallocatechin gallate, curcumin, and resveratrol: from dietary sources to human microRNA modulation. Molecules. 2019;25(1):63.

14.          Jaiswal N, Akhtar J, Singh SP, Ahsan F. An overview on genistein and its various formulations. Drug research. 2019;69(06):305-13.

15.          Stanić Z. Curcumin, a Compound from Natural Sources, a True Scientific Challenge - A Review. Plant Foods Hum Nutr. 2017;72(1):1-12.

16.          Liu D, Mao Y, Ding L, Zeng X-A. Dihydromyricetin: A review on identification and quantification methods, biological activities, chemical stability, metabolism and approaches to enhance its bioavailability. Trends in food science & technology. 2019;91:586-97.

17.          Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879-88.

18.          Totiger TM, Srinivasan S, Jala VR, Lamichhane P, Dosch AR, Gaidarski AA, 3rd, et al. Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer. Mol Cancer Ther. 2019;18(2):301-11.

19.          Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018;359(6374):eaan2788.

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